Download clinical practice guidelines for diagnosis, treatment and follow

'The supplement, 'Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up of Patients with Diabetes and its Complications' has
been prepared by Diabetes Study Group of the Society of Endocrinology and Metabolism of Turkey (SEMT), and published by SEMT. Bilim
Pharmaceuticals and Turkish Clinics Journal of Medical Sciences have provided unrestricted educational support for English translation of
the original Turkish guidelines. Bristol-Myers Squibb, Istanbul has provided an unrestricted educational support for this publication, and is
not related with the content of this material.’
UPDATED FOURTH EDITION
Society of
Endocrinology and
Metabolism of
Turkey
(SEMT)
CLINICAL PRACTICE GUIDELINES FOR
DIAGNOSIS, TREATMENT AND FOLLOW-UP
OF DIABETES MELLITUS AND ITS
COMPLICATIONS
Translation Editor
Prof. Ilhan Satman, MD
Translation
Efsun Müftüo¤lu, MD
Diabetes Study Group SEMT
WRITING COMMITTEE
Prof. ‹lhan SATMAN, MD
Istanbul University Istanbul Faculty of Medicine Dept. Internal Medicine Div. Endocrinology and Metabolism
Prof. fiazi ‹MAMO⁄LU, MD
Uluda¤ University Faculty of Medicine, Dept. Internal Medicine, Div. Endocrinology and Metabolism
Prof. Cande¤er YILMAZ, MD
Ege University Faculty of Medicine, Dept. Internal Medicine, Div. Endocrinology and Metabolism
And
Diabetes Study Group, SEMT
CONFLICT OF INTEREST
The members of the Writing Committee and contributors of the ‘Clinical Practice Guidelines for Diagnosis, Treatment and
Follow-up of Patients with Diabetes Mellitus and its Complications’ have no conflict of interest with any company or
industrial group during preparation, writing and original Turkish printing processes of this material.
01
DIAGNOSIS, CLASSIFICATION AND DESCRIPTION OF GLYCEMIC
DISORDERS
1. 1 DEFINITION
Diabetes is a chronic metabolic disease caused by absolute insulin deficiency or decreased insulin action which leads to several
defects in carbohydrate, fat and protein metabolism. Diabetes requires continuing medical care. Both health care providers
and patients should be educated continuously to reduce the risk of acute complications and to prevent chronic, long-term and costly
treated sequelae (retinal, renal, neural, and cardiovascular) of the disease.
On the other hand, disglycemia is a qualitative term used to describe other disorders of glucose metabolism.
The recommendations presented here are aimed to reduce the health problems of patients with diabetes in the light of
evidence-based medicine and current international consensus.
1. 2 DIAGNOSIS AND CLASSIFICATION
The diagnosis and classification of diabetes mellitus and other disorders of glucose metabolism have been changed in the last fifteen
years. The International Experts Committee on the Diagnosis and Classification of Diabetes including experts from the American
Diabetes Association (ADA) published in 1997 new recommendations for the diagnosis and classification of diabetes, after that in 1999
World Health Organization (WHO) accepted these criteria with a few revisions.
In 2003, ADA has recommended a small revision in definition of impaired fasting glucose (IFG). WHO and International Diabetes
Federation (IDF) preserved 1999 criteria in their report published in the late 2006. In contrast, ADA and European Association for the
Study of Diabetes (EASD) suggest keeping 2003 revisions unchanged in their last consensus report published in 2007.
1.2.1 Diagnostic Criteria
A. Diabetes mellitus
The last diagnostic criteria (arranged in 1997), for diabetes and other disorders of glucose metabolism including 2003 revision are seen
in Table 1.1.
Accordingly, diabetes can be diagnosed in three ways. Except conditions with severe diabetes symptoms, diagnosis of diabetes should
be confirmed with another method on the following day.
Although standard oral glucose tolerance test (OGTT) with 75 g glucose is more sensitive and specific than fasting plasma glucose
(FPG), its routine use is complicated due to high variability from day to day in an individual patient, and being labour-intensive and
costly. On the other hand, FPG is commonly used in clinical practice since it is easier to use and cheap. Given the clinical presentation
of the disease is more manifest, mostly OGTT is not needed to diagnose type 1 diabetes.
Diagnostic criteria are based on the glucose measurements performed by glucose oxidase method in venous plasma samples.
Glucose levels in the whole blood, capillary blood and serum samples, used in clinics or by patients at home to monitor glycemia, are
1
2
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Diagnosis, Classi›fication and Description of Glycemic Disorders
Table 1.1 Diagnostic criteria for diabetes mellitus and other disorders of
glucose metabolism
(*)
Diabetes mellitus
Random glucose (plus diabetes symptoms)
OGTT 2 h PG
FPG (at least 8 h fasting)
Impaired glucose tolerance (IGT)(*)
OGTT 2 h PG
Impaired fasting glucose (IFG)(**)
FPG (at least 8 h fasting)
≥200 mg/dL
≥200 mg/dL
≥126 mg/dL
140-199 mg/dL
100-125 mg/dL
(*)
Blood glucose level is measured by glucose oxidase method in venous plasma as ‘mg/dL’.
In the report by WHO/IDF in 2006, it is stated that the cut-point for normal FPG is 110 mg/dL and
the definition of IFG is 110-125 mg/dL.
FPG; Fasting plasma glucose, 2 h PG; Two hours plasma glucose, OGTT; Oral glucose tolerance
test, IGT; Impaired glucose tolerance, IFG; Impaired fasting glucose, WHO; World Health
Organization, IDF; International Diabetes Federation.
(**)
slightly lower than plasma levels as shown in the following formulas. Based on these formulas, recently International Federation of
Clinical Chemists (IFCC) recommended using devices measuring glucose levels in capillary whole blood samples, after calibrated to PG
levels.
According to WHO, postprandial (PP) capillary whole blood glucose levels are equal to venous PG level, however fasting capillary PG
levels are considered to be approximately 10% lower than PG levels(*).
Accordingly, glucose level of 126 mg/dL measured in venous plasma is found 11% less in whole blood (112 mg/dL), 7% less in capillary
blood (118 mg/dL) and 5% less in serum (120 mg/dL).
Haemoglobin A1c as a diagnostic test (HbA1c: A1C)
The use of glycosylated haemoglobin A1c as a diagnostic test for diabetes has not been recommended for many years because a lack
of standardization, and uncertainty of diagnostic threshold. Even though patients who have not been diagnosed diabetes with FPG
could be diagnosed with OGTT, however due to standardization problems, A1C might be found in normal range (<6.0%) in these cases.
But in recent years raising efforts about the standardization of A1C in all over the world as well as the accumulation evidence of its
prognostic importance has raised the question of using A1C as a diagnostic test in diabetes.
Experts Committee on Diabetes, consisted of the representatives of ADA, EASD, IDF and International Federation of Clinical Chemistry
(IFCC), has determined the cutoff value of A1C as 6,5% for the diagnosis of diabetes providing that it complies with the international
standardization rules on a serial of meetings in 2008. Nevertheless considering A1C is not being performed in every center routinely,
having technical problems, lack of standardization, and being costly, the test is not advisable for today to be used as a diagnostic test
in our country as in many others.
B. Gestational diabetes mellitus
Gestational diabetes mellitus (GDM) is defined as a carbohydrate intolerance, with onset or first recognition during pregnancy. The
diagnostic criteria for GDM are controversial mainly because lack of correlation to outcome. Many populations use a 3 h 100 g oral
glucose tolerance test (OGTT) in all pregnant women who are found to be positive with a 50 g glucose screening test to diagnose GDM.
Alternatively a 2 h OGTT with 75 g glucose is also recommended (Table 1.2).
Screening test with 50 g glucose: If PG level, obtained 1 h after a 50 g glucose load, without regard the timing of the last meal, is
≥140 mg/dL at the 24th to 28th weeks of gestation, it is considered as doubtful for GDM and needs further testing.
Some researchers do not recommend OGTT if 1 h PG after 50 g glucose is >180 mg/dL and advise to follow and treat these cases as
GDM.
OGTT with 100 g glucose: If the screening test is positive with 50 g glucose, a 3 h OGTT must be performed to confirm the diagnosis.
GDM is diagnosed with at least two values exceeding the upper normal ranges.
OGTT with 75 g glucose: WHO and some authors find it sufficient to perform a 2 h OGTT with 75 g glucose in pregnant women. WHO
recommends same evaluation criteria for OGTT in pregnants as it is done in non-pregnant adults.
(*)
Plasma glucose (mg/dL) = 0.558 + [20.254 X complete blood glucose (mg/dL) / 18]
Plasma glucose (mg/dL) = 0.102 + [19.295 X capillary blood glucose (mg/dL) / 18]
Plasma glucose (mg/dL) = 0.137 + [18.951 X serum glucose (mg/dL) / 18]
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3
C. Prediabetes
IGT and IFG, which were previously called as ‘borderline diabetes’ or ‘latent diabetes’ are replaced with the term, ‘prediabetes’. Both
are associated with increased risk of diabetes and cardiovascular diseases as well.
As seen in Table 1.1, it is widely accepted that FPG and OGTT 2 h PG should be 100-125 mg/dL and <140 mg/dL respectively for ‘isolated IFG’,
and FPG <100 mg/dL and 2 h PG 140-199 mg/dL for ‘isolated IGT’. However, if both FPG is between 100-125 mg/dL and 2 h PG is between
140-199 mg/dL, the condition is known as ‘combined IFG + IGT’. This category indicates further impairments of glucose metabolism.
Depending on the fact that few persons with FPG 100-110 mg/dL may have diabetes and that performing OGTT to borderline cases will
bring extra costs, WHO and IDF reported in 2006 that the upper limit of FPG should be 110 mg/dL, and IFG description in 1999 has to
be kept as 110-125 mg/dL. WHO/IDF report also recommends using the term of “intermediate impairment of glucose metabolism” for
IFG and/or IGT categories. On the contrary, in their last consensus report published in 2007 ADA and EASD decided to keep
the normal upper level of FPG as 100 mg/dL, and did not change IFG criteria as well as the term of ‘prediabetes’ used for these
disturbances.
International Experts Committee on Diabetes states that people with A1C between 5.7-6.4% are at high risk for diabetes and should
be taken into prevention programs. But when considering the lack of standardization, technical difficulties, and high cost, it is not
appropriate for our country to use this test to detect high risk people at this point.
Table 1.2 Diagnosis of GDM based on the ADA and WHO criteria(*)
ADA criteria
OGTT with 100 g glucose
(≥2 patological values are diagnostic)
OGTT with 75 g glucose(**)
(≥2 patological values are diagnostic)
WHO criteria
OGTT with 75 g glucose
(≥1 patological value is diagnostic)
Fasting
1h
2h
3h
≥95
≥180
≥155
≥140
≥95
≥180
≥155
-
≥126
-
≥200
-
(*)
Blood glucose level is measured by glucose oxidase method in venous plasma as ‘mg/dL’. GDM;
Gestational diabetes mellitus.
(**)
Recently published ‘the hyperglycemia and adverse pregnancy outcome study (HAPO)’ identified
FPG levels, and 1 h and 2 h post glucose (75 g OGTT) PG levels correlated to maternal, perinatal
and neonatal outcomes. Accordingly, there is an attempt to reduce thresholds for PG levels (FPG;
92, 1 h PG 180, and 2 h PG 153 mg/dl. ‘RG Moses Diabetes Care 2010;33:690-91’)
SEMT RECOMMENDATIONS FOR THE DIAGNOSIS OF DIABETES
1. FPG should be the main diagnostic test of diabetes.
2. OGTT should be performed in persons at high risk for diabetes mellitus.
3. A 3 h 100 g OGTT should be applied to all pregnant women with a positive 50 g glucose challenge test for definitive
diagnosis of GDM.
4. Considering the lack of standardization and high cost, at this moment, A1C is not appropriate in our country to be used
for diagnosis of diabetes mellitus.
1.2.2 Diabetes Symptoms
The usual symptoms commonly seen in patients with diabetes and rarely seen symptoms of diabetes are listed below.
Usual Symptoms
Polyuria
Polydipsia
Polyphagia or loss of appetite
Weakness and fatigue
Dry mouth
Nocturia
Rare Symptoms
Blurred vision
Unexplained weight loss
Persistent infections
Repeated fungal infections
Pruritus
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SEMT RECOMMENDATIONS
1. In the light of the fact that the lifestyle in our society has changed to increase the risk of diabetes, SEMT recommends
keeping 2003 prediabetes criteria in order to raise the awareness about diabetes. According to these criteria normal FPG
values should be <100 mg/dL and FPG values of 100-125 mg/dL should be considered as IFG.
2. Considering the lack of standardization and technical difficulties, at this point A1C is not appropriate for our country to be
used with this aim.
1.2.3 Classification
Based on the last classification in 1997, there are four clinical types of diabetes as given in Table 1.3. Three of them (type 1 diabetes,
type 2 diabetes and GDM) are known as primary, while the other one (specific diabetes types) as secondary forms of diabetes.
Table 1.3 The aetiological classification of diabetes mellitus
I. Type 1 diabetes (Generally appeared due to β-cell destruction leading to absolute insulin deficiency)
A. Immune-mediated
B. Idiopathic
II. Type 2 diabetes (it is characterized by insulin resistance and impaired insulin secretion)
III. Gestational diabetes mellitus (GDM) (defined as diabetes mellitus first diagnosed during pregnancy and recovered after delivery)
IV. Other specific diabetes types
A. Genetic defects of β-cell functions (Monogenic forms of diabetes)
• Chromosome 20, HNF-4α (MODY1)
• Chromosome 7, Glucokinase (MODY2)
• Chromosome 12, HNF-1α (MODY3)
• Chromosome 13, IPF-1 (MODY4)
• Chromosome 17, TCF2/HNF-1ß (MODY5)
• Chromosome 2, NeuroD1 (MODY6)
• Chromosome 2, KLF11 (MODY7)
• Chromosome 9, CEL (MODY8)
• Chromosome 7, PAX4 (MODY9)
• Chromosome 11, INS (MODY10)
• Chromosome 8, BLK (MODY11)
• Mitochondrial DNA (MTTL1, MTTE, MTTK mutations)
• Neonatal diabetes (e.g. Kir6.2/KJNC11 mutations)
• Others
B. Genetic defects in insulin action
• Leprechaunism
• Lipoatrophic diabetes
• Rabson-Mendenhall syndrome
• Type A insulin resistance
• Others
C. Pancreatic Exocrine Tissue Diseases
• Fibrocalculous pancreopathy
• Hemochromatosis
• Cystic fibrosis
• Neoplasia
• Pancreatitis
• Trauma/pancreatectomy
• Others
D. Endocrinopathies
• Acromegaly
• Aldosteronoma
• Cushing syndrome
• Feochromocytoma
• Glucagonoma
• Hyperthyroidism
• Somatostatinoma
• Others
E. Drugs and chemical agents
• Atypical anti-physicotic drugs
• Anti-viral drugs
• β-adrenergic agonists
• Diazoxide
• Phenytoin
• Glucocorticoids
• α-interferon
• Nicotinic acid
• Pentamidine
• Protease inhibitors
• Thiazide diuretics
• Thyroid hormone
• Vacor
• Others
G. Uncommon forms of immune-mediated diabetes
• Anti-insulin receptor antibodies
• Stiff-man syndrome
• Others
H. Genetic syndromes associated with diabetes
(Other monogenic forms of diabetes)
• Alström syndrome
• Down syndrome
• Friedreich’s ataxia
• Huntington’s chorea
• Klinefelter syndrome
• Laurence-Moon-Biedl syndrome
• Myotonic dystrophy
• Porphyria
• Prader-Willi syndrome
• Turner syndrome
• Wolfram (DIDMOAD) syndrome
• Others
HNF-1α; hepatocyte nuclear factor-1α, MODY1-11; (maturity onset diabetes of the young 1-11), HNF-4α; hepatocyte nuclear factor-4α, IPF-1; insulin promoter factor-1, HNF-1β; hepatocyte
nuclear factor-1β, TCF2; transcription factor 2, NeuroD1; neurogenic differentiation 1, KLF11; Kruppel like factor 11, CEL; carboxyl ester lipase, PAX4; paired box 4, INS; insulin, BLK; B lymphoid
tyrosine kinase, Kir6.2; inwardly rectifying potassium channel 6.2, KCNJ11; potassium channel inwardly rectifying subfamily J member 11, DNA; Deoxy-ribonucleic acid, DIDMOAD syndrome;
diabetes mellitus, diabetes insipidus, optic atrophy, deafness (Wolfram syndrome).
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5
1. 3 TYPE 1 DIABETES MELLITUS
1.3.1 Pathophysiology and aetiology
There is an absolute insulin deficiency. Approximately 90% of people with type 1 diabetes are positive for islet auto-antibodies causing
cell destruction and are deemed to have type 1A while the remaining individuals are negative for auto antibodies and are classified as
having type 1B diabetes.
Type 1A diabetes: Environmental triggering factors (viruses, toxins, emotional stress) could trigger an autoimmune reaction in
genetically-predisposed individuals (with high-risk HLA) to develop progressive β-cell destruction. When 80-90% of β-cells have been
destroyed, patients develop clinical symptoms of diabetes. Islet auto antibodies are early markers for type 1A diabetes mellitus.
1. 4 TYPE 2 DIABETES MELLITUS
1.4.1 Pathophysiology and aetiology
A. Insulin resistance: The cells fail to uptake glucose from the blood and turn it into energy due to reduced endogenous insulin action
and glucose utilization generating from impaired cell-receptor-postreceptor interactions (there is an intracellular hypoglycemia). The
defect in insulin action is seen at the peripheral tissues (primarily muscle, liver and fat tissues). Glucose uptake into muscle and fat cells
was reduced.
B. Reduced insulin secretion: Pancreas does not release enough insulin in response to increased blood glucose level. The rate
of hepatic glucose production is increased. Insulin secretion defect and counter-regulatory factors, reaching the highest rate during
morning hours (i.e. cortisol, growth hormone and adrenaline; Dawn phenomenon), are responsible for excessive hepatic glucose
production.
Although insulin resistance is generally present for many years before impairment of glucose metabolism are evident and then
continued, insulin secretion decreases late in the illness and with complications.
1.4.2 Characteristics
Type 2 diabetes most often occurs after the age of 30, but obesity has led to a dramatic increase in the incidence of type 2 diabetes
among children and adolescents within the last 10-15 years.
Genetic predisposition seems to be the strongest factor. As genetic density increases in the family, next generations are at higher
risk of developing the illness, and it presents at a younger age.
Patients are generally overweight or obese. Body mass index (BMI) >25 kg/m2.
Initially there is no tendency towards DKA, but it presents in late stages following a long term hyperglycemic state and loss of
endogenous β-cell reserve.
It has an insidious onset. Many persons have no history of symptoms.
Some patients may present with blurred vision, numbness and tingling in hands and feet, foot pain, repeated fungal infections
(genitourinary infections in women) and itching.
1.4.3 Treatment
MNT and weight control
Physical activity
Oral antidiabetic drugs (OAD) (insulin sensitizers, insulin secretogogues, alpha-glucosidase inhibitors) and insulin, if needed
SMBG
Education
Treatment of comorbidities (hypertension: HT, dyslipidemia etc.) and anti-platelet agents (when needed)
1. 5 GESTATIONAL DIABETES MELLITUS (GDM)
1.5.1 Pathophysiology and Aetiology
Insulin resistance due to pregnancy
Transient diabetes during pregnancy
Genetic predisposition
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Diagnosis, Classi›fication and Description of Glycemic Disorders
Turk JEM 2010; 14: Suppl 1-10
1.5.2 Characteristics
Screening tests should be conducted in women at high risk to investigate GDM and gestational glucose intolerance.
GDM is generally asymptomatic.
Most of the women with GDM recover to normal glucose levels after delivery, but GDM recurs during the following pregnancies.
GDM is a significant risk factor for development of permanent type 2 diabetes.
1.5.3 Treatment
Insulin therapy is recommended when MNT and exercise fail to maintain glucose targets. FPG and PP (preferably 1 h or 2 h)
PG levels should be controlled (see Chapter 15.3).
SEMT RECOMMENDATIONS FOR GESTATIONAL DIABETES
1. FPG and 1 (or 2) h PPPG levels should be used for the follow-up of GDM.
2. If diet and exercise are inadequate to control glucose levels, insulin therapy may become necessary.
1.6 INDICATIONS FOR DIABETES SCREENING AND DIAGNOSTIC TESTS
1.6.1 Screening for Type 1 Diabetes
There is no indication for routine screening of type 1 diabetes. However, in many populations family screening for research
purposes (autoantibody screening in first degree relatives of patients with type 1 diabetes mellitus) are being performed.
When marked symptoms and findings exist (polyuria, polydipsia, dry mouth, polyphagia, weight loss, blurred vision, etc.) blood
glucose levels should be obtained for diagnosis.
1.6.2 Screening for Type 2 Diabetes
All adults should be evaluated for type 2 diabetes risk factors in accordance with their population-based demographics and clinical
features.
Screening should be conducted once every 3 years, preferably with FPG evaluation, beginning at the age of 45 in overweight/obese
persons with a BMI ≥25 kg/m2 and particularly in persons with central obesity with waist circumference of over ≥88 cm for women and
≥102 cm for men.
Additionally, peoples belong to at least one of the following risk groups and have BMI ≥25 kg/m2 should be screened more often
starting from younger ages;
1. family history of diabetes in a first degree relative
2. a member of an ethnic group with high diabetes prevalence
3. previous history of GDM or delivery of a macrosomic infant
4. hypertension (blood pressure BP ≥140/90 mmHg
5. dyslipidemia (HDL cholesterol ≤35 mg/dL or triglyceride ≥250 mg/dL)
6. previously diagnosed with IFG and/or IGT
7. women with polycystic ovary syndrome (PCO)
8. clinical disease or findings related to severe insulin resistance (acanthosis nigricans)
9. coronary heart disease, cerebrovascular disease or peripheral vascular disease
10. individuals born with low birth weight
11. sedentary lifestyle, physical inactivity
12. high saturated fat and low fiber diet
13. people with schizophrenia or people treated with antipsychotic drugs
Also, children and adolescents at high risk for diabetes should be screened in every two years beginning at the age of 10. Screening
and diagnostic scheme for investigating of type 2 diabetes is shown in Figure 1.1.
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7
SEMT RECOMMENDATIONS
1. All adults should be evaluated for type 2 diabetes risk factors in accordance with their demographic and clinical features
(Class D, evidence-based on common consensus).
2. FPG should be evaluated in all patients with a BMI ≥25 kg/m2 beginning at age 45 (Class D, evidence-based on
common consensus).
3. The persons with additional risk factors should be evaluated with FPG and OGTT (if needed) more often, starting from
younger ages (Class D, evidence-based on common consensus).
4. OGTT with a 75 g glucose should be performed in patients with FPG 100-125 mg/dL and be evaluated with a 2 h PG
levels (Class D, evidence-based on common consensus).
• Persons ≥45 years of age with BMI ≥25 kg/m2 should be screened once every 3 years
• Persons with risk factors should be screened more often and starting from younger ages
FPG
FPG <100 mg/dL
FPG ≥126 mg/dL
FPG 100-125 mg/dL
OGTT (75 g glucose)
FPG
<100 mg/dL and
OGTT 2 h PG
<140 mg/dL
FPG
<100 mg/dL
and OGTT
2 h PG 140-199
mg/dL
FPG
100-125 mg/dL
and
OGTT 2 h PG
<140 mg/dL
FPG
100-125 mg/dL
and
OGTT 2 h PG
140-199 mg/dL
NORMAL
Isolated IGT
Isolated IFG
IGT + IFG
FPG
≥126 mg/dL
and/or
OGTT 2 h PG
≥ 200 mg/dL
DIABETES
PREDIABETES
Figure 1.1 Screening and diagnostic scheme for type 2 diabetes in adults
BMI: Body mass index, FPG: Fasting plasma glucose, OGTT: Oral glucose tolerance test, 2 h PG: 2-hour plasma glucose,
IGT: Impaired glucose tolerance, IFG: Impaired fasting glucose.
1.6.3 Gestational diabetes mellitus (GDM)
The risk evaluation should be performed from the first prenatal examination. Pregnant women in the following risk groups are
recommended to be tested for diabetes at the beginning of their pregnancy, and negative results are retested in further trimesters.
1. Obesity
2. Previous history of GDM
3. Glycosuria
4. Family history of diabetes in first degree relatives
The current recommendation is to perform screening test between 24th and 28th weeks of gestation who are not in the high risk group.
In Turkish population all pregnant women, whether or not belong to any of the high risk groups, should be screened for GDM between
24th and 28th weeks of gestation to reduce the risk factors for macrosomia, to control mother’s health, and after delivery to prevent
permanent type 2 diabetes and insulin resistance.
Alternatively, ADA and some other authorities do not recommend routine screening for low-risk pregnant women. According to this
argument, the pregnant women remained in the following groups are considered to be at low-risk for diabetes:
8
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1. Age <25 years
2. Normal body weight before pregnancy
3. Low-risk ethnicity
4. No abnormality of glucose tolerance in the past
5. No prior obstetric adverse outcome
A glucose threshold value >140 mg/dL by measuring PG 1 h after 50 g oral glucose load identifies approximately 80% of women with
GDM. However, the yield is further increased to 90% by using a cutoff of >130 mg/dL. Confirmative diagnostic procedures could be
established in both conditions.
Those found positive in the screening test with 1 h PG levels 140-180 mg/dL after a 50 g oral glucose administration are subjected to a
3 h 100 g OGTT test to confirm the positive diagnosis. Screening and diagnostic criteria of GDM are summarized in Figure 1.2.
If 1 h PG levels are ≥180 mg/dL on 50 g glucose screening test, OGTT is not required. These women are deemed to have
gestational glucose intolerance and monitored as GDM.
If there is a high suspicion, 100 g OGTT without any prescreening test is widely accepted.
GDM is diagnosed if 2 of 4 PG levels met or exceeded the suggested cutoff values on 3 h 100 g OGTT. Only one glucose level
exceeding the cutoff value is considered as gestational glucose intolerance and closely monitored as GDM.
All pregnant women should be screened at 24th to 28th weeks of gestation
(Pregnant women with risk factors for GDM should be screened in the first trimester
and if negative should be retested in the further trimesters.)
50 g glucose screening test
(at any time of the day)
1 h PG =140-180 mg/dL
1 h PG >180 mg/dL
1 h PG <140 mg/dL
OGTT (100 g glucose)
No need for OGTT,
follow-up as GDM
FPG ≥95 mg/dL
1 h PG ≥180 mg/dL
2 h PG ≥155 mg/dL
3 h PG ≥140 mg/dL
≥2 values
greater than
normal
Gestational Diabetes
Mellitus
1 value greater
than normal
Impaired glucose
toleraance in pregnancy
Normal
Retest at 3rd trimester if high
risk for GDM
Figure 1.2 Screening and diagnostic tests for gestational diabetes mellitus
(*)
FPG: Fasting plasma glucose, OGTT: Oral glucose tolerance test, 1 h PG: 1-hour plasma glucose, 2 h PG: 2 hour plasma
glucose, 3 h, PG: 3 hour plasma glucose, GDM: Gestational diabetes mellitus.
(*)
Recently published ‘the hyperglycemia and adverse pregnancy outcome study (HAPO)’ identified FPG levels, and 1 h
and 2 h post glucose (75 g OGTT) PG levels correlated to maternal, perinatal and neonatal outcomes. Accordingly,
there is an attempt to reduce thresholds for PG levels (FPG; 92, 1 h PG 180, and 2 h PG 153 mg/dl. ‘RG Moses Diabetes
Care 2010;33:690-91’).
Turk JEM 2010; 14: Suppl 1-10
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9
SEMT RECOMMENDATIONS
1. In Turkish population all pregnant women, whether or not at risk, should be screened for GDM in order to reduce
fetal mor bidity and to predict the future development of type 2 diabetes and insulin resistance among candidate
mothers [Class C, Level 3 evidence (1,2)].
2. The vast majority of pregnant women should be screened for GDM between 24th and 28th weeks of gestation (Class D,
evidence-based on common consensus).
3. Pregnant women with multiple risk factors for GDM should be tested in the first trimester, and if negative should be
retested in the further trimesters (Class D, evidence-based on common consensus).
4. A screening test for GDM is performed by measuring 1 h PG levels after a 50 g oral glucose administration at any time of
the day [Class D, Level 4 evidence (3)].
5. Pregnant women found positive at 50 g screening test with 1 h PG 140-180 mg/dL are subject to a 100 g OGTT test to con
firm the positive diagnosis.6. If there is a high suspicion for GDM, a diagnostic OGTT is indicated without any
prescreening test (Class D, evidence-based on common consensus).
6. If there is a high suspicion for GDM, a diagnostic OGTT is indicated without any prescreening test (Class D, evidence-based
on common consensus).
7. If 1 h PG is ≥180 mg/dL after a 50 g glucose it is not necessary to perform an OGTT. These cases should be followed as GDM.
8. GDM is diagnosed if at least 2 of the 4 PG levels exceeded pre-defined threshold values on a 100 g OGTT (Class D,
evidence-based on common consensus);
• Fasting PG ≥95 mg/dL
• 1 h PG ≥180 mg/dL
• 2 h PG ≥155 mg/dL
• 3 h PG ≥140 mg/dL
REFERENCES
1. Cosson E, Benchimol M, Carbillon L, et al. Universal rather than selective screening for gestational diabetes mellitus may improve fetal outcomes. Diabetes
Metab 2006;32:140-6.
2. Griffin ME, Coffey M, Johnson H, et al. Universal vs. risk factor-based screening for gestational diabetes mellitus: detection rates, gestation at diagnosis and
outcome. Diabet Med. 2000;17:26-32.
3. Rey E, Hudon L, Michon N, et al. Fasting plasma glucose versus glucose challenge test: screening for gestational diabetes and cost effectiveness. Clin
Biochem 2004;37:780-4.
1.6.4 Preparation for OGTT
The rules that are considered during OGTT are as follows;
The patient should consume an unrestricted carbohydrate (CH) diet (≥150 g CH daily) and have usual physical activity for at least 3
days before the test.
The test should be performed after at least an 8 h fasting.
It is recommended to consume about 30-50 g CH the evening before OGTT.
During the OGTT, the patient should not eat or drink anything except water. The patients should be advised to refrain from tea,
coffee and smoking immediately before or during the procedure.
The patient is advised to relax and comfortably throughout the test.
OGTT should not be performed during an acute/chronic infection, if the patient is physically inactive or if there is a treatment with
drugs known to impair CH tolerance.
After fasting blood sample is taken, a standard dose of glucose, 75 g anhydrous glucose (or a 82.5 g glucose monohydrate),
dissolved in a 250-300 mL of water is given orally over a 5 minute period.
Blood sample is drawn 2 h after drinking glucose.
For children the oral glucose load should be calculated as 1.75 g per kg (maximum 75 g).
Plasma samples for glucose concentration are collected in tubes containing sodium fluoride (6 mg per 1 mL blood sample),
centrifuged to separate plasma and remained frozen until assayed.
1.6.5 Other Diagnostic Tests
C-peptide levels
There is a considerable reserve capacity of β-cells (endogenous insulin) in the pancreas. The routine measurement of this parameter is not
necessary in type 1 diabetes mellitus. Fasting and stimulated C-peptide levels can be used to differentiate autoimmune diabetes forms such
as LADA from type 2 diabetes, and to detect type 2 diabetes cases who require insulin treatment. However, C-peptide
levels may not reflect the actual endogenous insulin reserve due to the effect of glucose toxicity on β-cells during excessive hyperglycemia.
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Turk JEM 2010; 14: Suppl 1-10
Islet cell autoantibodies
These are anti-glutamic acid decarboxylase autoantibodies (Anti-GAD), islet cell cytoplasmic antibodies (ICA); insulin autoantibody (IAA)
and anti-tyrosine phosphatase antibody (IA2), anti-phogrin antibody (IA2-β), and anti-zinc transporter 8 antibody (Anti-ZnT8). Routine
measurement of these autoantibodies is not necessary in type 1 diabetes mellitus. They can be used in differential diagnosis of some
autoimmune diabetes forms such as LADA.
SEMT RECOMMENDATIONS
• Diabetes in children and non-pregnant women except in high risk individuals for diabetes and suspicious conditions
(Class D, evidence-based on common consensus).
• A diagnostic OGTT is indicated in high risk peoples for diabetes and suspicious conditions even if FPG is within normal
ranges (Class D, evidence-based on common consensus).
• Considering technical and standardization problems and being costly, A1C is not advisable for today to be used as a
screening and diagnostic test for diabetes.
02
STANDARDS OF MEDICAL CARE IN DIABETES
In this chapter, guidelines for the standards of medical care in patients with diabetes are summarized. Each topic involved in the
medical evaluation is defined separately. Physical examination details as well as laboratory tests, and their frequency of use are
briefed. The current evidence-based recommendations for medical treatment of hypertension and lipid disorders are provided.
In the complications chapter, we are focused particularly on atherosclerosis, and its prevention, smoking cessation, and self
monitoring and education.
Figure 2.1 shows the algorithm for the standards of medical care in adults with diabetes.
ANNUAL MONITORING
INITAL EVALATION
Diagnosis and assessment
(acute care if needed)
Initial training and
improving skills
Starting insulin and dose
adjustments
Assessment of conformity
of glycemic control with
predefined targets
Annual assessment of
education and skills
Annual assessment of
arterial risk factors according
to targets
Annual assessment of
complications
Compensate for the lack
of education (improving
skills and encouraging,
avoiding prejudice)
Follow-up of
CV risk factors
Follow-up of complications
Structured training,
lifestyle and dietary
advices
Treatment of CV risk
factors
Complication- specific
treatments, referral to other
disciplines
Assessment of diabetes
knowledge and skills
Assessment of conformity
of CV risk factors with
predefined targets
More frequent evaluation of
complications
REGULAR FOLLOW-UP
Figure 2.1 Diabetes care for adult with type 1 diabetes
CV; Cardiovascular
11
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Standards of Medical Care in Diabetes
Turk JEM 2010; 14: Suppl 12-6
2. 1 ANAMNESIS
The following issues should be questioned when taking anamnesis in a patient with diabetes mellitus.
The symptoms of diabetes, physical examination findings and laboratory results
Previous A1C values
Eating habits, nutritional status, weight history, growth and development of children and adolescents
Details of previous treatment programs (nutrition, self monitoring ‘SMBG’, habits and health-related believes
Current diabetes treatment (medicines, meal plan, SMBG results)
Work out details
The frequency, degree and causes of acute complications (DKA, hypoglycemia)
Previous and current infections (skin, feet, teeth, genitourinary)
The symptoms associated with chronic complications (ocular, renal, nervous system, gastrointestinal, cardiovascular, diabetic foot,
cerebrovascular accident) and treatment details
Other drugs that may affect blood glucose levels
Risk factors of atherosclerosis (smoking, hypertension, obesity, dyslipidemia, family history)
Other diseases related to endocrine disruption and eating behaviors
Family history of diabetes and other endocrine disorders
Factors that may affect treatment and follow up of diabetes (lifestyle, cultural, psychosocial, educational and economical factors)
Smoking and alcohol consumption, substance abuse
Contraception, reproductive life, sexual life
2.2 PHYSICAL EXAMINATION
The following items should be checked when examining patient with diabetes mellitus.
Height and weight measurement (comparison of growth charts in children and adolescents)
Measurement of waist circumference (in all diabetic patients)
Puberty stage, sexual developmental level
Blood pressure (orthostatic measurement if needed, comparison with normal values for age)
Fundus examination
Oral examination
Thyroid palpation
Cardiac examination
Abdominal examination (liver palpation)
Pulse examination (palpation and oscultation)
Hand and finger examination (for sclerodactyly and Dupuytren's contracture)
Foot examination (those at risk for diabetic foot)
Skin examination (acanthosis nigricans, reactions in insulin injection sites)
Neurological examination
Findings related to certain forms of secondary diabetes (hemochromatosis, pancreatic diseases, endocrinopathies, genetic syndromes)
2.3 CONSULTATIONS
Medical nutrition therapy, ‘MNT’ (if possible, patient should be referred to a dietitian)
Fundus examination (in accordance with a follow up protocol)
Family planning for reproductive age women
Diabetes educator (if a diabetes educator is not available, then the physician should assume education)
Psychologist (if behavior therapy is necessary)
Because of the lack of podiatrist in our country, diabetes nurses, dermatologists and physiotherapists should replace them.
If necessary, other disciplines and other areas of expertise (neurology, nephrology, cardiology, gynecology) should be consulted
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Standards of Medical Care in Diabetes
13
2.4 LABORATORY EXAMINATIONS
A1C (every 3 to 6 months)
Fasting lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides): Every year
Microalbuminuria (urinary albumin excretion rate, ‘UAE’): Screening for microalbuminuria should be performed annually, starting 5
years after diagnosis of type 1 diabetes or earlier in the presence of puberty, and then annually. In all patients with type 2 diabetes
screening for microalbuminuria should start at the time of diagnosis and then annually. Albuminuria is measured in an early morning
spot urine sample and calculated as ‘urinary albumin/creatinine’ ratio. UAE is interpreted according to the principles showed in Table 2.1.
Creatinine in adults (proteinuria in children): Every year
TSH measurement (in all subjects with type 1 diabetes, and if necessary in type 2 diabetes): If TSH is abnormal, free T4 should
be measured. Patients with type 1 diabetes mellitus should be screened for autoimmune thyroiditis by anti-thyroid peroxidase and
anti-thyroglobulin autoantibodies at initial diagnosis. TSH should also be monitored after metabolic control has been established, if the
test is normal it should be repeated every 1 or 2 years or when symptoms of thyroid disease occur.
ECG in adults: Annually
A urine sample should be obtained at each visit for complete urine analysis (ketones, protein, sediment, etc.).
Additionally autoantibodies (anti-tissue transglutaminase and anti-endomysium IgA, if serum IgA level is in normal range) related to
gluten enteropathy should be tested in children and adolescents with type 1 diabetes. All antibody positive or symptomatic cases
should be referred to gastroenterologist for endoscopic evaluation for definitive diagnosis.
Table 2-1. Evaluation of urinary albumin excretion rate (UAE)
Normoalbuminuria
Microalbuminuria(*)
Macroalbuminuria
(Clinical albuminuria)
First morning spot urine
Albumin/creatinine
(mg/g)
<30
30-300
>300
24 hour urine
UAE
UAE rate
(mg/day)
(μg/min)
<30
<20
30-300
20-200
>300
>200
(*)
Microalbuminuria is defined as at least 2 of 3 measurements are higher than normal within the last 3 to 6
months.
Excessive urinary albumin excretion levels may be associated with intensive exercise within the last 24 hours,
infection, high fever, congestive heart failure, prominent hyperglycemia and hypertension.
Glomerular filtration rate
Glomerular filtration rate (GFR) is estimated by determining creatinine clearance. The calculated estimate of glomerular filtration rate
(eGFR) is based on two widespread adapted formulas in the lack of clinical renal failure.
Cockroft – Gault formula(*)
eGFR = [(140-age) x weight (kg)] / [serum creatinine (mg/dL) x 88.6]
(*)
The resulting value is multiplied by a constant of 0.85 if the patient is female.
Some sources have suggested this formula as follow;
eGFR = [(140-age) x weight (kg)] / [serum creatinine (mg/dL) x 72]
MDRD formula
Alternatively, eGFR is calculated using MDRD (Modification of Diet and Renal Disease) study equation. MDRD has been proposed to
give more accurate results than Cockroft-Gault, especially in elderly diabetic patients. The following web site can be used to calculate
eGFR with MDRD formula (http//www.kidney.org/professionals/kdoqi/gfr_calculator.cfm).
2.4.1 Glycemic Control
Self-monitoring of blood glucose (SMBG)
SMBG frequency should be determined according to patient characteristics (3-4 times daily in type 1 diabetics treated with insulin
with basal-bolus regimen, pregnant women and diabetics treated with insulin pump; 3-4 times weekly in type 2 diabetics).
Postprandial glycemia (PPG): It is measured in diabetics whose A1C target is not reached although their fasting and preprandial
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Turk JEM 2010; 14: Suppl 12-6
glucose levels are under control, and in those on nutrition and anti-hyperglycemic agents to control postprandial glycemia levels.
Postprandial glucose measurements should be made 2 hours after the beginning of a main meal, from the time of the first bite. One
hour postprandial glucose level is used in pregnant women.
Patients should be taught how to made MNT and insulin/OAD dose adjustments according to the SMBG results.
SMBG technique should be reviewed regularly.
Long term glucose control (A1C)
A1C is measured periodically every 3 months in patients with type 1 diabetes and in those with type 2 diabetes using insulin, and
every 3 to 6 months in other type 2 diabetic patients.
2.4.2 Blood Pressure (BP) Control
A1C should be evaluated together with SMBG results.
Target BP
The optimal BP target is ≤130/80 mmHg. BP follow-up should be recommended to patients under appropriate conditions at home.
The cardiovascular (CV) risk factors should be taken into account together with BP levels.
The lowest tolerated BP levels without any risk of severe hypotension (≤120/ <70 mmHg), should be targeted.
2.4.3 Lipid Profile
Target levels
LDL-cholesterol <100 mg /dL (<70 mg/dL in diabetic patients with primary CV event)
Triglycerides <150 mg/dL
HDL-cholesterol >40 mg /dL (>50 mg/dL in women)
Frequency of measurement
Once a year (it may vary depending on the patient; once every 2 years in children)
2.5 COMPLICATIONS
2.5.1 Prevention of Coronary Artery Disease
Especially patients with type 2 diabetes are associated with a greater risk and mortality of coronary artery disease (CAD). The routes to
prevent coronary artery disease are summarized below:
Antithrombocyte (antiaggregant) therapy
Acetyl salicylic acid (80-150 mg/day) should be used in all adults with diabetes and macrovascular events for secondary prevention.
Acetyl salicylic acid should be used in all diabetic patients with a high risk of CV events for primary prevention (see Chapter 13.1)
Aspirin therapy should not be recommended for patients under the age of 21 years because of the increased risk of Reye's syndrome
associated with aspirin.
The preventive role of aspirin has never been studied in patients under the age of 30 years.
Smoking cessation
Epidemiological case-control studies revealed the cause-effect relationship between smoking and health risks. Statistics of developed
countries show that smoking is responsible for 1 in 5 deaths.
Cigarette smoking is the most changeable risk factor for CV disease (CVD).
The risk of CVD morbidity and early mortality rates are significantly increased in smoking diabetic patients compared with the
general population.
Smoking is found to be associated with the earlier development and progression of microvascular complications.
Some forward-looking studies have shown that smoking increases the risk of development of type 2 diabetes.
All members of the diabetes team (physician, nurse, dietitian and psychologist) should advice diabetic patients on stopping
smoking at every opportunity.
The amount and duration of smoking should be ascertained.
The patients with a risk of starting smoking again should be supported.
Proven methods for smoking cessation should be included in routine diabetes care/education programs.
Consequently smoking cessation is an efficient and cost-effective approach in reducing above-mentioned risks.
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Standards of Medical Care in Diabetes
15
2.5.2 Diabetic Nephropathy
Screening for CVD
1. Patients with high risk for CVD should undergo exercise stress testing.
2. Patients should be referred to cardiologists as needed.
General recommendations
Optimal glycemia and BP control should be provided.
Screening for nephropathy
1. Microalbuminuria (UAE) should be measured
In patients with type 1 diabetes of ≥5 years' duration
In all patients with type 2 diabetes.
2. eGFR should be calculated by measuring serum creatinine annually
2.5.3 Diabetic Retinopathy
General recommendations
Optimal glycemia and BP control should be provided.
Screening for retinopathy
Fundus examination should be performed yearly, starting at puberty or 5 years after diagnosis in type 1 diabetes, and annually in all
patients with type 2 diabetes starting at time of diagnosis.
Follow up
Annual fundus examination after the diagnosis
Fundus examination and other necessary control should be performed in diabetic women who plan pregnancy, then in the first
trimester and then as often as needed.
Patients with macular edema, advanced non-proliferative retinopathy and proliferative retinopathy should be referred to
ophthalmologists.
2.5.4 Diabetic Foot
Patients at high risk for amputation
Patients with following conditions are at high risk for amputation:
Sensory neuropathy
Altered foot biomechanics
Evidence of increased pressure (erythema, hemorrhage under a callus)
Bone deformities
Peripheral artery disease (weak or absent pulses in the limb)
History of ulceration or amputation
Severe nail pathology
Approach
Multidisciplinary approach is essential. Detailed examination of the feet and vascular assessment should be performed, and patients
must be educated about foot care and diabetic foot protection.
2.6 EDUCATION
Education constitutes the backbone of treatment both in type 1 and type 2 diabetes. Following the diagnosis of diabetes, patients should
be referred to a diabetes center. After establishing glycemic control, they should be included in the education program conducted by
a physician, a nurse and a dietitian. Education should be repeated at regular intervals. Diabetic patients should gain the following skills
with education.
Patients with type 1 diabetes must know
What and when to eat
What to do during and after exercise
How to make glucose measurements 3-4 times (more frequent if needed) a day at home (SMBG)
How to inject insulin 2-5 times daily
Symptoms and treatment of hypoglycemia
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Turk JEM 2010; 14: Suppl 12-6
How to inject glucagon when needed
How to cope with anxiety due to fear of hypoglycemia and hyperglycemia
How to overcome with anxiety caused by the risk of development of microvascular complications
How to protect from microvascular complications
Foot care
How to regulate diabetes in case of comorbidity or during intercurrent illnesses, and when to communicate with health care team
The application of contraceptive methods and the importance of glycemic control during pregnancy.
Patients with type 2 diabetes must know
The importance of healthy and balanced diet to ensure weight loss
How to perform SMBG in number and time appropriate to treatment
When and which OADs will be used
The other accompanied disorders that may affect diabetes
How to inject insulin when needed
Symptoms and treatment of hypoglycemia
How to protect microvascular complications
Foot care
How to regulate diabetes in case of comorbidity and exceptions, and when to communicate with health team
The application of contraceptive methods and the importance of glycemic control during pregnancy
In addition to the above matters, all patients with type 1 and type 2 diabetes should be informed about the teeth and gum diseases,
and recommended to visit a dentist once a year. Also, they should be given information about the application and timing of the
vaccines (see Chapter 15.7)
SEMT RECOMMENDATIONS FOR PATIENT EDUCATION
1. Education should be provided to all patients with diabetes and their family members in the appropriate time to improve
their knowledge and skills in self-management of diabetes [Class A, Level 1A evidence (1,2)].
2. All diabetic patients and their family members should learn how to evaluate SMBG at home, and to change the treatment
according to self-monitoring glucose results [Class A, Level 1A evidence (1)].
REFERENCES
1. Norris SL, Engelgau MM, Narayan KMV. Effectiveness of self management training in type 2 diabetes: a systematic review of randomized controlled trials.
Diabetes Care 2001;24:561-7.
2. Ellis S, Speroff T, Dittus R, et al. Diabetes patient education: a meta-analysis and meta-regression. Patient Educ Couns 2004;52:97-105.
03
PRINCIPLES OF HOSPITALIZATION
3. 1 ACUTE METABOLIC COMPLICATIONS
Diabetic ketoacidosis (DKA)
Plasma glucose >250 mg/dL, arterial pH <7.3, and serum bicarbonate <15 mEq/L, and mild/severe ketonuria or ketonemia.
Hyperosmolar hyperglycemic state (HHS)
Impaired mental status, severe hyperglycemia (>600 mg/dL), and elevated serum osmolality (>320 mOsm/kg).
Severe hypoglycemia and neuroglycopenia
Blood glucose <50 mg/dL and unresolved consciousness in spite of the treatment of hypoglycemia; or coma, convulsion, or altered
behavior (e.g., disorientation, ataxia, unstable motor coordination, dysphasia) due to documented or suspected hypoglycemia.
3. 2 UNCONTROLLED DIABETES
In the presence of any of the following reasons in patients with diabetes, hospitalization should be considered to investigate the
reasons and to provide treatment.
Hyperglycemia with accompanying volume loss
Metabolic deterioration associated with continuous and refractory hyperglycemia
Recurrent fasting hyperglycemia refractory to outpatient treatment (>300 mg/dL) or A1C is two times higher than the upper limit of
normal
Recurrent severe hypoglycemic episodes despite treatment (<50 mg/dL)
Metabolic imbalance; frequent episodes of hypoglycemia (<50 mg/dL) and fasting hyperglycemia (>300 mg/dL)
Recurrent DKA episodes without any precipitant cause such as infection or trauma
Disruption of school or work life due to serious psychosocial problems which impairs metabolic control and unresponsive to
outpatient treatment.
Also in some cases listed below hospitalization may be required;
In the beginning of renal, retinal and neurological complications and acute cardiovascular events
Other health problems which diabetes increases severity
Situations requiring rapid metabolic control such as pregnancy
Lack of metabolic control due to primary health problems or specific treatment (e.g. use of high dose glucocorticoids).
17
04
TARGETS OF GLYCEMIC CONTROL IN PATIENTS WITH DIABETES
4. 1 TARGETS OF GLYCEMIA
According to widely accepted suggestions targets of glycemic control for adults and pregnant women with diabetes are summarized
in Table 4.1.
Table 4.1 Targets of glycemic control
A1C
Ideal
<6%
Target
≤6.5%(*)
FPG and
70-100
preprandial PG
mg/dL
1 h postprandial PG <120 mg/dL
70-120
mg/dL(*)
-
2 h postprandial PG
<140
mg/dL(*)
<130
mg/dL
In pregnancy
≤6.5%
(preferably <6%)
60-90 mg/dL
<140 mg/dL(**)
(preferably <120 mg/dL)
<120 mg/dL
(*)
The most recent glycemic goals recommended by the American Diabetes Association (ADA) are
A1C level of <7%, preprandial PG 70-130 mg/dL and postprandial peak level of PG <180 mg/dL
(postprandial peak is 90-120 minutes after a meal), and to measure postprandial blood glucose
levels when A1C do not reach the target despite preprandial PG levels are in the
target ranges.
(**)
1 h postprandial blood glucose levels should be monitored in pregnant women with
diabetes.
ADA Clinical Practice Recommendations. Standards of medical care. Diabetes Care 2009;32 (Suppl.1):
S13-61.
Nathan DM, et al. Management of hyperglycemia in type 2 diabetes: A consensus statement from the
DA and EASD. Diabetes Care 2006;29:1963-72.
AACE/ACE. Endocrine Practice. 2002;8(Suppl. 1):40-82
IDF Global Guideline for Type 2 Diabetes, 2005.
4.1.1 Targets of Glycemic Control in Different age Groups
In children and adolescents
Targets of glycemic control in prepubertal children should be determined by a pediatric endocrinologist to minimize the risk of
hypoglycemia (especially at night). ADA recommendations on this issue are summarized below;
In preschool children (younger than 6 years of age) target fasting/preprandial and bedtime/late night PG concentrations are 100-180
and 110-200 mg/dL, respectively, and A1C concentration should be 7.5-8.5%
In school-age children (8-12 years of age) recommended fasting/preprandial and bedtime/late night target PG concentrations are
100-180 and 110-200 mg/dL, respectively, A1C concentration should be less than 8%.
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Targets of Glycemic Control in Patients with Diabetes
19
In adolescents (13-18 years of age) glycemic goals should be close to the targets of adults. Accordingly, fasting/preprandial and
bedtime/late night target PG concentrations of 80-120 and 90-130 mg/dL, and postprandial 2 h PG concentration of <150 mg/dL are
recommended; target A1C is 6.5-7.0%.
In elderly patients and those with short life expectancy
Generally strict metabolic control is not recommended in elderly patients with diabetes and in patients with short life expectancy or
those who have severe/advanced comorbidities. The results of ACCORD and VA-DT studies, reported in 2007 and 2008, have shown
that strict metabolic control may be associated with increased CVD in elderly patients with diabetes for more than 10 years.
Hypoglycemia is associated with increased risk of mortality.
To determine the targets of glycemic control individually, life expectancy should be considered beyond the patient’s chronological
age;
life expectancy >15 years without any major comorbidity; A1C ≤6.5%
life expectancy between 5-15 years with moderate comorbidity; A1C ≤7.5%
life expectancy <5 years with any major comorbidity; A1C ≤8.5%.
In women with diabetes planning for pregnancy
Preconception A1C threshold for women with diabetes should not exceed 2 standard deviations above the upper limit of nondiabetic
range (≤6.5%), preferably it should be ≤6.0% in well-motivated patients.
4.1.2 Measurement and Evaluation of Haemoglobin A1C
The HbA1c (A1C) level reflects the average blood glucose concentration over the previous three months. A1C test does not require fasting.
The normal range of A1C by ‘high performance liquid chromatography (HPLC)’ assay as used in DCCT is 4.0-6.0%.
In this study the upper limit of the non-diabetic A1C range is 6.0% (mean 5.9% + 2 standard deviation). Table 4.2 shows estimated
average glucose levels corresponding to A1C values measured by standard method used in DCCT and to ‘The A1C-derived average
glucose (ADAG) study’.
ADAG average glucose levels can be calculated by the following formula;
‘Average glucose =28.7xA1C–46.7’
Glucose levels can be calculated from the related website
(http://professional.diabetes.org/eAG).
Table 4.2 The relationship between A1C and average glycemia
A1C (%)
5
6
7
8
9
10
11
12
DCCT average
glucose (mg/dL)
ADAG average
glucose(*) (mg/dL)
100
135
170
205
240
275
310
345
97
126
154
183
212
240
269
298
(*)
ADAG; A1C-derived average glucose.
‘Average glucose = 28.7 X A1C-46.7’
Nathan DM, Kuenen J, Borg R, et al. Diabetes Care 2008;31:1473-8.
Generally 50% of an A1C result represents the previous month's glycemia, and about 30% represents the levels over the preceding
2nd month whereas the remaining 20% represents 3rd month glycemia, respectively.
The contribution of fasting glycemia increases with the higher levels of A1C. On the other hand, contribution of postprandial glycemia
is prominent when A1C value is close to normal. The studies conducted in patients with type 1 and type 2 diabetes have shown that
the risk of development of microvascular complications is closely related to the level of glycemic control (Table 4.3). It is accepted that
the closer the A1C to normal ranges the lower the complication rate.
Until achievement of glycemic goals A1C should be measured every 3 months, and in stable patients it should be measured every
6 months.
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Targets of Glycemic Control in Patients with Diabetes
Table 4-3. The effect of 1% reduction in A1C associated with the risk
reduction of development of complications in diabetes
Type 1 diabetes (DCCT)
Retinopathy 35%
Nephropathy 24-44%
Neuropathy 30%
DCCT Research Group. NEJM 1993;329:977
Type 2 diabetes (UKPDS)
Diabetes-related death 25%
All-cause mortality 7%
Myocardial infarction 18%
Any microvascular complication 35%
UKPDS Group. Lancet 1998;352:837
4.1.3 Fructosamine
Fructosamine is a glycosylated protein (over 90% of fructosamine is come from glycosylated albumin). It is an indicator of blood
glucose control over the previous 1 to 3 weeks.
Serum fructosamine level is a useful marker to assess short-term glucose control in pregnancy, and also provides reliable
information in certain hemoglobinopathies.
4.1.4 Ketonuria and Ketonemia Tests
Keton bodies
β-hydroxybutyric acid, acetoacetatic acid and acetone are the main keton bodies.
Keton bodies are the waste products of fat metabolism. Presence of keton bodies in the blood or urine indicates that foods are not
metabolized properly due to insulin deficiency, or insufficient carbohydrate intake (ketones may be elevated mildly in the blood after
prolong fasting).
Ketones in the urine or blood may indicate DKA.
Ketones should be followed when blood glucose excessively increased in type 1 diabetes mellitus, during pregestational diabetes
and GDM.
Method
β-hydroxybutyric acid is measured qualitatively by immersion of test strip in the urine sample or dripping blood onto a test strip.
Measurement of keton levels in the blood is a more sensitive method in determining keton products earlier, and in monitoring the
response to treatment.
When to measure
When the blood glucose levels are >300 mg/dL (>200 mg/dL in pregnancy)
In the existence of stress factors such as acute diseases, trauma or surgery
When nausea, vomiting, abdominal pain and fever is accompanied to hyperglycemia symptoms; also if there is smell of acetone in
breath.
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21
SEMT RECOMMENDATIONS FOR THE TARGETS OF GLYCEMIC CONTROL
1. A1C should be measured every 3 months in patients with diabetes (Class D, evidence-based consensus).
2. A1C may be measured every 6 months in adult patients with optimal glycemic control, stable life style and on appropriate
treatment (Class D, evidence-based consensus).
3. Glycemic targets should be determined on individual basis in accordance with patient’s characteristics and clinical status
to reduce the long-term complications in patients with type 1 and type 2 diabetes (Class D, evidence-based consensus).
4. A1C level should be maintained ≤6.5% to reduce microvascular complications if patients do not have prominent risk of
severe hypoglycemia, and have long life expectancy [Class A, Level 1A evidence (1-3)].
5. Lowering of A1C should be targeted to reduce macrovascular complications in patients with type 1 diabetes [Class C,
Level 3 evidence (4)].
6. The benefits of decreased A1C should not increase the risks of hypoglycemia and mortality in patients at high risk for CVD
[For hypoglycemia: Class A, Level 1A evidence (3,4); For mortality in patients at high risk for CVD: Class A, Level 1A evidence (4)].
7. To achieve A1C goal ≤6.5%, blood glucose levels should be as follows;
• FPG and preprandial PG levels 70-120 mg/dL [For type 1 diabetes: Class B, Level 2 evidence (1); For type 2 diabetes: Class
B, Level 2 evidence (2,5)].
• 2 h PG levels <140 mg/dL [For type 1 diabetes: Class D, evidence-based consensus; For type 2 diabetes: Class D,
Level 4 evidence (6,7)].
8. Blood or urine keton testing should be performed in patient with acute disease especially when PG >250 mg/dL (Class D,
evidence-based consensus), and in pregnant women when PG >200 mg/dL (Class D, evidence-based consensus).
9. Measurement of keton levels in blood sample should be preferred to determine keton products earlier, and to monitor the
response to treatment [Class B, Level 2 evidence (8)].
REFERENCES
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of
long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood- glucose control with sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-53.
3. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med.
2008;358:2560-2572.
4. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Eng J Med
2005;353:2643-53.
5. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with
non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17.
6. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2
diabetic patients. Diabetes Care 2003;26:881-5.
7. Woerle HHJ, Neumann C, Zschau S, et al. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes. Importance of
postprandial glycemia to achieve target HbA1c levels. Diab Res Clin Pract 2007;77:280-5.
8. Bektas F, Eray O, Sari R, et al. Point of care blood keton testing of diabetic patients in the emergency department. Endocr Res 2004;30:395-402.
4.2 SELF MONITORING OF BLOOD GLUCOSE (SMBG)
4.2.1 ADA Recommendations
Type 1 diabetes
SMBG should be regarded as an integral part of the treatment of type 1 diabetes.
Type 2 diabetes
SMBG is a part of insulin therapy.
SBMG should be recommended 3-4 times per day in patients receiving multiple insulin injections.
SMBG is a useful tool to achieve glycemic targets in patients using insulin or OAD 1-2 times a day, or followed by MNT.
SMBG may help to achieve postprandial glycemic targets.
Patients should be educated for SMBG and the technique of SMBG and ability to reflect SMBG results to the treatment should be
reviewed routinely.
There is no consensus on optimal frequency and timing of SMBG in patients with type 2 diabetes.
The role of SMBG in stable diet-treated patients with type 2 diabetes is not known.
22
Targets of Glycemic Control in Patients with Diabetes
Turk JEM 2010; 14: Suppl 18-23
4.2.2 IDF Recommendations
Standard treatment
In people with newly diagnosed type 2 diabetes, SMBG should be offered as an integral part of self-management education.
Patients with type 2 diabetes on insulin therapy should perform SMBG with glucose meters regularly.
Patients with type 2 diabetes on OAD therapy should perform SMBG regularly to monitor
1. hypoglycemia
2.increase of blood glucose caused by medication and lifestyle
3. glycemic changes during intercurrent illnesses.
Patients with type 2 diabetes not using insulin or OAD should perform SMBG intermittently to monitor
1. increase of blood glucose caused by lifestyle
2. glycemic changes during intercurrent illnesses.
SMBG skills, quality of measurements, interpretation of results and applying them into treatment practice should be reviewed on a
yearly basis.
Intensive treatment
Patients with type 2 diabetes on insulin or OAD therapy should perform SMBG with glucometers regularly.
Minimum treatment
Patients with type 2 diabetes using insulin only should perform SMBG with glucometer regularly.
Frequency of monitoring
In type 1 diabetes mellitus, patients on an insulin pump and pregestational diabetic patients should perform SMBG 3 to 4 times a
day, before meals and at bedtime, and also as indicated by the treatment protocol.
In type 2 diabetic patients as indicated to ensure glycemic control.
In patients with GDM at fasting and postprandial (preferably 1 hour later)
When planning physical activity; before and after the activity to monitor the effects on metabolic control in patients with type 1
diabetes (and also in type 2 diabetes if necessary)
In hypoglycemia; to confirm the diagnosis and to measure the treatment response.
In case of acute diseases glycemia should be monitored every 4-6 hours.
SEMT RECOMMENDATIONS
1. SMBG is an essential part of diabetes self-management in all insulin-requiring patients [For type 1 diabetic patients: Class
A,
Level 1 evidence (1); For type 2 diabetic patients: Class C, Level 3 evidence (2)].
2. Glucometers approved by the international authorities (e.g. IFCC) and calibrated for PG levels, should be used, and a
simultaneous measurement with fasting venous plasma sample should be performed at least once a year and also
during doubtful conditions to ensure accuracy of the device (Class D, evidence-based consensus).
3. SMBG should be carried out 3-4 times daily before meals, and if needed after a main meal, and also at bedtime once a
week, and early morning between 02:00-04:00 am once a month in all patients on a basal-bolus insulin regiment (type 1
or type 2 diabetes, and pregnant women with GDM or pregestational diabetes) [For type 1 diabetic patients: Class A, Level 1
evidence (2-4); For type 2 diabetic patients: Class C, Level 3 evidence (2,5); For pregnant diabetics: Class D, evidence-based
consensus].
4. SMBG should be performed at least once a day at various times in patients with type 2 diabetes using basal insulin plus
OAD (Class D, evidence-based consensus).
5. SMBG should be recommended 3-4 times per week to type 2 diabetic patients treated with MNT and OAD according to the
level of glycemic control, personal characteristics and type of treatment (Class D, evidence-based consensus).
6. Fasting and 1 h PPG levels should be monitored in pregnant women with diabetes.
7. SMBG should be performed more frequently at the time of treatment changes, during acute illnesses and in patients
treated with insulin pump (Class D, evidence-based consensus).
Turk JEM 2010; 14: Suppl 18-23
Targets of Glycemic Control in Patients with Diabetes
23
REFERENCES
1. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. The DCCT Research Group. Am J Med 1991;90:450-9.
2. Karter AJ, Ackerson LM, Darbinian JA, et al. Self-monitoring of blood glucose levels and glycemic control: the Northern California Kaiser Permanent Diabetes
Registry. Am J Med 2001;111:1-9.
3. Rohlfing CL, Wiedmeyer HM, Little RR, et al. Defining the relationship between plasma glucose and HbA(1c): analysis of glucose profiles and HbA(1c) in the
Diabetes Control and Complications Trial. Diabetes Care 2002;25:275-8.
4. Sheppard P, Bending JJ, Huber JW. Pre- and post-prandial capillary glucose self-monitoring achieves better glycaemic control than pre-prandial only
monitoring. A study in insulin treated diabetic patients. Practical Diabetes Int 2005;22:15-22.
5. Murata GH, Shah JH, Hoffman RM, et al; Diabetes Outcomes in Veterans Study (DOVES). Intensified blood glucose monitoring improves glycemic control in
stable, insulin-treated veterans with type 2 diabetes: the Diabetes Outcomes in Veterans Study (DOVES). Diabetes Care 2003;26:1759-63.
05
MEDICAL NUTRITION THERAPY IN DIABETES
5. 1. GENERAL PRINCIPLES OF MEDICAL NUTRITION THERAPY (MNT)
American Dietitians Association and the ADA recommend referring patients with type 1 and type 2 diabetes to a dietitian who is a
member of the diabetes team within the first month and patients with GDM within the first week of diagnosis, and the dietitian should
allocate 2.5-3 hours to MNT in 2 or 3 visits.
MNT consists of four components:
1. General assessment
Individual assessment of parameters such as anthropometric measurements, history of social life, history of food consumption
and medical treatment of patients is needed to recommend individual MNT. Macronutrient and energy consumption suitable to a
particular patient should be determined after evaluation of nutritional status based on food consumption diary.
2. Education
Interviews with diabetic patients are required for granting simple and detailed training.
3. Target identification
Dietitian and diabetic patient together determine the achievable goals and feasible specific behaviors.
4.Evaluation of treatment
Applications, compliance and clinical results should be evaluated, and current problems should be detected to focus the solutions.
Table-5.1 shows the criteria and timing of assessment.
Table 5.1 Evaluation of the criteria of medical nutrition therapy
Criteria
Timing
Control of adaptation to meal times
In every control visit
Evaluation of SMBG and food
In every control visit
consumption records together
Control of behavioral changes
In every control visit
Control of adaptation to exercise program
In every control visit
Weight and height measurement
Once every 3 months
FPG and PPG; together with 3 days food
In every control visit
consumption
A1C
Once every 3 months
Fasting lipid profile
In the first week; 6 months later
(LDL-chol and HDL-chol, TG)
if it is high; then once a year
MNT: medical nutrition therapy; FPG: fasting plasma glucose; PPG: postprandial plasma
glucose; A1C: glycosylated hemoglobin A1c; LDL-chol: low-density lipoprotein cholesterol;
HDL-chol: high-density lipoprotein cholesterol; TG: triglycerides level.
24
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Medical Nutrition Therapy in Diabetes
25
5.1.1 Purposes of Medical Nutrition Therapy in Prevention and Treatment of Diabetes
1. To ensure metabolic control
to keep blood glucose in normal or near normal levels
to ensure lipid profile to reduce the risk of CVD
to keep blood pressure in normal or near normal levels
2. To reduce or prevent the development of chronic complications of diabetes by modifying eating habits and life style.
3. To determine the nutritional requirements taking into account the personal and cultural preferences and willingness to change.
4. To ensure the pleasure of eating while putting restrictions supported by scientific evidences in the selection of food.
5. To meet the needs of essential nutrients for type 1 and type 2 diabetic patients, pregnant and breast-feeding women with diabetes
during various stages of life.
6. To provide self management education about acute illnesses, diabetes treatment, prevention and treatment of hypoglycemia, and
exercise in patients using insulin or insulin secreting medication.
5.1.2 Effectiveness of Medical Nutrition Therapy
7. Individuals who have prediabetes or diabetes should receive individualized MNT; such therapy is best provided by a registered
dietitian familiar with the components of MNT in diabetes.
8.Nutrition counseling should be sensitive to the personal needs, willingness to change, and ability to make changes by the person
with prediabetes or diabetes.
9.MNT can reduce A1C about 1% in type 1 diabetes, 1-2% in type 2 diabetes, and LDL-cholesterol levels by 15-25 mg/dL.
5.1.3 Evidence Based Recommendations of Medical Nutrition Therapy
American Dietitians Association and ADA published evidence-based MNT recommendations for diabetic patients in 2002 for the first
time. The final recommendations published in 2007 are summarized below.
A. Recommendations for energy balance in overweight and obesity
In overweight and obese insulin-resistant individuals, even 5% weight loss has been shown to improve insulin resistance. Thus,
weight loss is recommended for all such individuals who have or are at risk for diabetes.
Diet with less than 30% of energy from fat, regular physical activity and structured programs focused on lifestyle changes including
regular follow-up may provide 5-7% weight reduction from the initial weight.
Low-CH diets with daily CH intake of less than 130 g are not recommended in obese or overweight individuals. Low-CH diets
provide similar weight loss with low-fat diets, but their effects on CVD risk profile is uncertain.
Physical activity and behavior modification are important components of weight loss programs and are most helpful in maintenance
of weight loss.
Weight loss medications combined with lifestyle changes may provide 5 to 10% weight loss.
Surgery should be considered for adults with type 2 diabetes if their BMI is >35 kg/m2. The long-term benefits and risks of bariatric
surgery in individuals with prediabetes and diabetes are still being investigated.
B. Recommendations for the prevention of diabetes
Among individuals at high risk for developing type 2 diabetes, structured programs that emphasize lifestyle changes that include
moderate weight loss (7% body weight) and regular physical activity (150 min/week), with dietary strategies including reduced calories
and dietary fat intake can reduce the risk for developing diabetes
Individuals at high risk for type 2 diabetes should be encouraged to receive dietary fiber (14 g fiber/1.000 kcal) and foods containing
whole grains (one-half of grain intake).
There is not consistent information to conclude that low-glycemic load diets reduce the risk for diabetes. Nevertheless, low-glycemic
index foods that are rich in fiber and other important nutrients are to be encouraged.
Observational studies report that mild alcohol intake may be associated with reduced risk of diabetes, however clinical data do not
support recommending alcohol consumption to individuals at risk of diabetes.
No nutrition recommendation can be made for preventing type 1 diabetes.
Although there are insufficient data at present to warrant any specific recommendations for prevention of type 2 diabetes in youth,
it is reasonable to apply approaches demonstrated to be effective in adults, as long as nutritional needs for normal growth and
development are maintained.
26
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Medical Nutrition Therapy in Diabetes
C. Recommendations for the treatment of diabetes
Carbohydrate in diabetes management
A dietary pattern that includes CH from fruits, vegetables, whole grains, and low-fat milk is encouraged for good health.
The low-CH diets with daily CH intake of less than 130 g are not recommended in the treatment diabetes.
Monitoring CH by CH counting, exchange lists or experience-based estimation remains a key strategy in achieving glycemic control.
Taking into consideration the amount of CH consumed (glycemic load) and glycemic index as well may provide an additional
benefit to achieve optimal glycemic control.
Sucrose-containing foods can be substituted for other carbohydrates in the meal plan, if added to the meal plan without substation appropriate
dose adjustment for insulin or other glucose-lowering medications should be made. Care should be taken to avoid excess energy intake.
As for the general population, people with diabetes are encouraged to consume a variety of fiber-containing foods. However,
evidence is lacking to recommend a higher fiber intake for people with diabetes than for the population as a whole.
Artificial sweeteners in diabetes management
1. Energy-reduced sweeteners (sugar alcohols: polyols): Erythritol, isomalt, lactilol, maltilol, sorbitol, mannitol, xylitol, tagatose and
hydrogenated starch hydrolysates are low-calorie sweeteners (energy values ranging between 0.2-3.0 kcal/g) approved by US Food
and Drug Administration (FDA).
2. Calorie-free sweeteners: Acesulfam K, aspartame, neotame, saccharine and sucralose are calorie-free (non-nutritive)
sweeteners. Maximum daily intake of these sweeteners, recommended by the FDA, is shown in Table 5.2.
Table 5.2 Maximum daily doses of calorie-free sweeteners
recommended by the FDA
Maximum dose
Saccharine/Cyclamate
Aspartame
Acesulfam K
2.5
11
50
8
19
175
mg/tb
(*)
tb/day
(*)
for a person of 70 kg weight
Recommendations for artificial sweeteners
1. The caloric content of foods containing artificial sweeteners should be written visible on the label, and patients should be
encouraged to read labels.
2. The sweeteners do not have an indication for ensuring weight loss or preventing diabetes in overweight or obese individuals.
3. The increasing consumption of fructose sweeteners in high dose may result in hypertriglyceridemia.
4. The use of sweeteners, such as mannitol or sorbitol, has been associated with diarrhea especially in children.
5. Aspartame derivatives may exacerbate phenylketonuria in children.
6. Sugar alcohols and non-nutritive sweeteners are safe when consumed within the levels approved by FDA.
Fat and cholesterol in diabetes management
Limit saturated fat intake to <7% of total calories.
Intake of trans fat should be minimized.
In individuals with diabetes, lower dietary cholesterol intake to <200 mg/day.
Two or more servings of fish per week should be recommended to provide omega-3 (n-3) polyunsaturated fatty acids.
Protein in diabetes management
For individuals having diabetes with normal renal function, there is insufficient evidence to suggest that usual protein intake (15–20%
of energy) should be modified.
In individuals with type 2 diabetes, ingested protein can increase insulin response without increasing PG concentrations. Therefore,
protein should not be used to treat or prevent acute and nighttime hypoglycemia.
High-protein diets are not recommended as a method for weight loss at this time. The long-term effects of protein intake >20% of
calories on diabetes management and its complications are unknown. Although such diets may produce short-term weight loss and
improved glycemia, it has not been established that these benefits are maintained long term, and long-term effects on kidney function
for persons with diabetes are unknown.
Alcohol in diabetes management
Patients with diabetes are not recommended to consume alcohol. In patients with impaired glucose control, uncontrolled
hyperglycemia, and at high risk for hypoglycemia alcohol consumption can cause health problems such as severe hypoglycemia,
ketosis, acute CV events, pancreatitis, and liver steatosis.
(*)
If adults with diabetes desire to use alcohol, daily intake should be limited to one unit per day for women and two units for men,
and not more than two days per week.
To reduce risk of nocturnal hypoglycemia in individuals using insulin or insulin secretagogues, alcohol should be consumed with food.
(*)
One unit of alcohol is defined as 7.9 g pure alcohol (ethanol). However, as it is liquid, it is easier quantifying alcohol in volume. And one unit of alcohol is 10 mL by volume. It is
roughly equivalent of a half a pint (half glass) of beer, apple wine or lager bear; about 25 mL of a spirit (gin, vodka, whisky), or approximately 50 mL of strong wines, such as Porto
or Spanish wines, or a small bottle of wine (125 mL).
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27
In individuals with diabetes, moderate alcohol consumption has no acute effect on glucose and insulin concentrations, but CH
containing alcoholic beverages may raise blood glucose.
Micronutrients in diabetes management
As in the general population, there is no clear evidence of benefit from vitamin or mineral supplementation in people with diabetes
who do not have underlying deficiencies.
Routine supplementation with antioxidants, such as vitamins E and C and carotene, is not recommended because of lack of evidence
of efficacy and concern related to long-term safety.
Benefit from chromium supplementation in individuals with diabetes or obesity has not been clearly demonstrated and therefore is
not recommended.
D. Nutrition recommendations for specific populations
Nutrition recommendations for people with type 1 diabetes
For individuals with type 1 diabetes, insulin therapy should be integrated into their dietary and physical activity pattern.
Individuals using rapid-acting insulin by injection or an insulin pump should adjust the meal and snack insulin doses based on the
CH content of the meals and snacks.
For individuals using biphasic insulin preparations (in fixed combination), CH intake on a day-to-day basis should be kept consistent
with respect to time and amount.
Nutrition recommendations for people with type 2 diabetes
Individuals with type 2 diabetes are encouraged to implement lifestyle modifications that reduce intakes of energy, saturated and
trans fatty acids, cholesterol, and sodium and to increase physical activity in an effort to improve glycemia, dyslipidemia, and BP.
SMBG can be used to determine whether adjustments in foods and meals will be sufficient to achieve blood glucose goals or if
medications need to be combined with MNT.
Nutrition recommendations for pregnant and lactating women with diabetes
Adequate energy intake that provides appropriate weight gain is recommended during pregnancy. Weight loss is not recommended;
however, for overweight and obese women with GDM, modest energy and CH restriction may be appropriate.
Due to risk of ketoacidosis starvation ketosis or ketonemia should be avoided.
MNT for GDM focuses on food choices for appropriate weight gain, normoglycemia, and avoiding ketones.
Because GDM is a risk factor for subsequent type 2 diabetes, after delivery, lifestyle modifications aimed at reducing weight and
increasing physical activity are recommended.
Nutrition recommendations for older adults with diabetes
Obese older individuals with diabetes may benefit from modest energy restriction and an increase in physical activity; energy
requirement may be less than for a younger individual of a similar weight.
A daily multivitamin supplementation may be appropriate, especially for those elders with reduced energy intake.
E. Nutrition recommendations for treating and controlling of diabetes complications
Microvascular complications
Reduction of protein intake to 0.8-1.0 g/kg body weight/day in individuals with diabetes and at earlier stages of chronic kidney
involvement and to 0.8 g/kg body weight/day in the later stages of kidney failure may improve measures of renal function (UAE and
GFR).
MNT that favorably affects CVD risk factors may also have a favorable effect on microvascular complications such as retinopathy and
nephropathy.
Treatment and management of cardiovascular disease risk
Target A1C is as close to normal as possible without causing significant hypoglycemia.
For patients with diabetes at risk for CVD, diets high in fruits, vegetables, whole grains, and nuts may reduce the risk.
For patients with diabetes and symptomatic heart failure, dietary sodium intake of <2,000 mg/day may reduce symptoms.
In normotensive and hypertensive individuals, a reduced sodium intake (<2,300 mg/day) with a diet high in fruits, vegetables, and
low-fat dairy products lowers BP.
In most individuals, a modest amount of weight loss beneficially affects BP.
Hypoglycemia
Ingestion of 15-20 g glucose is the preferred treatment for hypoglycemia, although any form of CH that contains glucose may be used.
The response to treatment of hypoglycemia should be apparent in 10-20 min; however, PG should be tested again in one hour, as
an additional treatment may be necessary.
Acute illnesses
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Medical Nutrition Therapy in Diabetes
Turk JEM 2010; 14: Suppl 24-9
During acute illnesses, insulin and oral glucose-lowering medications should be continued.
During acute illnesses, testing of PG and ketones, drinking adequate amounts of fluids, and ingesting CH are all important.
Acute health care facilities
Establishing an interdisciplinary team, implementation of MNT, and diabetes-specific education planning improves the care of
patients with diabetes during and after hospitalizations.
Hospitals should consider implementing a diabetes meal-planning system that provides consistency in the CH content of specific
meals.
Long-term care facilities
Residents with diabetes should be served a regular menu, with consistency in the amount and timing of CH.
An interdisciplinary team approach is necessary to integrate MNT into overall management for patients with diabetes.
There is no evidence to support prescribing diets such as “no concentrated sweets” or “no sugar added.”
Changing drug treatment instead of food restriction for glucose, lipid and BP control may reduce the risk of iatrogenic malnutrition.
5.2 CARBOHYDRATE COUNTING METHOD
Carbohydrate counting is an useful tool of meal planning method which is used to regulate the amount of CH consumed in one
meal for better glycemia control, to adjust insulin doses suitable for CH consumption and preprandial PG level. With this method,
individuals with diabetes can easily learn the effect of the amount of CH they consumed or the amount of consumption of any food
containing CH on PG levels, and they can plan meals according to daily changes. Using CH counting tool allows the individual
with diabetes to learn the relationship between consumption of foods, activities and glucose measurement results, and to make
appropriate regulations in the treatment of diabetes.
CH counting method can be given in three levels; namely basic, intermediate and advanced levels. A dietitian should meet with
diabetic patient 1 to 3 times to teach every level. The first level can be taught in 30-90 minutes at intervals of 1-4 weeks, and second
and third levels in a period of 30-60 minutes at intervals of 1-2 weeks.
CH counting method can be used by patients with type 1 and type 2 diabetes, GDM, by people at risk for diabetes and even with
reactive hypoglycemia.
Diabetic patients using insulin analogues and especially those on insulin pump should be introduced to third level education
for equalization of CH to insulin. Patients using premixed insulin preparations are not recommended to receive advanced level CH
counting training.
Diabetic patients should have well-controlled glycemia and adjusted basal insulin dose in order to begin advanced education
for CH counting. In this level diabetic patients on insulin pump or frequent (multiple) insulin injections should be educated about
calculating and using “Carbohydrate/Insulin Ratio” (CH/I) and “Insulin Sensitivity Factor” (ISF). Applications should be checked with
frequent visits.
5.2.1 Carbohydrate/Insulin Ratio (CH/I)
Carbohydrate/insulin ratio is calculated either with “CH/I = (The absolute amount of CH or number of servings of CH in a meal)/
(short-or fast-acting insulin dose [IU])” formula; or
“CH/I = 500/TID” formula. (TID: Total daily insulin dose)
In order to determine CH/I and to adjust insulin dose appropriate with the amount of CH which will be consumed in a meal,
persons with diabetes should keep pre- and postprandial PG in target levels. CH/I should not be calculated in diabetic patients with
uncontrolled glycemia levels and inconsistency of CH intake from day to day and meal to meal.
5.2.2 Insulin Sensitivity Factor (ISF)
Insulin sensitivity factor is defined as amount of PG (mg/dL) decreased by 1 unit of rapid or short acting insulin. ISF is sometimes referred
to as “correction factor”, “correction bolus” or “addition factor”. Health-care professionals use the “1500 rule” to calculate insulin
sensitivity factor for people who use short-acting insulin or resistant to insulin, and the “1800 rule” for people who use the rapid-acting
insulin analogues or sensitive to insulin.
ISF can be calculated with “IDF=1500/TID” or “IDF=1800/TID” formulas.
Alternatively, it can be estimated by “CH/I = IDF/3” formula.
As a result of calculation of CH/I along with ISF;
The insulin dose or the amount of CH is increased or decreased according to preprandial PG levels.
The insulin dose is regulated according to the amount of CH which is planned to be consumed in a meal.
If an experienced dietitian is not available, patients are simply provided information about CH counting on the basis of certain foods
Turk JEM 2010; 14: Suppl 24-9
Medical Nutrition Therapy in Diabetes
29
equivalent to 15 g CH (i.e. one slice of bread weighing 25 g, two spoons of rice, 3 spoons of pasta, 300 mL yoghurt, 300 mL milk, or
one medium size fruit).
The importance of the consumption of protein and fat should also be explained to patients during education for CH counting.
otherwise eating habits may change depending only on CH.
SEMT RECOMMENDATIONS FOR MDICAL NUTR‹T‹ON THERAPY IN PATIENTS WITH DIABETES
1. Individuals who have diabetes should receive individualized MNT to reduce A1C. Nutrition education should be given by a
professional dietitian [For type 1 diabetic patients: Class D, evidence-based consensus; For type 2 diabetic patients Class
B, Level 2 evidence (1)].
2. Patients with type 1 diabetes should be educated about CH counting and how to calculate CH/I ratio [Class B, Level 2
evidence (2)] or, if it is not possible, they should be advised to consume a fixed amount of CH [Class D, Level 4 evidence (3)].
Type 2 diabetic patients should be advised to eat regular meals at regular timing in order to achieve optimal glycemic
control [Class D, Level 4 evidence (4)].
3. Type 1 and type 2 diabetes patients with poor glycemic control should be advised to prefer the low glycemic index foods to
high glycemic index foods [Class B, Level 2 evidence (5,6)].
4. Diabetic patients with good glycemic control may consume sucrose or sucrose containing foods not to exceed 10% of daily
energy without disrupting glucose and lipid control [Class B, Level 2 evidence (7,8)].
5. Saturated fat intake should not exceed 7% of total daily energy requirement in adult patients with diabetes, and trans fatty
acid intake should be restricted (Class D, evidence-based consensus).
6. Patients with type 1 diabetes should be informed that alcohol may induce late hypoglycemia [Class C, Level 3 evidence (9)].
Measures such as restricted alcohol intake, additional CH intake, insulin dose reduction and frequent SMBG should be
taken to reduce the risk of alcohol-induced hypoglycemia (Class D, evidence-based consensus).
REFERENCES
1. Franz MJ, Monk A, Barry B, et al. Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin-dependent diabetes
mellitus: a randomized, controlled clinical trial. J Am Diet Assoc 1995;95:1009-17.
2. DAFNE Study Group. Training in flexible, intensive insulin management to enable dietary freedom in people with type 1 diabetes: dose adjustment for
normal eating (DAFNE) randomized controlled trial. BMJ 2002;325:746.
3. Wolever TM, Hamad S, Chiasson JL, et al. Day-to-day consistency in amount and source of carbohydrate associated with improved blood glucose control
in type 1 diabetes. J Am Coll Nutr 1999;18:242-7.
4. Savoca MR, Miller CK, Ludwig DA. Food habits are related to glycemic control among people with type 2 diabetes mellitus. J Am Diet Assoc 2004;104:560-6.
5. Brand-Miller J, Hayne S, Petocz P, et al. Low glycemic index diets in the management of diabetes: a meta-analysis of randomized controlled trials. Diabetes
Care 2003;26:2261-7.
6. Opperman AM, Venter CS, Oosthuizen W, et al. Meta-analysis of the health effects of using the glycaemic index in meal-planning. Br J Nutr 2004;92:367-81.
7. Chantelau EA, Gösseringer G, Sonnenberg GE, et al. Moderate intake of sucrose does not impair metabolic control in pump-treated diabetic out-patients.
Diabetologia 1985;28:204-7.
8. Colagiuri S, Miller JJ, Edwards RA. Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus.
Am J Clin Nutr 1989;50:474-8.
9. Ashley MJ, Ferrence R, Room R, et al. Moderate drinking and health. Implications of recent evidence. Can Fam Physician1997;43:687-94.
06
EXERCISE AND PHYSICAL ACTIVITY IN DIABETES
6. 1. GENERAL PRINCIPLES
6.1.1 Exercise Goals
All patients with diabetes are recommended to perform regular planned physical activity adapted to existing complications.
Such a program is important for general health benefits and to facilitate weight loss.
Regular physical activity reduces insulin resistance and prevents type 2 diabetes at high-risk individuals.
6.1.2 Assessment Before Exercise
Safety principles must be observed before starting, during and after exercise to reduce the risks related to exercise.
The presence of chronic complications is investigated regardless of patient's age. The investigations carried out in this context are
summarized below;
Glycemic control level and A1C are reviewed.
CV system is examined. A stress test should be performed in patients with diabetes belonging to the following groups;
1. All patients over 35 years of age
2. Patients over 25 years old and who have type 2 diabetes for more than 10 years and type 1 diabetes more than 15 years
3. Diabetic patients at risk for CAD
4. Patients with peripheral vascular disease, microvascular disease and autonomous neuropathy
Neurological and musculoskeletal examination, foot examination
Fundus examination
6.1.3 Glycemic Regulation in Exercise
Plasma glucose levels are to be monitored to see glycemic changes with exercise. PG monitorization allows to take necessary
measures to avoid hypoglycemia in diabetic patients treated with insulin or insulin secretogogues.
1. Physical activity and increased body temperature may increase insulin actions.
2. The patient must avoid exercise unless he/she has rapidly available source of CH (glucose tablets, glucose gels, cube sugar,
juice), especially when insulin reaches its peak level.
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3. A reduction in insulin dosage is often required before exercise.
4. Exercise decreases PG levels up to 24 hours.
5. If PG<100 mg/dL 15 g CH (i.e. one fruit, a slice of bread) should be eaten before exercise.
6. If PG>250 mg/dL and keton test is positive exercise should not be performed until ketones disappeared.
Types and timing of exercise
The aerobic exercises (brisk walking, jogging and swimming) should be preferred. On the other hand, some sports such as deep water
diving and high altitude solo flying are not recommended. Table 6.1 exhibits the examples of activities in an adult of 70 kg body weight
for energy expenditure of 150 kcal.
Table 6.1 The examples of activities in adults for 150 kcal energy
expenditure
Type of exercise
Distance (km)
Duration (minutes)
Walking
5
40
Bicycling
8
30
Dance and table tennis
-
30
Swimming and basketball
-
20
Skipping rope
Jogging
Climbing up stairs
-
15
2.5
15
-
15
Exercise while stomach is empty or soon after a meal may be harmful. There is no consensus on the subject that what time of the day
would be better to do exercise. Although it would be determined by the patient's conditions, en exercise performed one hour after the
dinner would be effective to reduce PPG and the next morning FPG, especially in patients with type 2 diabetes.
6.2 EXERCISE RELATED PROBLEMS
6.2.1 General Health Problems
Sensory and vascular problems
If there is any suspicion, it is recommended the feet should be checked for trauma, infection and ulcers.
Diabetes identity
All diabetic patients should wear a visible marker providing medical information such as jewelry, either a bracelet or necklace, or carry
on an ID card.
Discontinuing the exercise
Exercise should be discontinued immediately in case of presence of fatigue or the following findings;
1. Dizziness and faintness
2. Discomfort, tightness or pain in the chest
3. Unexpected and severe shortness of breath
6.2.2 Contraindications of Exercise
Exercise may be harmful in the following conditions;
1.Poorly controlled glycemia levels (<80 mg/dL or >250 mg/dL)
2. Neuropathy with loss of sensory
3. CVD
4. Proliferative retinopathy
5. Hypoglycemia unawareness
32
Exerc›se and Physical Activity in Diabetes
Turk JEM 2010; 14: Suppl 30-2
SEMT RECOMMENDATIONS FOR EXERCISE AND PHYSICAL ACTIVITY IN DIABETES
1. Increased physical activity in patients with diabetes facilitates controlling PG and lipid levels, and BP.
2. Before beginning any exercise program aiming to increase physical activity, patients with diabetes should be investigated
carefully for potential side effects or contraindications of exercise. A stress test (exercise ECG) should be performed in
patients with sedentary life style and at high risk of CVD before starting an exercise program (Class D, evidence-based consensus).
3. Exercise should be individualized according to personal requirements, limitations and individual performance (Class D,
evidence-based consensus).
4. Patients with prediabetes and diabetes (especially type 2) should perform moderate physical activity (brisk walking) at least
150 minutes per week in addition to caloric restriction planned for weight loss [Class B, Level 2 evidence (1)].
5. Exercise program should be performed at least 3 days per week not more than 2 days apart from each other [For type 1
diabetic patients: Class C, Level 3 evidence (2); For type 2 diabetic patients: Class A, Level 1 evidence (3)].
6. If there is no contraindication, patients with diabetes should be advised to perform light resistance exercises 3 days per
week [Class D, Level 2 evidence (4,5)].
7. Exercise program should be organized by an exercise specialist in accordance with individual requirements, and
conducted under the supervision of experts at the beginning (Class D, evidence-based consensus).
8. The patient is recommended to monitor heart rate by himself during exercise and keep it 60-75% of maximal heart rate
(Maximal heart rate = 220 – age). Heart rate during exercise can be adjusted individually according to the heart rate in rest
(Class D, evidence-based consensus).
9. Warm-up and cool-down exercises should not be neglected before and after the exercise session (Class D, evidencebased consensus).
REFERENCES
1. Sigal RJ, Kenny GP, Boulé NG, et al. Effects of aerobic exercise training, resistance exercise, or both on glycemic control in type 2 diabetes: a randomized
trial. Ann Intern Med 2007;147:357-69.
2. Moy CS, Songer TJ, LaPorte RE, et al. Insulin-dependent diabetes mellitus, physical activity, and death. Am J Epidemiol1993;137:74-81.
3. Snowling NJ, Hopkins WG. Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: a
meta-analysis. Diabetes Care 2006;29:2518-27.
4. Castaneda C, Layne JE, Munoz-Orians L, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with
type 2 diabetes. Diabetes Care 2002;25:2335-41.
5. Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care
2002;25:1729-36.
07
PRINCIPLES OF ORAL ANTIDIABETIC AND
INSULINOMIMETIC DRUG THERAPY
Oral antidiabetic drugs (OADs) are being used in addition to lifestyle recommendations (MNT and physical activity) in type 2 diabetes.
OADs are contraindicated in pregnancy.
Current OADs include insulin secretagogues, insulin sensitizers and alpha-glucosidase inhibitors. Also newly developed
“insulinomimetic” drugs, some of which can be used by oral administration, will find a wide application area in the treatment of type
2 diabetes.
7. 1. INSULIN SECRETAGOGUES
This group includes sulfonylureas, that increase secretion of insulin from pancreatic β-cells, and glinides, that has a mechanism of
action similar to sulfonylureas, but shorter duration of action (Table 7.1).
Table 7.1 Insulin secretagogues
Generic name
Trade name
Daily dose
Timing of intake
Two times in a day, with
breakfast and dinner
Once in a day, before
or with breakfast
A. Sulfonylureas (Second generation sulfonylureas)
Glipizide
Minidiab 5 mg tb
2.5-40 mg
Glipizide controlled
release form
Glucotrol XL 5, 10 mg tb
5-20 mg
Gliclazide
Diamicron, Betanorm, Oramikron,
Glumikron, Glikron 80 mg tb
Diamicron MR,
Betanorm MR, Efikas 30 mg tb
80-240 mg
1.25-20 mg
Glibornurid
Gliben, Dianorm 5 mg;
Diyaben 3.5, 5 mg tb
Amaryl, Diaglin, Diameprid, Glimax,
Glirid, Sanprid 1, 2, 3, 4 mg; Mepiriks 1, 2, 3 mg tb
Glutril 25 mg tb
12.5-75 mg
Gliquidone
Glurenorm 30 mg tb
15-120 mg
Gliclazide modified
release form
Glibenclamide
Glimepiride
30-90 mg
1-8 mg
B. Glinides (Meglitinides: Short-acting secretagogues)
Repaglinide
Novonorm, Novade 0.5, 1, 2 mg tb
0.5-16 mg
Nateglinide
60-360 mg
Starlix, Incuria; Teglix 120 mg tb
33
One or two times in a day,
with breakfast (and dinner if needed)
Once in a day,
before or with breakfast
One or two times in a day, with
breakfast (and dinner if needed)
One or two times in a day, before or with
breakfast (and dinner if needed)
One or two times in a day, in breakfast
(and dinner if needed)
One or two times in a day, with breakfast
(and dinner if needed)
Three times in a day, just before main
meals
Three times in a day, just before main
meals
34
Turk JEM 2010; 14: Suppl 33-9
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy
7.1.1 Side Effects
Hypoglycemia
Weight gain
Allergy
Skin rashes
Alcohol flushing (especially seen with chlorpropamide which is not widely used nowadays because of the long duration of action)
Hepatotoxicity
Hematological toxicity (agranulocytosis, bone marrow aplasia)
7.1.2 Contraindications
Type 1 diabetes mellitus (differential diagnosis should carefully be performed with LADA)
Secondary diabetes (pancreatic diseases and other causes)
Hyperglycemic emergencies (DKA, HHS)
Pregnancy
Trauma, stress, operations
Severe infections
Sulfonylurea allergy
Predisposition to severe hypoglycemia
Liver and kidney failure
7.1.3 Drug Interactions
Numerous drugs used in patients with diabetes can change the effect sulphonylureas with a variety of mechanisms. The dosage of
sulphonylureas may need to be adjusted when using concomitantly with drugs shown in Table 7.2.
7.2 INSULIN SENSITIZERS
Two classes of drugs are used as insulin sensitizers: biguanides and thiazolidinediones (TZD, glitazons). Biguanides increase insulin
sensitivity in the liver level and TZDs in the adipose tissue.
Table 7.2 Interactions between sulphonylureas and other drugs
Drugs inducing hypoglycemia
Drugs inducing hyperglycemia
Drugs linked to albumin:
Aspirin, Fibrates, Trimethoprim
Drugs increasing metabolism of SUs:
Barbiturates, Rifampin
Competitive inhibitors of SUs metabolism:
Alcohol, H2-receptor blockers, Anticoagulants
Drugs antagonizing actions of SUs:
β-blockers
Drugs inhibiting renal excretion of SUs:
Probenecid, Allopurinol
Drugs blocking insulin secretion/action:
Diuretics, β-blockers, Corticosteroids, Estrogenes, Phenytoine
Counterregulatory antagonists of SUs:
β-blockers, Sympatholytics
SUs; sulfonylureas.
Turk JEM 2010; 14: Suppl 33-9
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy
35
Table 7.3 Insulin sensitizers
Generic name
Trade name
Daily dose
Timing of intake
A. Biguanides
Metformin HCl
Metformin HCl
extended release(*)
Glucophage, Glukofen, Matofin 500, 850, 1000 mg;
Glifor, Diaformin 850, 1000 mg;
Gluformin retard, Glukofen retard 850 mg tb
Glucophage XR 500, 1000 mg tb;
Glumetza extended release 1000 mg tb
500-2550 mg
One to three times in a day,
with or after meal
500-2000 mg
meal, preferably dinner
Once in a day, with or after
B. Thiazolidinediones (TZDs, Glitazones)(**)
(*)
Rosiglitazone(**)
Avandia 4 mg; Rosenda, Rosvel, Rositaz 4, 8 mg tb
2-8 mg
One or two times daily, with
meals or regardless of meal intake
Pioglitazone
Actos 15, 30 mg; Dropia, Glifix, Piogtan,
Piondia 15, 30, 45 mg tb
15-45 mg
Once in a day, regardless of meal
intake
Not available in Turkey.
Concerning cardiovascular safety, in Sept. 2010, the other agent of the TZD group, rosiglitazone has been banned by the Ministry of Health, Turkey
(**)
7.2.1 Side Effects of Metformin
Gastrointestinal irritation (side effects such as floating and distention are usually temporary)
Abdominal cramps
Diarrhea
Metallic taste in mouth
Vitamin B12 deficiency (Vitamin B12 replacement may be necessary)
Lactic acidosis (incidence <1/100.000 patient year)
Renal dysfunction (serum creatinine >1.4 mg/dL)
7.2.2 Contraindications of Metformin
Hepatic dysfunction
History of lactic acidosis
Chronic alcoholism
CV collapse, acute myocardial infarction
Ketonemia and ketonuria
Congestive heart failure
Chronic (obstructive) pulmonary diseases
Peripheral vascular diseases
Major surgical procedures
Pregnant and lactating women
Advanced age (according to some authors >80 years)
Edema
7.2.3 Side effects of Thiazolidinediones
Anemia
Congestive heart failure (especially when used concomitantly with intensive insulin therapy)
Fluid retention
Weight gain
Increase in LDL-cholesterol levels (higher with rosiglitazone)
Increase in aminotranpherase levels (not with new TZDs)
This group of drugs is still being questioned in terms of increased risk of cardiovascular events (fatal and non-fatal MI). In 2007, the
published results of serial meta-analyses, especially related to the rosiglitazone, were inconsistent with each other. ‘Rosiglitazone
Evaluated for Cardiovascular Outcome and Regulation of Glycaemia in Diabetes (RECORD)’ study results, declared in June 2009,
demonstrated that rosiglitazone was not different from other OADs (sulfonylureas and metformin) in terms of cardiovascular
36
Turk JEM 2010; 14: Suppl 33-9
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy
morbidity and mortality. However, concerning cardiovascular safety, the other agent of the TZD group, rosiglitazone has been banned
by the Ministry of Health, Turkey. The decision is given following the advice by the European Union in Sept. 24, 2010. Despite of strict
limitations in use this drug has not been banned by the FDA.
TZDs may exacerbate orbitopathy in patients with Graves disease.
Also they have been reported to lead to an increase in fracture risk in postmenopausal women and elderly men.
Thiazolidinediones should not be used in the following groups of patients;
7.2.4 Contraindications of Thiazolidinediones
Cases with high alanine aminotransferase levels (ALT >2.5 X upper limit of normal)
New York Heart Association Class I-IV congestive heart failure patients
Chronic severe renal failure
Pregnancy
Patients with type 1 diabetes
Patients at risk for macular edema
Adolescents and children
7.3 ALPHA GLUCOSIDASE INHIBITORS
This group of drugs delays intestinal absorption of glucose. Particularly they are effective in the treatment of postprandial
hyperglycemia. Of the drugs belonging to this group only acarbose is commercially available in Turkey (Table 7.4).
Abdominal distention, dyspepsia, diarrhea
Table 7.4 Alpha glycosidase inhibitors
Generic name
Trade name
Daily dose
Timing of intake
Acarbose
Acaris, Arokan, Glucobay, Glynose 50, 100 mg tb
25-300 mg
Three times in a day with the first bite of food
Miglitol(*)
Glyset 50, 100 mg tb
25-300 mg
One to three times in a day, at the beginning of the
meal
(*)
Not available in Turkey
7.3.1 Side Effects of Alpha-Glycosidase Inhibitors
Reversible increase in liver enzymes
Rarely can cause iron deficiency anemia
This group of drugs should not be used in the following cases;
7.3.2 Contraindications of Alpha-Glucosidase Inhibitors
Inflammatory bowel diseases
Chronic gastrointestinal ulcerations
Malabsorption
Partial bowel obstruction
Cirrhosis
Pregnancy
Lactation
Diabetic patients under 18 years old
7.4 INSULINOMIMETIC DRUGS
This new group comprises of amylin agonists, incretin mimetic drugs and newly developing agents. In general, their mechanism of
action depends on increasing endogenous insulin secretion (Table 7.5).
Turk JEM 2010; 14: Suppl 33-9
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy
37
7.4.1 Amylin Analogs
Pramlintide, a synthetic analog of β-cell hormone, amylin is used as a support to insulin treatment in type 1 and type 2 diabetes in the
United States. It is effective on postprandial glycemia and requires s.c. injection three times a day.
One of the significant defects in type 2 diabetes is the reduction of level and/or effects of incretin hormones (GLP-1 and GIP), and that
7.4.2 Incretin-Based Drugs (Incretin Mimetics)
glucagon secretion is not inhibited. The drugs belonging to this group have been developed to mimic incretin hormones or to inhibit
degradation of incretin. They do not cause hypoglycemia because they exert a glucose-dependent effect.
A. Incretinmimetics and GLP-1 Agonists
They mimic the endogenous incretin hormone glucagon-like peptide-1 (GLP-1). Example: GLP-1 receptor (GLP-1R) agonists (Exendin-4:
Exenatide, Exenatide LAR, and Liraglutide) are injected s.c.
Exenatide: It is used in the United States since 2005 and in EU countries since 2006. Exenatide, used in patients with type 2 diabetes,
became available in our country in 2010. It requires twice daily injections, is more effective in reducing postprandial glycemia, and in
contrast to other anti-hyperglycemic drugs and insulin, it provides a weight loss of approximately 2 to 4 kg. It is recommended to be
used in combination with metformin, sulfonylureas and TZDs in patients with BMI ≥35 kg/m2. But it should not be used in obese type
2 diabetic patients under the age of 18 due to safety concerns. If the patients treated with exenatide could not reach 1% reduction in
A1C after one-year treatment and if at least a 3% reduction of body weight is not obtained within 6 months, the therapy should be
discontinued.
The major side effect of these drugs is nausea. Post-marketing reports have been reported increased number of cases developed
acute pancreatitis in patients using exenatide. However, this issue remains controversial because diabetes itself can also cause
pancreatitis. Based on these reports FDA requested for an additional warning to insert to the drug package in 2008, and
the physicians have been advised to discontinue the treatment in case of suspicion of pancreatitis (severe abdominal pain,
nausea, vomiting, increase in amylase/lipase levels and any radiological sign indicating pancreatitis).
Liraglutide: This drug, available in foreign countries (in 2009 in some EU countries), is effective in similar way with exenatide, and
requires one s.c. injection per day. Indications and side-effects are similar to exenatide.
Exenatide LAR, designed to be given by injection once per week, has similar effects, however, it has not been approved for clinical use yet.
B. Incretin enhancer agents (DPP-4 inhibitors)
This group of agents inhibits the degradation of endogenous incretins (GLP-1 and GIP). Example: Dipeptidyl peptidase-4 (DPP-4)
inhibitors (sitagliptin, vildagliptin and saxagliptin) have been developed to be used with oral route. DPP-4 inhibitors can be used
concomitantly with sulfonylureas, metformin and TZDs. Generally they are used once (or twice if needed) a day and they are weight
neutral like metformin and acarbose. Sitagliptin was brought into use in 2006 in Europe and in USA and at the end of 2008 in our
country. Vildagliptin and Saxagliptin have been approved for use in 2009 in Europe and in 2010 in our country.
In clinical trials, no important side effect of these drugs has been reported. But some patients developed flu-like symptoms
after sitagliptin was brought to market. Also FDA requested a warning in package insert in September 2009 after several acute
pancreatitis cases had been reported.
7.5 GLYCEMIC RESPONSE TO ANTI-HYPERGLYCEMIC DRUGS USED IN MONOTHERAPY
The effects of various drug groups, when they are used alone, on glycemia and A1C in patients with type 2 diabetes are seen in Table
7.6. Initial good responses progressively decrease with the duration of diabetes, and the combinations are considered. The response
to TZD drugs begins after 10 to 12 days, and continues about 1 to 3 weeks after withdrawal of the drug.
38
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Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy
Table 7.5 Insulinomimetic drugs
Group
Generic name
Trade name
Daily dose
Timing of intak
lIncretinmimetics
Exenatide
Byetta 5, 10 μg cartridges
Two times a day 5 -10 μg
Two times in a day, 0-60
minutes before breakfast and
dinner, s.c. injection
Liraglutide(*)
Victoza 6 mg/mL cartridges
Once in a day 1.2-1.8 mg
Pramlintide acetate(*)
Symlin vial or cartridge
In type 1 diabetes 15-60 μg
(2.5-10 u)(**) three times a day,
in type 2 diabetes 60-120
μg (5-20 u)(**) three times a day
Once in a day, regardless of meal
intake, s.c. injection
Amylin mimetics
DPP-4 inhibitors
Two-three times a day, regardless
of meals, s.c. injection.
Sitagliptin phosphate
monohydrate
Januvia 100 mg tb
50-200 mg
Once a day, before or with breakfast
Vildagliptin
Galvus 50 mg tb
50-100 mg
Onglyza 2.5-5 mg tb
0.5-1 mg
Once or twice in a day, regardless of
meals
Once in a day, before or with
breakfast
(*)
Saxagliptin
(*)
Not available in Turkey
Insulin doses should be decreased by %50 whereas the amount of carbohydrates to be increased
(**)
Table 7.6 Glycemic responses to antihyperglycemic drugs in monotherapy of type 2 diabetes
Decrease in FPG (mg/dL)
Decrease in A1C (%)
Life style modifications
40-60
1.0-2.0
Metformin
50
1.5
Insulin
50-80
1.5-2.5
Sulfonylureas
40-60
1.0-2.0
Glinides
30
1.0-1.5(*)
Thiazolidinediones
25-55
0.5-1.4
Alpha-glycosidase inhibitors
20-30
0.5-0.7
Pramlintide/Exenatide/Liraglutide(**)
20-30
0.5-1.0
DPP-4 inhibitors
20-30
0.5-1.0
(*)
(**)
Repaglinide is more effective than Nateglinide. Not available in Turkey
OAD; oral antidiabetic drug, FPG; fasting plasma glucose, A1C; Haemoglobin A1c
‘Feld S. Endocr Pract. 2002;8(Suppl. 1):41-82’, ‘Nathan DM et al. Diabetes Care 2006;29:1963-72.
7.6 CURRENTLY AVAILABLE ORAL ANTIDIABETIC DRUG COMBINATIONS
Monotherapies are replaced by combination therapies in type 2 diabetes as a result of natural course of the disease. Insulin
sensitizers are insulin secretagogues are combined in accordance with the pathophysiological basis of the disease. Metformin
combinations should be the most preferred combination considering the cost and duration of experience. Metformin is usually
combined with sulfonylureas according to the characteristics of patients. Also it is possible to combine insulin sensitizer sub-groups
(e.g. rosiglitazone plus metformin). Different combinations of OAD group drugs were produced in order to improve the compliance of
patient to treatment (Table 7.7).
Turk JEM 2010; 14: Suppl 33-9
Principles of Oral Antidiabetic and Insulinomimetic Drug Therapy
Table 7.7 Available oral antidiabetic drug combinations
Generic name
Trade name
Daily dose
Timing of intake
Glibenclamide/Metformin HCl
Metformin 1.25/250 mg(*)
Glucovance tb (Glibenclamide/
2.5/500 mg, 5/500 mg)
2.5/500 mg-20/2000 mg
meals
Once or twice a day, with
Glipizide/Metformin HCl(*)
Metaglip tb (Glipizide/Metformin
2.5/250 mg, 5/250 mg, 5/500 mg)
2.5/250 mg-10/2000 mg
Once or twice a day, with meals
Rosiglitazone/Metformin HCl(**)
Avandamet tb (Rosiglitazone /Metformin
1/500 mg, 2/500 mg,4/500 mg(*)
1/500 mg-8/2000 mg
Once or twice a day, with meals
Rosiglitazone/Glimepiride(*)
Avandaryl tb (Rosiglitazone/ )
Glimepiride 4/1 mg, 4/2 mg, 8/4 mg
4/1 mg-8/4 mg
Once or twice a day, with meals
Pioglitazone/Metformin HCl(*)
Actos plus Met tb (Pioglitazone /
Metformin 15/1000 mg)
Competact tb (Pioglitazone /
Metformin 15/850 mg)
15/1000 mg-30/2000 mg
Once or twice a day, with meals
Pioglitazone/Glimepiride(*)’
Dueact tb (Pioglitazone/
Glimepiride 30/2 mg, 30/4 mg)
15/2 mg-30/4 mg
Once a day, with a main meal
Repaglinide/Metformin(*)’
PrandiMet tb (Repaglinide/
Metformin 1/500 mg, 2/500 mg)
2/1000 mg-6/2000 mg
2-3 times a day, just before or at a
main meal
Sitagliptin/Metformin(*)’
Janumet tb (Sitagliptin/
Metformin 50/850 mg, 50/1000 mg)
50/500 mg - 100/2000 mg
Two times daily, with meals
Vildagliptin/Metformin(*)
Euchres tb (Vildagliptin/
Metformin 50/500 mg, 50/1000 mg)
50/500 mg - 100/2000 mg
Two times daily, with meals or
after meals.
(*)
Not available in Turkey.
Rosiglitazone/Metformin HCl combination has been banned by the Ministry of Health Turkey due to cardiovascular safety.
(**)
39
08
PRINCIPLES OF INSULIN THERAPY
8.1 GENERAL PRINCIPLES
8.1.1 Indications of Insulin Therapy
The classical type 1 diabetes mellitus and LADA cases
Hyperglycemic emergencies (DKA, HHS)
Some cases of type 2 diabetes mellitus
GDM not controlled with diet and physical activity
8.1.2 Mechanism of Insulin Action
Stimulates entry of glucose into the cells
Increases glycogen storage
Inhibits hepatic glucose output
Inhibits the degradation of fat and protein
8.1.3 Insulin Sources
Recombinant DNA technique (human insulin, insulin analogues)
Traditional bovine and porcine insulins
Semi-synthetic insulin obtained from porcine insulin (not used in our country)
8.1.4 Insulin Absorption
Insulin absorption may be different on individual basis due to the reasons listed below:
Insulin source: Compared to animal insulin, human insulin has a shorter duration of action.
There are some differences depending on manufacturer (NovoNordisk, Eli Lilly and Sanofi-Aventis)
Injection site: From the fastest to the slowest absorbing site: insulin could be injected s.c. into upper abdomen (epigastrium), upper
arms, thighs, and buttocks.
Environmental temperature: The warm temperature is associated with higher insulin absorption compared to cold temperature.
Exercise, systemic fever and massage to the injection site increase insulin absorption.
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The Principles of Insulin Therapy
41
8.1.5 Insulin Preparations
A. Insulin Strength
Insulin preparations available in Turkey and used globally contain 100 IU insulin in 1 mL and called as ‘U-100-insulins’. Also ‘U-500
insulins’ can be used in patients with marked insulin resistance and insulin requirement in some European countries and USA).
B. Types and Action Profile of Insulins
The following table shows currently available insulin preparations and their action profiles (Table 8.1). Although insulin does not pass
through the placenta, there is not enough data available about the use of long-acting insulin analogs in pregnancy.
Table 8.1 Types and action profiles of insulin preparations
Insulin type
Generic name
Trade name
Onset of
action (min)
Peak action (h)
Duration
of action (h)
Short-acting (Regular) insulin
Human regular insulin
Actrapid HM,
Humulin R
30-60
2-4
5-8
Rapid-acting insulins
(Prandial analogs)
Glulisine insulin
Lispro insulin
Aspart insulin
Apidra
Humalog
NovoRapid
15
0.5-1.5
3- 5
Intermediate -acting (NPH) insulin
NPH human insulin
Humulin N
Insulatard HM
60 -180
8
12 - 16
Long-acting insulins(*)
(Basal analogs)
Glargine insulin
Detemir insulin
Lantus
Levemir
60
Peakless(**)
20-26
Premixed (biphasic) human insulin
(Regular + NPH)
30% regular + 70%
NPH human insulin
Humulin M 70/30
Mixtard HM 30
30 - 60
Variable
10 - 16
Premixed analogs
(Biphasic lispro + NPL)
25% insulin lispro +
75% insulin lispro protamin
50% insulin lispro +
50% insulin lispro protamin
30% insulin aspart +
Humalog Mix25
10-15
Variable
10-16
10-15
Variable
10-16
Premixed analogs
Humalog Mix50
NovoMix30
(*)
Long-acting (basal) analogs are not equivalent in efficiency. When used as basal insulin the requirement for glargine is at least 10 to 15% less than that for detemir.
Insulin detemir shows slightly less day to day variation and less weight gain effect (0.5-1 kg) than glargine.
The duration of action of insulin detemir shortens at low doses, therefore especially type 1 diabetes patients with <0.35 IU/kg/day basal insulin requirement may need a second basal dose
8.1.6 Routes of Insulin Delivery
Insulin is normally injected subcutaneously.
In case of emergency rapid- or short-acting insulins can be given intramuscularly or intravenously.
8.1.7 Insulin Dose Adjustment
Aim
To mimic normal basal insulin secretion in people with type 1 diabetes (insulin replacement)
Some cases with type 2 diabetes may need (basal) insulin support, and the need for insulin replacement arises over time.
8.1.8 Insulin Indications in Type 2 Diabetes
Failing to obtain good metabolic control with submaximal doses of OADs
Excessive weight loss
Severe hypoglycemia symptoms
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Turk JEM 2010; 14: Suppl 40-6
Acute MI
Acute diseases with fever, systemic diseases
Hyperosmolar hyperglycemic state (HHS) and ketotic coma (DKA)
Major surgical operation
Pregnancy and lactation
Kidney or liver failure
Severe allergy or side-effects to any OADs
Severe insulin resistance (with acanthosis nigricans)
8.1.9 Complications of ‹nsulin Treatment
Hypoglycemia: The main and most frequent complication during therapy with insulin is hypoglycemia. It is associated with strict
glycemic control and longer duration of diabetes. It is more frequent in type 1 diabetic patients treated with basal-bolus insulin
regimen. In DCCT study the frequency of hypoglycemia is 3 times higher in intensive insulin therapy group compared to conventional
treatment group. Risk of hypoglycemia with insulin analogues is slightly lower than human insulins.
Weight gain: At the beginning of insulin therapy few kilograms of weight gain is expected due to the regaining of previously lost
adipose and muscle tissue, and the disappearance of glucosuria. Then the fear of hypoglycemia and unbalanced diet may cause
continued weight gain.
Massive hepatomegaly: It is associated with excessive glycogen storage in the liver, and is rare nowadays.
Edema: Increased sodium reabsorption and decreased osmotic diuresis due to insulin may increase body fluid volume at the
beginning of treatment.
Anti-insulin antibodies and allergy to insulin: Both are rare complications nowadays with availability of human insulins and new
insulin analogues.
Lipoatrophy: It is a rare immunological event with newer pure insulins.
Lipohypertrophy: It occurs when the same injection site is used too frequently, and can be treated by rotating the injection sites.
Bleeding, leakage and pain: Bleeding can be prevented by administrating injection to a region which is not rich in capillary vessels.
Leakage is minimized by using long needle and by releasing the pinch 5 to 10 seconds before removing the needle from the skin.
Especially acid insulins, such as glargine, may cause slight and unimportant pain at the injection site.
Relationships between hyperinsulinemia and insulin resistance and risk of atherosclerosis and cancer: Although experimental
studies have pointed to the relationship between atherosclerosis and hyperinsulinemia, clinical evidence is not sufficient.
Insulin is an anabolic hormone. Insulin receptors are structurally similar to that of insulin-like growth hormone (e.g. IGF-1). The
power of insulin correlates with its receptor affinity. Powerful insulins have higher affinity for insulin and IGF-1 receptors. Therefore the
relationship between insulin and cancer risk has been considered for many years. However, because of conflicting data based on
cross-sectional studies, the discussions about this issue still continue. But randomized clinical studies on this issue are lacking.
8.2 INSULIN TREATMENT PROTOCOLS
8.2.1 Basal-Bolus Insulin Replacement
Basal-bolus insulin replacement should be recommended in type 1 diabetes, GDM that cannot be controlled with diet and type 2
diabetes with decreased endogenous insulin reserve. It can be applied in the following ways:
A. Multiple Subcutaneous Insulin Injections (MSII)
Rapid/short-acting (bolus) insulin three times in a day preprandial plus intermediate/long-acting (basal) insulin (preferably in the
evening) as a single dose.
Rapid/short-acting (bolus) insulin three times in a day preprandial plus intermediate/long-acting (basal) insulin two times in a day.
Premixed (biphasic) insulin analogs should be considered in patients with type 2 diabetes who have difficulty to implement basal
bolus insulin therapy with two different insulin preparations.
B. Continuous Subcutaneous Insulin Infusion (CSII)
Continuous subcutaneous insulin infusion, using basal, bolus and adjustment doses via external pump, could be a solution to
improve glycemic control (see Chapter 10).
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The Principles of Insulin Therapy
43
8.2.2 Insulin Supplement Therapy
It is recommended in elderly patients with type 1 diabetes with complications or at high risk of hypoglycemia, GDM that cannot be
controlled with diet, and some cases with type 2 diabetes.
A. Biphasic Insulin Mixtures
Intermediate/long-acting + rapid/short-acting premixed insulins two times in a day: Premixed insulin preparations can be used.
Alternatively, patients may inject two different insulin.
B. Basal insulin support
Intermediate/long-acting (basal) insulin support once or twice a day (in type 2 diabetic patients and some GDM cases). There is not
enough evidence about the safety of long-acting insulin analog during pregnancy, therefore glargine and detemir insulin should not
be used in cases of pregestational diabetes and GDM.
8.2.3 Insulin Dose Calculation and Adjustment
Initially it is adjusted per kilogram of body weight. Moreover, phenotype and physical activity status of individuals with diabetes, and
presence of diabetes complications should be taken into consideration. Recommendations for calculation of insulin dose are given in
Table 8.2. In general, maintenance of insulin dose for individuals with type 1 and type 2 diabetes is as follows:
Type 1 diabetes; 0.5-1.0 IU/kg/day
Type 2 diabetes; 0.3-1.5 IU/kg/day
In basal bolus insulin regimen about half of daily requirement (40-60%) is calculated as basal and the remaining half (40-60%) as
bolus dose.
Basal insulin support; 0.1-0.2 IU/kg/day can be given initially.
Insulin injection time
It depends on the type of insulin.
Rapid-acting insulins are administered 5 to 15 minutes and short-acting insulins 30 minutes before meal.
Insulin injection time can be changed according to blood glucose levels. For example, a meal may be delayed if preprandial PG level
is higher than the targeted value.
Insulin injections may be delayed to postprandial to avoid hypoglycemia in diabetic patients with extremely prolonged gastric
emptying time.
Table 8.2 Calculation of the insulin dose
Phenotype
Normal weight patients
Insulin dose (IU/kg/day)
Intense physical activity
0.3
Moderate physical activity
0.4
Mild physical activity
0.4
Obese patients
Intense physical activity
0.5
Moderate physical activity
0.6
Mild physical activity
Renal failure
- 0.2
0.8
Conditions with high risk of hypoglycemia
- 0.2
Frequent, binge eaters
+ 0.1
Newly onset type 1 diabetes (<30 years of age)
0.3
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Turk JEM 2010; 14: Suppl 40-6
8.2.4 Injection Methods
A. Insulin Pens
It allows safe and correct application of insulin, therefore it is more preferable. Most pens contain 300 IU (3 ml) of insulin and some of
them are disposable, while others use replaceable cartridges. Insulin pens are calibrated for 1 IU, moreover pens calibrated for 0.5 IU
are available for children. Insulin pen needles are in three lengths as 4 mm, 6 mm, 8 mm and 12 mm. Generally, 4, 6 or 8 mm
needles are used. Obese individuals may require 12 mm-length needles.
B. Insulin Syringes
This method is used less frequently in most developed countries as well as our country. Insulin syringes are available in three different
sizes; 0.3, 0.5, and 1 mL. They are calibrated for 1 IU, and syringes calibrated for 0.5 IU are available for children and for patients more
sensitive to insulin. In general syringes with 8 mm needles are in use but also 6 and 12 mm needles are available. Ten mL vials
(containing 1000 IU insulin) are used for syringes.
C. Insulin Pump
Continuous subcutaneous insulin infusion (CSII) or insulin pump therapy will be discussed in detail in the following sections (see Chapter
10 The Principles of CSII).
8.2.5 Insulin Storage Guidelines
Unopened vials and cartridges can be stored at 2-8oC in the refrigerator until the expiration date.
Opened vials and cartridges can be used at room temperature up to 30 days.
Intermediate/long-acting or premixed insulin preparations may lose their biological activity slightly 15 days after they have opened.
This should be considered if glycemic control begins to deteriorate although patient’s health condition has not changed.
8.2.6 Mixing of Insulin Preparations
Short-acting and NPH insulins should be used immediately after mixing (However, some authors suggest that these mixtures can be
kept in the refrigerator up to 2 weeks).
Glargine and detemir insulins should not be mixed with other insulins.
8.2.7 Drugs that Interact with Insulin
Given that some drugs in Table 8.3 may lead to hypoglycemia by increasing the effect of insulin whereas some others to hyperglycemia
by reducing the effect of it (some of them by inducing insulin resistance) they require insulin dose adjustments.
Turk JEM 2010; 14: Suppl 40-6
The Principles of Insulin Therapy
45
Table 8.3 Drugs that Interact with Insulin
A. Drugs increasing the hypoglycemic
effect and lowering glycemia
B. Drugs reducing the hypoglycemic
effect and increasing glycemia
β-blockers(*)
ACE-I
Alcohol
Anabolic steroids
Calcium
Chloroquine
Clofibrate
Clonidine
Disopyramide
Fluoxetine
Guanitidine
Lithium carbonate
Mebendezole
Monoamine oxidase inhibitors
OADs
Pentamidine(**)
Phenylbutazone
Piridoxine
Propoxyphene
Salicylate
Somatostatin analogs (Octreotide)
Sulfonamides
Sulphynpirazone
Tetracycline
Acetazolamide
Albuterol
Antiviral agents used in AIDS
Asparaginase
Calcitonin
Corticosteroids
Cyclophosphamide
Danazol
Dextrothyroxine
Diazoxide
Diltiazem
Diuretics
Dobutamine
Epinephrine
Estrogen hormones
Ethacrynic acid
Isoniazid
Lithium carbonate
Morphine sulphate
Niacin
Nicotine
Oral contraceptives
Phenytoin
Somatropin
Terbutaline
Thiazide diuretics
Thyroid hormones
(*)
They may delay the recovery from hypoglycemia.
Hypoglycemia is sometimes followed by hyperglycemia
(**)
SEMT APPROACHES TO INSULIN TREATMENT AND RECOMMENDATIONS
• Basal-bolus (intensive) insulin therapy should be preferred to provide glycemic control in adults with type 1 diabetes, and in
patients with type 2 diabetes whose beta cell reserves were depleted [For type 1 diabetic patients: Class A, Level 1A evidence;
For type 2 diabetic patients: Class D, evidence-based consensus].
• Insulin analogues are not superior to human insulin to obtain good glycemic control (A1C) [Class A, Level 1 evidence (2,3)].
• Basal insulin can be used together with rapid-acting insulin analogues (aspart, glulisine, lispro) to reduce the risk of
hypoglycemia and to provide PPG control while lowering A1C [Class B, Level 2 evidence (3,4)].
• Long-acting insulin analogues (glargine, detemir) can be used as an alternative to NPH insulin for basal insulin support [Class
B, Level 2 evidence (5-8)].
• Long-acting insulin analogues (glargine, detemir) should not be used in pregnancy (Class D, evidence-based consensus).
• It has been shown in clinical trials that the risks of severe hypoglycemia and nocturnal hypoglycemia with basal insulin
analogeus are slightly lower compared to NPH insulin:
- to reduce the risk of severe hypoglycemia [For glargine: Class B, Level 2 evidence (9); For detemir: Class C, Level 3 evidence (10)].
- to reduce the risk of nocturnal hypoglycemia [For glargine: Class B, Level 2 evidence (10); For detemir: Class D,
evidence-based consensus].
• All individuals with type 1 diabetes should be evaluated about the risk of hypoglycemia, be counseled about the risk and
prevention of insulin-induced hypoglycemia, and risk factors for severe hypoglycemia should be identified and addressed
(Class D, evidence-based consensus).
• In individuals with hypoglycemia unawareness, the following strategies should be implemented to attempt to regain
hypoglycemia awareness:
- Increased frequency of SMBG, including periodic assessment at night (Class D, evidence-based consensus).
Less strict glycemic control for a while (higher glycemia and A1C levels are targeted) until the patient is recovered [Class C, Level 3
evidence (11,12)].
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Turk JEM 2010; 14: Suppl 40-6
REFERENCES
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of
long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
2. Plank J, Siebenhofer A, Berghold A, et al. Systematic review and meta-analysis of short-acting insulin analogues in patients with diabetes mellitus. Arch
Intern Med 2005;165:1337-44.
3. Singh SR, Ahmad F, Lal A, et al. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 2009;180:385-97.
4. Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database
Syst Rev 2006;(2):CD003287.
5. Warren E, Weatherley-Jones E, Chilcott J, et al. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine. Health Technol
Assess 2004;8:1-57.
6. Wang F, Carabino JM, Vergara CM. Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther 2003;25:1541-77.
7. Dunn CJ, Plosker GL, Keating GM, et al. Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs 2003;63:1743-78.
8. Chapman TM, Perry CM. Insulin detemir: a review of its use in the management of type 1 and 2 diabetes mellitus. Drugs 2004;64:2577-95.
9. Mullins P, Sharplin P, Yki-Jarvinen H, et al. Negative binomial meta-regression analysis of combined glycosylated hemoglobin and hypoglycemia outcomes
across eleven phase III and IV studies of insulin glargine compared with neutral protamine Hagedorn insulin in type 1 and type 2 diabetes mellitus. Clin Ther
2007;29:1607-19.
10. Goldman-Levine JD, Lee KW. Insulin detemir – a new basal insulin analog. Ann Pharmacother 2005;39:502-7.
11. Liu D, McManus RM, Ryan EA. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent
diabetes mellitus after 3 months of less strict glycaemic control. Clin Invest Med 1996;19:71-82.
12. Lingenfelser T, Buettner U, Martin J, et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term
avoidance of hypoglycemia in IDDM. Diabetes Care 1995;18:321-5.
09
CURRENT APPROACH TO THE TREATMENT OF TYPE 2 DIABETES
The therapeutic approach to patients with type 2 diabetes has changed profoundly in recent years. According to new approaches
lower glycemic control targets as well as early onset of insulin and combination therapies instead of the traditional gradual therapy
were adopted. Two current (IDF and ADA/EASD) approaches widely accepted in the treatment of type 2 diabetes, are summarized
below, and moreover the SEMT approach is described in detail.
9.1 THE IDF AND THE ADA/EASD RECOMMENDATIONS
9.1.1 The IDF Recommendations
“Global Partnership Group in the Treatment of Type 2 Diabetes”, established by IDF Europe in 2005 to improve the compliance
of patients with type 2 diabetes to therapy and to reduce the morbidity and mortality due to diabetes by decreasing A1C, has
recommended to treat type 2 diabetes earlier and more aggressively. Accordingly;
to achieve a target A1C of ≤ 6.5% within the first six months of treatment,
to start OAD combinations, and insulin therapy if needed in patients with baseline A1C >9%,
to start OAD monotherapy based on the underlying pathology (insulin secretagogue or insulin sensitizer) in patients with baseline A1C <9%,
to add a second OAD or an insulin if A1C goal has not been achieved after three months.
9.1.2 The ADA/EASD Recommendations
“The Guide for Management of Type 2 Diabetes”, published by the ADA and the EASD in 2006, summarized the treatment algorithm
to be undertaken for patients with type 2 diabetes;
to keep a target A1C of <7%, fasting glycemia of 70-130 mg/dL and postprandial peak glycemia of <180 mg/dL.
to start metformin (if no contraindication) simultaneously with lifestyle modification in newly diagnosed type 2 diabetes patients.
to add either a sulfonylurea, a TZD or basal insulin to treatment if a target A1C has not been achieved within 2 to 3 months.
to add a third OAD or switch to intensive insulin therapy if a second-line treatment is insufficient.
to switch to basal-bolus insulin therapy if glycemic control has not been achieved.
to start a treatment with insulin in patients with baseline A1C of >8.5% and severe hyperglycemia symptoms.
ADA/EASD recommends using medications with proven efficacy and safety in long-term experience (sulfonylureas and basal insulin)
or alternatively somewhat new drugs with less sufficient experience (pioglitazone and exenatide) as second-line therapy if metformin
plus lifestyle modifications fails and emphasizes to give the priority to the former in 2009 recommendations. Intensive insulin is
recommended as the third line therapy in case second-line therapy is insufficient.
47
48
Turk JEM 2010; 14: Suppl 47-52
Current Approach to the Treatment of Type 2 Diabetes
9.2 SEMT TREATMENT ALGORITHM IN PATIENTS WITH TYPE 2 DIABETES
In the light of current approaches and also taking into account the realities of our country, SEMT Diabetes Study Group has been
identified "Type 2 Diabetes Treatment Algorithm". This algorithm is shown in Figure 9.1. The outlines of this algorithm are summarized
below in terms of glycemic control targets and treatment choice.
Newly diagnosed type 2 diabetes mellitus
Clinical evaluation + Lifestyle modifications
A1C ≥10% or metabolic decompensation or severe hyperglycemic symptoms. A1C <10%
Insulin ± MET
MET
SU2,3
First step therapy
A1C <8.5%
A1C >6.5%1
at 3 months
MET + Antidiabetic combinations
MET + SU
MET + Glinide
MET + TZD4
MET + DPP-4 inh.
MET + AGI
MET + GLP-1A5
A1C ≥8.5%
MET + Insulin combinations
1
A1C >6.5% every 3-6
months
MET + Basal insulin
MET + Premixed insulin
n
MET + Bolus insulin
Second step therapy
A1C
>6.5%1 every 3-6
months
Intensive insulin therapy
‘Basal-bolus insulin + MET’ or ‘CSII (insulin pump) treatment6
Third step therapy
A1C; Glycosylated HbA1c, MET; Metformin, SU; Sulfonylureas, TZD; Thiazolidinediones, DPP-4 inh; Dipeptidyl 3
peptidase-4 inhibitors, GLP-1A; Glucagon like peptide 1 analogues, AGI; Alpha glucosidase inhibitors.
1
Individual A1C should be considered in some cases.
SU can be started in patients who are thin at diagnosis or when MET contraindicated.
Other OADs can be started according to patients’ characteristics.
4
The risk of edema, CHF and fracture should be taken into consideration in patients on TZD.
5
GLP-1A should be preferred in patients that are desired weight loss.
6
It may be considered in trained and willing patients in whom glycemic control cannot be achieved with basal bolus
insulin therapy.
2
3
Figure 9.1 Treatment algorithm for patients with type 2 diabetes
9.2.1 Targets of Glycemic Control
Glycemic targets should be tailored to the individual with type 2 diabetes and consideration given to individual characteristics and
clinical situation.
If there is not a special condition that increases the risk of hypoglycemia or the life expectancy is long enough, therapy in most
individuals with type 2 diabetes should be targeted to achieve an A1C ≤6.5% in order to reduce the risk of microvascular complications.
However, A1C goal can be identified as 6% in special conditions (e.g. high risk pregnancy) and in patients with good compliance unless
they experience severe hypoglycemia.
The benefits of a lower A1C should not increase the risk of hypoglycemia and mortality particularly in patients at high risk of CVD.
Turk JEM 2010; 14: Suppl 47-52
Current Approach to the Treatment of Type 2 Diabetes
49
Targets of glycemic control should be set higher in patients with low life expectancy and those at high risk of hypoglycemia.
In general, new arrangements should be made if A1C >6.5% and the patient's individual glycemic targets are not achieved.
A1C should be measured in every 3 months until it reaches to a target level, and then every 3 to 6 months.
1. The objective is to achieve and maintain glycemic targets near to normal levels.
2. Principally FPG and preprandial PG levels should be desired to achieve glycemic control targets, and preprandial and FPG lev
els should be kept 70-120 mg/dL.
3. If FPG and preprandial PG targets cannot be maintained or A1C is >6.5% in spite of meeting the targets, then postprandial PG
control becomes necessary. Postprandial PG is measured 2 h (1 h in a pregnant) after the first bite of a meal. Postprandial PG
should be <140 mg/dL. Postprandial PG measurement may have different timing in patients who perform carbohydrate
counting or use insulin pump.
4. Patients with type 2 diabetes also should be educated with a multi-disciplinary approach about their diseases. Education should
aim to inform and empower the patient about self-management of diabetes, to gain skills for SMBG, and to share the
responsibility with healthcare providers.
9.2.2 Treatment Preference
In the selection of anti-hyperglycemic treatment, glucose-lowering effect as well as extra-glycemic effects, safety, tolerability and cost
characteristics of drugs should be taken into consideration. Necessary changes in treatment and dose adjustments should be made
at appropriate time to achieve target A1C identified to an individual patient within first 6-12 months. Treatment of type 2 diabetes should
be performed in three steps:
A. First Step Treatment
Considering its long-term safety and relatively low-cost, and if there is no contraindication, metformin is indicated for use in patients
diagnosed with type 2 diabetes as concomitant therapy to lifestyle modifications. Lifestyle modifications should be implemented at all
stages of treatment.
Initially FPG should be measured three days per week and then SMBG should be administered as the selected drugs required. The
frequency of SMBG should be increased, based on the changes in treatment, initiation of insulin, and dose titration.
Weight loss (at least 4 kg or 5% of body weight) is essential for positive impact on CV problems, HT, and dyslipidemia frequently
accompanying to diabetes.
A nutritionally balanced diet, and regular physical activity for overweight and obese people should be implemented to achieve a
healthy body weight, unfortunately these attempts are insufficient in the long term.
At first line metformin treatment is initiated 500 mg twice daily, and in patients with gastrointestinal discomfort 500 mg once daily
and is titrated weekly in 500 mg increases to a 1000 mg twice daily in one to two months (maximum total daily dose of metformin is
3000 mg).
The sulfonylureas are an alternative if metformin is contraindicated or not tolerated, particularly in thin patients, in those who have
severe symptoms of hyperglycemia, and when a rapid response is required. Long-acting sulfonylureas like glibenclamide should not
be preferred.
In some cases other OAD (such as glinides and alpha-glucosidase inhibitors) can be initiated as the first line treatment according to
patient characteristics and physician’s experience.
In patients with initial A1C ≥10%, and in those with severe hyperglycemia symptoms and metabolic decompensation the therapy
should be initiated with insulin. In fact some patients, as in this case, are likely to have previously undiagnosed type 1 diabetes, while
others are type 2 diabetes patients with severe insulin deficiency. Insulin therapy should be initiated with preferably a basal-bolus
regiment or at least a pre-mixed insulin, and metformin should be added if possible.
B. Second Line Treatment
When glycemic goals cannot be reached or maintained new drugs should be added to the treatment or new treatment modalities
should be initiated in short time.
If glycemic targets are not achieved and A1C is >6.5% within 3 months of lifestyle modification and 2000 mg/day metformin use,
another pharmaceutical agent should be initiated.
The second drug should be chosen according to the individual characteristics, and the cost-effectiveness along with the efficacy and
safety of a particular drug should be taken into account. Metformin should be continued in the second line therapy as long as there is
no contraindication.
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Turk JEM 2010; 14: Suppl 47-52
The drugs with proven long-term efficacy (insulin, sulfonylureas) should be preferred primarily in second line therapy.
Insulin is the most effective therapeutic choice in the second line therapy. Especially if A1C ≥8.5% insulin (preferably a basal insulin)
should be considered. The risk of hypoglycemia and weight gain should be taken into account. The algorithm for insulin therapy in
patients with type 2 diabetes is summarized in Figure 9.2. Insulin therapy should be intensified if basal insulin is insufficient.
Alternatively a premixed human or analogue insulin can be used.
If A1C is >6.5% but <8.5%, a second OAD (sulfonylurea, glinide, TZD, DPP-4 inhibitor, alpha-glucosidase inhibitor or GLP-1 analogue)
can be added to the treatment.
A sulfonylurea is the cheapest option and more effective than a TZD. The risk of hypoglycemia and weight gain should be taken into
account. Long-acting sulfonylureas such as glibenclamide have a greater risk of hypoglycemia.
The risk of hypoglycemia with TZDs is lower than sulfonylureas, and the long-term efficacy is higher than that. But because TZD group
of drugs are associated with increased risk of edema, congestive heart failure, and fractures, patients taking TZD in addition to
metformin in the second line therapy should be followed carefully.
Glinides, alpha-glucosidase inhibitors or DPP-4 inhibitors can also be used for postprandial glycemia control. But in general the cost
and gastrointestinal side effects with the second group should be taken into account.
Although the risk of hypoglycemia with incretin-based drugs (GLP-1 agonists, DPP-4 inhibitors) is lower than insulin and sulfonylureas,
their efficiency is lower than these medications. However, the high cost and insufficient evidence regarding the long-term efficacy and
side effects restrain widespread use of these agents. DPP-4 inhibitors may be beneficial as they do not cause weight gain, and are
used orally.
If the physician has sufficient experience a GLP analogue, exenatide can be used in patients for whom weight loss is desired. But the
high cost and the absence of sufficient evidence regarding the long-term efficacy and side effects prevent its widespread use. It should
not be used in obese children and adolescents under 18 years of age with type 2 diabetes. If weight loss obtained with exenatide is
less than expected, the treatment should be discontinued. In addition, patients should be followed for the risk of pancreatitis.
If A1C is >6.5% within 3 to 6 months using metformin together with a second OAD (or GLP-1A), or individual glycemic targets are not
met, insulin treatment should be initiated immediately.
C. Third line Treatment
If A1C is >6.5% within 3 to 6 months after using a basal or a mixed insulin, or individual glycemic targets are not met insulin treatment
should be intensified.
Intensive insulin treatment consists of basal-bolus multiple daily injections (See Chapter 8.2).
Insulin pump (SCII) treatment may be considered among educated and motivated young patients in whom glycemic control cannot
be achieved with basal-bolus insulin, and in those who have flexible lifestyle.
If A1C is <8.5% a third antidiabetic drug can be added. But in this case the treatment cost rises, and the effectiveness of treatment is
lower than insulin. Moreover, the treatment is generally become insufficient within relatively short time..
9.2.3 Insulin Therapy in Type 2 Diabetes
Intensification of insulin therapy is summarized in the algorithm (Figure 9.2).
Getting started with insulin therapy in type 2 diabetes basal insulin therapy is preferred.
In some patients with high insulin requirements a second dose of basal insulin, or pre-mixed human insulin analogue may be
necessary starting from the beginning of the treatment.
Basal insulin regimen consists of either NPH insulin at night or long-acting analogue insulin (glargine, detemir) at night, in the evening
or in the morning at a dose of 0.1-0.2 IU/kg. Since long-acting insulin analogues (glargine, detemir) have lower risk of symptomatic
hypoglycemia and hypoglycemia at night, they may be preferred instead of NPH in patients with this type of risks.
The dose is increased by 2 IU every 3 days until FPG levels are ≤120 mg/dL (it may be increased by 4 IU when FPG is >180 mg/dL).
If hypoglycemia occurs or if FPG is <70 mg/dL in patients using insulin at night, the insulin dose is reduced 4 IU (if insulin dose is more
than 60 IU it is decreased by 10%). The insulin dose in the evening or at night should be reduced if FPG is <100 mg/dL in elderly patients
with coronary problems or dementia.
Basal-bolus insulin regimen should be preferred in patients with high basal insulin requirements (>0.5 IU/kg/day).
If A1C is measured >6.5% three months after start of basal insulin therapy, 4 IU rapid or short-acting insulin is initiated at noon, in
the evening or at night according to PG level, and the daily dose is increased by 2 IU every 3 days until PG reaches ≤120 mg/dL.
Turk JEM 2010; 14: Suppl 47-52
Current Approach to the Treatment of Type 2 Diabetes
Start basal insulin.
(NPH at night; Long-acting at night, in the evening or morning)
51
Start biphasic insulin.
(Premixed human or analogue insulin twice daily)
If FPG is >120 mg/dL, increase insulin dose.
If there is hypoglycemia or FPG is
<70 mg/dL decrease bedtime
insulin dose(*).
A1C>6.5%
after 3 months
If PG >120 mg/dL, in the
morning or evening,
increase insulin dose.
YES
NO
Continue treatment.
Measure A1C every 3-6
months.
NO
YES
If FPG <120 mg/dL,
increase the number of
injections as below.
If preprandial PG is >120
mg/dL at noon, add
rapid-acting insulin in the
morning.
If preprandial PG is >120
mg/dL in the evening,
add a morning basal or
a rapid-acting insulin at
noon.
If PG is >130 mg/dL at
bedtime,
add a rapid-acting
insulin
in the evening.
A1C>6.5%
after 3 months
YES
Switch to basal-bolus (intensive) insulin treatment.
(Increase number of rapid/short-acting insulin according to 2hr PPG,
adjust the doses, add second basal insulin if needed).
(*)
If FPG is <100 mg/dL in elderly, coronary heart disease or dementia; bedtime/evening insulin dose should be reduced
Figure 9.2 Insulin therapy in type 2 diabetes
9.2.4 Type 2 Diabetes Treatment in Special Circumstances
If A1C is over 6.5% a second dose of basal insulin can be added. Alternatively the number of rapid-acting analogue (aspart, glulisine
and lispro) can be increased depending on the 2hr postprandial PG levels.
Insulin secretagogues (sulfonylureas or glinides) should be discontinued once a rapid or a short-acting insulin is commenced.
Insulin therapy is recommended to be used in combination with an insulin sensitizer, preferably metformin. Intensive insulin
therapy combined with TZDs has been shown to increase the risk of edema and congestive heart failure. However, a TZD (preferably
pioglitazone) can be added to therapy for short-term in patients requiring very high doses of insulin until the insulin resistance is
relieved. These patients should be monitored closely.
Insulin therapy should be preferred concomitantly with lifestyle modifications in patients with uncontrolled diabetes and increased
catabolism as details shown below.
FPG >250 mg/dL, at any time PG >300 mg/dL or A1C >10%
In the presence of ketonuria
If there are serious diabetes symptoms (e.g. polyuria, polydipsia, weight loss)
In these patients OAD can be added to therapy after the symptoms have resolved, and even the insulin therapy can be discontinued
at that time.
Comorbidities accompanying to type 2 diabetes
The problems accompanying to type 2 diabetes, particularly dyslipidemia and hypertension, should be treated aggressively and in
accordance with the current guidelines to achieve success. This is also important to reduce the risk of microvascular complications.
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SEMT RECOMMENDATIONS FOR TREATMENT OF TYPE 2 DIABETES
1. If there is no contraindication metformin should be initiated concomitantly with lifestyle modifications in newly diagnosed
type 2. Diabetes patients [For obese patients: Class A, Level 1A evidence (1); for non-obese patients: Class D, evidence-based consensus].
• The treatment can be initiated with a sulfonylurea in patient with symptoms of hyperglycemia, who is asthenic or cannot
tolerate metformin (Class D, evidence-based consensus).
• Insulin therapy should be preferred concomitantly with lifestyle modifications in patients with hyperglycemia symptoms
and A1C>10%.
2. Glycemic targets must be individualized, taking into consideration the risk of hypoglycemia (Class D, evidence-based consensus).
• The majority of the patients should aim for an A1C target of ≤6.5% (Class D, evidence-based consensus).
3. If glycemic control has not been achieved at the end of 3 months another OAD or insulin should be added to the treatment.
• The necessary changes in treatment and dose adjustments should be made to achieve patient-specific A1C target
within 6 to 12 months (Class D, evidence-based consensus).
4. Pharmacological treatment regimens of type 2 diabetes patient should be individualized taking into consideration the
degree of hyperglycemia and the specifications of the antihyperglycemic agents (effectiveness, side effects,
contraindications, risk of hypoglycemia, and cost) presence of diabetes complications or comorbidities, and patient
preferences (Class D, evidence-based consensus).
5. When basal insulin is used, long-acting analogues may be considered instead of NPH to reduce the risk of nocturnal and
symptomatic hypoglycemia [Class A, Level 1A evidence (2)].
6. The following agents (listed in alphabetical order), should be considered to lower postprandial BG levels:
• Alpha-glucosidase inhibitors [Class B, Level 2 evidence (3)]
• DPP-4 inhibitors [Class A, Level 1 evidence (4-6)]
• Glinides [Class B, Level 2 evidence (7,8)]
• Premixed insulin analogues [Class B, Level 2 evidence (9,10)]
• Rapid-acting insulin analogues [Class B, Level 2 evidence (11-13)]
7. All individuals with type 2 diabetes using insulin or insulin secretagogues should be counseled about the recognition and
prevention of drug-induced hypoglycemia, and risk factors for severe hypoglycemia should be identified and addressed
(Class D, evidence-based consensus).
REFERENCES
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of
long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
2. DeVries JH, Lindholm A, Jacobsen JL, et al; Tri-Continental Insulin Aspart Study Group. A randomized trial of insulin aspart with intensified basal NPH insulin
supplementation in people with type 1 diabetes. Diabet Med 2003;20:312-8.
3. Zinman B, Tildesley H, Chiasson JL, et al. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes 1997;46:440-3.
4. Bode B, Weinstein R, Bell D, et al. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion:
a randomized study in type 1 diabetes. Diabetes Care 2002;25:439-44.
10
PRINCIPLES OF CONTINUOUS SUBCUTANEOUS INSULIN
INFUSION (CSII) THERAPY
The medical approaches widely accepted in the world about insulin pump therapy, also known as ‘subcutaneous continuous insulin
infusion therapy’ are summarized below.
The goals of intensive treatment of diabetes based on DCCT results can be outlined as follows:
To achieve the goal of near normal glycemia
To avoid severe hypoglycemia requiring assistance of a third person or an intervention
To improve the quality of life and to extend life by minimizing chronic complications of diabetes mellitus.
10.1 INDICATIONS OF CSII THERAPY
1. Recurrent and assistance-requiring hypoglycemia.
2. No success in achieving tight glycemic control (A1C ≤6.5%) with multiple dose (basal-bolus) insulin injection regimens.
3. Frequent experience of Dawn phenomenon (FPG >140-160 mg/dL due to early morning uncontrolled growth hormone surges)
4. Significant day to day variations of blood glucose levels
5. Pregnancy: In order to decrease the risk of spontaneous abortions and congenital malformations, women with diabetes should
receive preconception care to optimize glycemic control; the treatment should be started 2 to 3 months before pregnancy.
6. Lifestyle flexibility: Frequent traveler patients or those who work at variable working hours, or working in jobs where safety is important.
7. Lower insulin requirement: Patients having daily insulin requirement less than 20 IU.
10.2 CONTRAINDICATIONS OF CSII THERAPY
1. Patients who are not ready to perform 4-6 blood glucose measurements daily, those who are not willing to make SMBG and
carbohydrate counting.
2. Patients who are not willing to establish a close cooperation with the diabetes team (diabetes team should consist of at least a
physician, a nurse and a dietitian).
3. Lack of constant devoted support environment
4. Low socioeconomic status
5. Lack of maturity or educability
6. Lack of intelligence
7. Severe psychosis and major depression
8. Patients who are concerned and worried even after education and counseling about daily activities such as sexual relationships and
contact sports
9. Patients who would feel physically and emotionally uncomfortable wearing insulin pump device.
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10.3 PREPARATION FOR CSII
10.3.1 Prerequisites
Patients should be educated and willing to make SMBG and carbohydrate counting.
10.3.2 Type of Insulin Used in CSII
The insulin of choice for CSII is monomeric insulin: Regular insulin, insulin lispro, insulin aspart and insulin glulisine. It has been
reported that treatment with insulin lispro is associated with lower A1C levels. Rapid-acting insulin analogues have advantages over
regular human insulin in keeping glycemia in a more stable way and applying boluses without wait, just before the meal. Some insulin
analogues may lead to precipitation in the catheter, and because this situation may lead to flow irregularities and catheter occlusion,
patients should be well educated about the control of catheter.
10.3.3 Starting Dose
Total insulin dose (TID) is calculated by decreasing 25-30% of total insulin dose that the patient has received before CSII treatment.
The total daily dose is given as 50% basal insulin and 50% bolus insulin. These rates vary between 40-50% basal and 50-60% bolus
insulin according to the patient’s clinical condition (e.g. young children or pregnant women).
The initial hourly rate of insulin infusion is determined by dividing the total daily insulin requirement by 24. The snacks are not given
initially until the correct basal dose is established. The adequacy of basal and bolus doses is evaluated by glucose levels measured
preprandial, 2hr postprandial, bedtime and at 03 am.
The aim is to keep the changes in basal glycemia levels (increase and decrease) <35 mg/dL and 2 h postprandial glycemia <180
mg/dL (preferably <140 mg/dL).
Basal insulin infusion rate is changed by 0.05-0.10 IU/h to maintain the changes in basal glycemia <35 mg/dL.
If FPG level is more than 35 mg/dL higher than the value obtained at 03 am, then the basal rate should be increased to 1.5 times
higher than 12 pm rate. This should be started 2-3 hours before breakfast and applied for 4 to 6 hours.
Sensors monitoring subcutaneous glucose levels continuously can be applied in selected patients, in these case basal rates and
bolus insulin doses are reviewed, and adjusted whenever needed.
10.3.4 Carbohydrate Counting
All CSII patients should be educated about carbohydrate counting technique which has been previously mentioned in the chapter for
MNT. Carbohydrate/insulin ratio (the amount of CH in gram consumed in a meal divided by bolus insulin dose as IU given before that
meal) indicates the amount of insulin needed to cover a specific amount of carbohydrates.
1. CH/I ratio is between 5/1 to 25/1 and varies from meal to meal.
2. Body weight, age, physical activity, insulin resistance, comorbidities and existing diabetes complications have been found to affect
CH/I ratio.
10.4 COMPLICATIONS OF CSII TREATMENT
10.4.1 Hypoglycemia
The incidence of hypoglycemia during CSII is less than that of multiple-dose insulin therapy. The main possible causes of this are
better pharmacokinetic profiles of insulin therapy, keeping glycemia above the certain levels in patients with hypoglycemia problems,
and less insulin requirements compared to multiple-dose insulin therapy.
10.4.2 Ketoacidosis
CSII is characterized by no subcutaneous insulin depot; hence ketoacidosis may develop more rapidly if insulin infusion is interrupted
for any reason. The interruption of insulin may be intentional, or caused by pump or battery failure, depleted insulin supply,
catheter occlusion, or catheter disinsertion. In most cases it is related to insufficient training of the patient. There is no difference in the
frequency of DKA between CSII and multiple dose insulin therapy among well-trained patients.
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55
10.4.3 Infection at the Infusion Site
Infection at the infusion site is more common in CSII than in MDI therapy. The annual rate of infusion site infection has been estimated to
7.3-11.3 events per 100 years of patient follow-up. The organisms that are mainly responsible for infusion site infections are
Staphylococcus aureus, Staphylococcus epidermidis and Mycobacterium fortuitum. Occasionally local infection may lead to cellulites
or abscess formation requiring surgical treatment. The risk of infusion site infections can be reduced by changing the infusion set every
2-3 days, avoiding reusing cannulas, washing hands before insertion, and covering the implanted needle with an appropriate sterile
dressing.
SEMT RECOMMENDATIONS FOR CSII
1. CSII can be applied to achieve glycemic targets in adults with type 1 diabetes, and in type 2 diabetes patients with limited
β- cell reserve [For type 1 diabetic patients: Class A, Level 1A evidence (1); For type 2 diabetic patients: Class D,
evidence-based consensus].
2. CSII therapy should be started in the experienced centers and these patients should be followed by the same centers (Class
D, evidence-based consensus).
3. Rapid-acting insulin analogues can be used as an alternative to short-acting human insulin in adult patients with type 1 and
type 2 diabetes in CSII treatment.
REFERENCES
1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of
long-term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
2. DeVries JH, Lindholm A, Jacobsen JL, et al; Tri-Continental Insulin Aspart Study Group. A randomized trial of insulin aspart with intensified basal NPH insulin
supplementation in people with type 1 diabetes. Diabet Med 2003;20:312-8.
3. Zinman B, Tildesley H, Chiasson JL, et al. Insulin lispro in CSII: results of a double-blind crossover study. Diabetes 1997;46:440-3.
4. Bode B, Weinstein R, Bell D, et al. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion:
a randomized study in type 1 diabetes. Diabetes Care 2002;25:439-44.
11
INDICATIONS OF PANCREAS AND ISLET TRANSPLANTATIONS
Pancreas transplants have been performed for more than 30 years. It is usually performed in type 1 diabetes patients with more than
20 years of diabetes duration to eliminate insulin requirement, to prevent acute complications, and to improve the quality of life. The
long-term results of pancreas transplantation in type 2 diabetes are limited.
Pancreas and islet transplantation should be performed in well equipped and experienced centers with suitable infrastructure settings.
Long-term medical and psychological care should be provided to patients in co-operation with relevant disciplines after
transplantation.
ADA and WHO have prepared guidelines to provide recommendations for patients undergoing pancreas transplantation. The
recently published ADA recommendations are summarized below.
11. 1 ADA RECOMMENDATIONS
1. Pancreas transplantation can be performed as an alternative to chronic insulin treatment in type 1 diabetes patients with kidney
failure or at very high risk to develop kidney failure.
• Pancreas transplantation performed simultaneously with kidney transplantation does not increase mortality significantly.
Even though it may extend the kidney survival.
• Simultaneous pancreas and kidney transplantation improves glycemic control.
• Medical and surgical risks of patients must be suitable for simultaneous pancreas and kidney transplantation.
2. If there is no indication for kidney transplantation, pancreas transplantation can be performed alone in patients meeting the
following three criteria;
• History of frequent and severe metabolic complications (hypoglycemia, acute hyperglycemia, DKA)
• Existence of clinical and emotional problems difficult to control clinically with exogenous insulin therapy.
• Progression of diabetic complications despite intensive insulin therapy.
3. Pancreatic islet transplants hold significant potential advantages in technical aspects over organ transplants.
• Recent studies have been reported to increase insulin-free remission rates.
• But the patients require continuous use of immunosuppressive.
• Pancreatic islet transplantation is recommended to be used only in controlled clinical trials performed in well established centers
until immunosuppressive use to be safer and technical issues make progress.
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57
SEMT RECOMMENDATIONS FOR PANCREAS AND ISLET TRANSPLANTATION
1. Pancreas and islet transplantation should be performed in experienced centers with well established settings (Class D,
evidence-based consensus).
2. For individuals with type 1 diabetes and end-stage renal disease who are undergoing (or have undergone) kidney transplant,
pancreas transplant should also be considered (Class D, evidence-based consensus).
3. For individuals with type 1 diabetes and preserved renal function, but with persistent metabolic instability characterized by
severe hyperglycemic levels and severe hypoglycemia unawareness despite best efforts to optimize glycemic control,
pancreas transplant [Class D, Level 4 evidence (1)] or islet transplant [Class D, Level 4 evidence (2)] may be considered.
REFERENCES
1. Robertson RP, Sutherland DE, Lanz KJ. Normoglycemia and preserved insulin secretory reserve in diabetic patients 10-18 years after pancreas
transplantation. Diabetes 1999;48:1737-40.
2. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes 2005;54:2060-9.
12
ACUTE COMPLICATIONS OF DIABETES
Despite all the developments in screening and treatment of diabetes, the mortality of diabetic emergencies has remained unchanged.
• Diabetic emergencies can be examined under four main headings.
• Diabetic ketoacidosis (DKA)
• Hyperosmolar hyperglycemic state (HHS)
• Lactic acidosis (LA)
• Hypoglycemia
DKA and HHS are two metabolic disorders with a largely similar pathogenesis and treatment, and caused by insulin deficiency and
severe hyperglycemia. DKA occurs in the setting of insulin deficiency whereas severe dehydration is the cardinal feature of HHS. DKA
and HHS represent two extremes in the spectrum of decompensated diabetes mellitus. The pathogenesis of DKA and HHS are simlar.
DKA is the ultimate expression of absolute insulin deficiency resulting in unsuppressed lipolysis, ketonemia and ketonuria. In HHS, the
plasma insulin concentration is sufficient to inhibit lipolysis and subsequent ketogenesis. Pathogenesis of DKA and HHS is shown in
Figure 12.1.
Absolute/relative insulin deficiency + counterregulatory hormone excess
↓Glucose utilization
↑Hepatic glucose production
↑Protein degradation
↑Amino acid
↑Nitrogen loss
↑Lipolysis
↑Glycerol
↑FFA
Gluconeogenesis
Ketogenesis
Electrolyte loss
Ketonemia
Hyperglycemia
Osmotic diuresis
Dehydration
Fluid loss
Ketonuria
ACIDOSIS
Figure 12.1 Pathogenesis and DKA and HHS(*)
(*) The third pathway does not exist in HHS. FFA: Free fatty acids
Adapted from ‘ADA Clinical Practice Recommendations. Diabetes Care 2004;27(Suppl.1):94-102
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LA is rare but a serious complication with a high mortality rate due to serious health problems (cardiac, renal, cerebral, etc.)
accompaying diabetes.
Hypoglycemia, a life threatening condition among diabetic emergencies that should be intervened immediately, results from absolute
or relative excess of antidiabetic therapy (insulin and OAD).
12.1 DIABETIC KETOACIDOSIS (DKA)
12.1.1 Precipitant Factors
Infections
New onset type 1 diabetes (accounting for 20-25% of cases)
Errors in insulin therapy
Cerebrovascular events
Alcohol
Pancreatitis
Myocardial infarction
Trauma
Drugs impairing carbohydrate tolerance
Eating disorders (especially in young females with type 1 diabetes with a history of recurrent DKA)
12.1.2 Diagnosis
Symptoms
Polyuria, polydipsia, polyphagia, weight loss, nausea, abdominal pain, weakness, confusion and coma.
Clinical findings
Decreased skin turgor with dehydration, tachycardia, hypotension, hyperpnea (Kussmaul respiration), and rarely vomiting due to
hemorrhagic gastritis
Many cases have no fever due to vasodilation despite infection. Also, some patients with poor prognosis are hypotermic.
Laboratory findings
PG level >300 mg/dL (in pregnancy >250 mg/dL)
Ketonemia ≥3 mmol/L
Arterial blood pH ≤7.30
Serum bicarbonate (HCO-3) levels ≤15 mEq/L
Although slightly increased, serum osmolality is <320 mOsm/L
Increased anion gap (generally >12)
Also most of the patients with DKA and HHS may have mild to moderate leukocytosis, depending on dehydration and acidosis.
Concomitant infection may increase leukocyte count.
Serum amylase and lipase levels rarely increase up to 2 to 3 times of upper limits of normal.
Some formulas used in the diagnosis and monitoring of hyperglycemic emergencies are shown in Table 12.1.
Table 12.1 The formulas used in the diagnosis and follow-up of DKA
and HHS
Anion gap= [Na+ - (Cl- +HCO-3)] (Normal value ± 12 mmol/L)
Corrected Na+ = Measured Na+ 1.6 x [(Glucose – 100) / 100]
SOsm = 2 x (Na++ K+) + Glucose / 18 + BUN / 2.8
Effective osmolality = 2 x (Na+ + K+) + Glucose / 18
Normal TBW = Lean body mass x 60%
Current TBW = Normal SOsm x Normal TBW / Current SOsm
Water deficit = Normal TBW-Current TBW
SOsm: Serum osmolality, TBW: Total body water
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12.1.3 Clinical course
Clinical course of DKA is a primary anion gap acidosis. Hyperchloremic acidosis may develop during the initial 8 hours of treatment.
Rarely, patients with DKA may have a mixed acidosis.
Patients with DKA have a fluid deficit of nearly 5 to 7 liters.
Since serum Na+ levels may be reduced initially as a result of flux of water into the extracellular space due to hyperglycemia,
“corrected Na+” should be considered in treatment adjustment.
In some cases serum Na+ can be measured low due to accompanied severe hypertriglyceridemia (pseudohyponatremia).
Potassium moves out into the extracellular space due to severe insulin deficiency, hypertonicity and acidosis, thus serum potassium
levels may be high initially. If first measured K+ level is reduced or in the lower limit of normal, it should be considered as severe
K+ deficiency.
Deficiencies in HCO3-, Ca2+, PO3-2 and Mg2 also can be seen in DKA.
12.1.4 Treatment
Successful treatment of DKA depends on assessment of fluid and electrolyte balance, correction of hyperglycemia, and treatment of
concomitant diseases. Clinical and laboratory findings must be monitored at frequent intervals during treatment.
Fluid and electrolytes therapy
Fluid and electrolyte replacement in DKA are summarized in Figure 12.2.
The aim of the therapy in adults with DKA is to increase intra- and extracellular volume and to correct renal perfusion with fluid
replacement.
0.9% NaCl 1000-1500 mL (or 15-20 mL/kg/h) can be given in the first hour of therapy to a patient without any cardiac problems and
with predisposition to shock.
Infusion rate is calculated according to hydration and urination in the following 2-4 hours. If corrected serum Na+ level is lower 0.9%
NaCl can be given in the same dose. If corrected Na+ is normal or high 0.45% NaCl (4-14 mL/kg/h) should be given by decreasing.
Overall infusion rate in the first 4 hours should not be less than average of 500 mL/h.
Total fluid deficit should be replaced in 24-36 hours.
Give i.v 0.9% NaCl (15-20 mL/kg/h) at first hour
Assess urine flow and hydration status
Hypovolemic shock
Mild hypotension
0.9% NaCl
(20 mL/kg/h)
Calculate corrected serum Na+
(Add 1.6 mEq Na+ for + 100 mg/dL glycemia)
+
↑Na
Na+ Normal
0.45% NaCl
(4-14 mL/kg/h)
Cardiogenic shock
Hemodynamic
monitoring
Na+ ↓
0.9% NaCl
(4-14 mL/kg/h)
If glycemia <250 mg/dL, add 5% dextrose
Target glycemia: 150-200 mg/dL. Monitor BUN, creatinine, electrolyte and glycemia every 2-4 hours.
Figure 12.2 DKA treatment: Fluid and electrolytes balance
The third pathway does not exist in HHS. FFA: Free fatty acids.
Adapted from ‘ADA Clinical Practice Recommendations. Diabetes Care 2004;27(Suppl.1):94-102
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61
Insulin treatment
In all except mild cases continuous i.v. insulin infusion should be preferred to replace insulin deficiency. Figure 12.3 displays insulin
treatment algorithm in DKA.
Insulin infusion should be started 1-2 hours after starting fluid replacement therapy in children.
In severe cases insulin administration should be started with a priming i.v. bolus of 0.10-0.15 IU/kg short-acting (regular) insulin
unless K <3.5 mEq/L.
In adult patients continuous i.v. insulin infusion dose is 0.10 IU/kg/h (or 5-7 IU/h).
If PG concentration could not be reduced 50 mg/dL (or 10% reduction from baseline level) in the first 2 hour and also hydration
status is satisfactory, the infusion rate should be doubled.
When blood glucose level reduced to <250 mg/dL, insulin infusion rate is decreased to 0.05-0.10 IU/kg/h (or 2-4 IU/h), and 5-10%
dextrose infusion is initiated. At this stage ‘glucose/insulin/potassium (GIK) infusion’ may be preferred due to practical reasons. GIK
infusion protocol is described in ‘Surgery and Diabetes’ chapter (see Chapter 15.1).
Infusion should be continued by setting dextrose and insulin infusion rates to keep the blood glucose levels around 150-200 mg/dL
until recovery from acidosis.
Consider to give i.v. a priming bolus of regular insulin, 0.10-0.15 IU/kg in severe cases
Start regular insulin i.v. infusion 0.1 IU/kg/h
If PG level not reduced 50 mg/dL within the first 2 hour, double the infusion rate
When glycemia is <250 mg/dL, add 5% dextrose (150-200 mL/h)
• Decrease insulin infusion rate (0.05-0.10 IU/kg/h).
• Continue insulin infusion until recovery from DKA or pH >7.3, HCO3 >15 mmol/L has been achieved.
• Change to subcutaneous insulin once oral nutrition is started. Continue insulin infusion for the first 2 hours.
• Identify and treat predisposing factors
Figure 12.3 DKA treatment: Fluid and electrolytes balance
Adapted from ‘ADA Clinical Practice Recommendations. Diabetes Care 2004;27(Suppl.1):94-102
Potassium replacement
Potassium should be added to the infusion when the patient begins to urinate (Figure 12.4).
Usually 20-30 mEq/L K+ is given beforehand.
Hyperchloremic acidosis coexists with hypophosphatemia during DKA. Although it is recommended to initiate intravenous K+ with
two-thirds as potassium chloride [KCl] and one-third as potassium phosphate [K2PO4] to treat PO4- deficiency in DKA, only KCl is used
in our country, because K2PO4 is not available.
For replacement ampoules of 7.5% KCl containing 10mEq K+ is preferred.
Serum K+ level should be measured in every 2-4 hours, and intracellular K+ should be monitored with ECG in required cases.
If the serum K+ level is within the normal range 20-30 mEq/L, if low 40 mEq/L KCl is used for replacement, and if K+ level is high the
replacement is discontinued.
K+ supplementation should be continued until the patient becomes clinically stable and there is adequate oral intake.
Glucose infusion
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Measure serum potassium levels
• f K+ <3.3 mEq/L, do not give
insulin.
• Give K+ 40 mEq/h (2/3 KCl+1/3
K2PO4)(*)
• Target K+ levels >3.3 mEq/L.
• If K+ =3.3-5.0 mEq/L, give K+
20-30 mEq/L (2/3 KCl+1/3 K2PO4)(*)
• Target K+ levels: 4.0-5.0 mEq/L.
• If K+ >5.0 mEq/L, do not give K+.
• But measure in every 2 hours until
K+ <5.0 mEq/L.
Figure 12.4 DKA treatment: potassium replacement
(*)
Only the ampoules of 7.5% KCl containing 10mEq K+ is used, as K2PO4 is not available in our country)
Adapted from ‘ADA Clinical Practice Recommendations. Diabetes Care 2004;27(Suppl.1):94-102
Glucose infusion should be started once the PG level falls below 250 mg/dL. Glucose can be given within NaCl at a dose of 5-10 g/h,
or 5-10% dextrose is infused at a dose of 100 mL/h via different i.v. line.
Bicarbonate treatment
In general, routine administration of sodium bicarbonate is not recommended in the treatment of DKA. At a pH >7.30, administration
of insulin blocks lipolysis and resolves ketoacidosis without needing any bicarbonate replacement. The principles of bicarbonate
therapy are summarized in Figure 12.5.
If the pH is <6.9, NaHCO3 100 mmol dissolved in 400 mL sterile water at a rate of 200 mL/h is administered.
If the pH is 6.9-7.0, NaHCO3 50 mmol dissolved in 200 mL sterile water at a rate of 200 mL/h is administered.
pH should be measured in every 2 hours, and NaHCO3 infusion is repeated until pH is >7.0.
If pH >7.0, NaHCO3 is not given.
Alternative routes for insulin therapy
In mild DKA cases the therapy may be initiated with an i.v. bolus dose of regular insulin, followed by low-dose i.m. or s.c regular
insulin injection regimen. In recent years rapid-acting insulin analogues via s.c. route have been used with success in the treatment of
DKA.
Correction of ketonemia
The clearance of ketone bodies takes a longer time than the resolution of hyperglycemia.
β-hydroxybutyrate (β-OHB) is the predominant ketone in DKA, so the preferred method is measurement of ketones (‚-hydroxybutyrate)
in whole blood.
Nitroprusside method detects acetone and acetoacetic acid but not β-OHB. Because β-OHB is converted to acetoacetic acid during
successful treatment of DKA, acetoacetic acid levels rise, which may lead to confusion as to whether the acidosis is improving or
worsening.
Estimate the amount of HCO-3 to be given based on pH.
If pH <6.9
• Administer NaHCO3 (100
mmol) in 400 mL sterile
water.
• Give at 200 mL/h rate.
If pH = 6.9-7.0
• Administer NaHCO3
(50 mmol) in 200 mL
sterile ater.
• Give at 200 mL/h rate.
If pH >7.0
• Do not give NaHCO3.
• Measure pH in every 2 hours.
• Repeat HCO-3 infusion until pH is > 7.0.
• Check K+ levels regularly.
Figure 12.5 DKA treatment: bicarbonate treatment
Adapted from ‘ADA Clinical Practice Recommendations. Diabetes Care 2004;27(Suppl.1):94-102
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Maintenance treatment of diabetes after DKA
Criteria for resolution of DKA include a blood glucose <200 mg/dL, a serum HCO3- level ≥18 mEq/L, and a venous pH >7.3.
The patients taking oral nutrition can begin s.c. insulin treatment with basal-bolus insulin with multiple injections. It is essential that
the i.v. infusion of regular insulin be continued for 1 to 2 hours after the first dose of s.c. insulin is injected.
In patients with newly onset type 1 diabetes mellitus, the recommended starting dose of s.c insulin is 0.3-0.5 IU/kg/day.
Patients with new-onset type 2 diabetes should continue insulin therapy at least for a few months.
12.2 HYPEROSMOLAR HYPERGLYCEMIC STATE (HHS)
It is estimated that the rate of hospital admissions due to HHS is around 1%. The half of the cases represents predominantly HHS.
However, acidosis has been reported in one-third of HHS patients. In recent years, it has been argued that HHS represents an extreme
part of metabolic decompensation rather than a specific syndrome.
Precipitating factors
Infections
Myocardial infarction
Central nervous system diseases (cerebrovascular accidents)
Gastrointestinal problems
Renal failure
Endocrine system diseases (hyperthyroidism, acromegaly, etc)
Drugs impairing carbohydrate tolerance
Inadequate treatment due to administration errors
Typically seen in people over the age of 50
Of the HHS cases, about 25-35% have not been diagnosed previously with type 2 diabetes.
Prognosis
HHS mortality varies from 12 to 42%.
Mortality is higher in patients aged over 70 years, and among nursing home residents.
Delayed hospitalization for HHS compared to DKA, due to the slower course of the disorder (clinical course can last from several
hours to several weeks), worsens prognosis.
12.2.1 Diagnosis
HHS is distinguished from DKA by the absence of ketone bodies in plasma and urine, high plasma glucose levels and high osmolarity.
HHS is diagnosed when PG is >600 mg/dL and serum osmolarity is ≥320 mOsm/kg.
Extreme hyperglycemia and hyperosmolarity indicate poor prognosis.
12.2.2 Clinical course
Signs and symptoms
In fact, in HHS, plasma insulin concentration is sufficient to inhibit lipolysis.
Since elderly people often have a reduced sense of thirst due to aging and dementia, and unable to concentrate urine, dehydration
is more severe compared to DKA.
The lack of the vomiting triggered by ketosis prevents to counsel patient about fluid loss.
HHS should be observed among all elderly patients, whether they have diabetes or not, with acute or subacute deterioration in the
functions of central nervous system, or dehydration.
Blood pressure is low or may be normalized in previously hypertensive patients.
Laboratory findings
Fluid and electrolyte losses are more significant in HHS compared to DKA.
Estimate of fluid deficit in HHS patient is 8 to 10 liters.
In addition, there is a loss of multiple minerals and electrolytes (Na+, K+, Cl-, Mg2+, Ca2+, and PO4-2).
There may be B complex vitamin, especially thiamine loss depending on the increase of the catabolism.
The patient generally has PG of 1000 mg/dL and serum osmolarity of 360 mOsm/kg at the presentation.
Serum Na+ level is often >140 mg/L. Pseudohyponatremia may be found in the presence of hyperglycemia and hypertriglyceridemia.
Serum K+ level, even if normal or high at the beginning, is reduced during treatment with insulin and fluid replacement.
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Patients may present with prerenal azotemia (due to advanced age, comorbidities and dehydration).
There may be moderate leukocytosis and increased hematocrit (dehydration).
Accompanying hepatosteatosis can lead to elevated amino transferase levels.
Low T3 and T4 levels with low to normal TSH levels are seen due to ‘euthyroid sick syndrome’, but the patient is clinically euthyroid.
In some cases pancreas enzymes are elevated.
Creatinine phosphokinase (CPK) levels increases in 25% of cases and even can reach over 1000 u/L.
12.2.3 Treatment
The principles of the treatment of HHS and DKA are similar. During treatment nasogastric aspiration, lumbar puncture and urinary
catheterization should be performed, if necessary, and airway support (to prevent obstruction) should be provided, by taking into
account the age of cases.
Fluid and electrolyte therapy
The most critical factor in the treatment is the selection and the rate of fluid replacement.
At a serum osmolarity of greater than 320 mOsm/kg, 1000-1500 mL of 0.45% isotonic NaCl solution may be infused over the first
hour of treatment, and then followed by 500- 750 mL/h over 2 to 4 hours.
When serum osmolarity <320 mOsm/kg, i.v. fluids may again be switched to 0.9% isotonic sodium chloride solution.
Patients with hypotension may require colloid or pressor support.
In elderly patients, it is necessary to monitor central venous pressure during fluid replacement therapy.
If acute renal failure occurs, fluid infusion should be reduced.
Replacement therapy of K+ and other electrolytes is applied as in the DKA treatment protocol.
When glycemia decreases to 250-300 mg/dL, the infusion is changed to 5% dextrose in 0.9% isotonic sodium chloride solution.
Low-dose or low-molecular-weight heparin therapy should be considered for prophylaxis in patients at high risk of thrombosis, if
there is no contraindication.
Insulin therapy
Regular insulin infusion of 0.1 IU/kg/h is initiated as in DKA.
If a decrease of 50 mg/dL does not occur over the first 2 hours, the insulin infusion rate is increased twofold.
For a blood glucose concentration of 250-300 mg/dL, the insulin infusion rate is decreased by half (0.05 IU/kg/h), and 5% dextrose
is added.
12.2.4 Complications of DKA and HHS
The most common complications in hyperglycemic crisis are;
Hypoglycemia due to excessive insulin
Hypokalemia due to insulin administration and treatment of acidosis with bicarbonate
Hyperglycemia secondary to discontinuance of i.s. insulin before starting s.c. insulin therapy.
Hyperchloremia and transient hyperchloremic acidosis (non-anion gap metabolic acidosis) caused by excessive saline replacement
in patients recovering from DKA.
Brain edema
Brain edema is a rare and often fatal complication of DKA. Most of the cases are newly onset type 1 diabetic patients. Cerebral edema
is very rare in HHS. Brain edema usually evolves within a short period, and may result in brain stem herniation. Clinically characterized by;
1. Headache
2. Recurrent vomiting
3. Slow heart rate
4. Increased blood pressure
5. Decreased oxygen saturation
6. Dyspnea and impaired respiration
7. Neurological changes (anxiety, irritability, drowsiness, incontinence)
8. Specific neurological findings (convulsions, cranial nerve paralysis, abnormal pupillary reflex and postural changes)
9. Unconsciousness, lethargy and reduction in arousal.
Mechanism of brain edema
The mechanism of brain edema in DKA is poorly understood. It is thought that administration of fluids during treatment may
precipitate a rapid fall in plasma osmolarity and movement of water into brain cells, and is associated with the development of
cerebral edema. Insulin therapy worsens the edema by activating Na+ pump.
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Treatment of brain edema
Patients need to be intubated and given i.v mannitol immediately (0.26-1.0 g/kg). Alternatively a hypertonic saline solution (3% NaCl
5-10 mL/kg/30 min) can be used.
In order to avoid brain edema, water and sodium deficits should not be replaced quickly in adult patients as in the pediatric patients.
Maximal reduction in osmolality should not exceed 3 mOsm/kg H2O/h
Especially in HHS cases dextrose infusion should be performed to keep glycemia around 250-300 mg/dL
Rare complications
Hypoxemia and noncardiogenic pulmonary edema in DKA, and acute respiratory distress syndrome (ARDS) and disseminated
intravascular coagulation (DIC) in HHS are rarely seen complications.
12.3 LACTIC ACIDOSIS (LA)
Lactic acidosis (LA) is identified by an elevated plasma lactate concentration and high anion gap.
Lactic acidosis occurs from an inadequate blood delivery of oxygen to tissues, and is highly dependent on the underlying etiology.
12.3.1 Diagnosis and clinical findings
Blood levels of lactic acid reflect impaired the balance between lactic acid production and use.
Blood lactate level >5 mmol/L (normally 0.4-1.2 mmol/L)
pH <7.30
Lactic acidosis can be the result of inadequate tissue oxygen delivery resulting from hemodynamic shock, heart failure, severe
hypoxemia or anemia, and CO intoxication, and also is a rare complication of diabetic patients during biguanide (metformin) therapy.
The incidence of LA with metformin is very low (<0.003/1000 patient year).
Most of these cases have severe liver or kidney failure, or a severe hypoxia or hypoperfusion, and over 80 years of age (in fact,
metformin is contraindicated in this age).
The prognosis of acutely developed severe LA is usually poor depending on underlying disease.
12.3.2 Treatment
LA should be treated in intensive care unit.
Despite the debate and uncertainty about the benefits of alkaline treatment, massive doses of i.v. NaHCO3 may be used in severe
Type B LA cases in order to raise blood pH.
Hemodialysis is recommended to remove water and Na+ loads that may arise in these patients. Also it can be used in
metformin-dependent LA to remove the drug.
The use of alternative agents stimulating pyruvate dehydrogenase such as dichloroacetate is controversial.
The most logical approach in type 2 diabetes patients prone to LA is to avoid risky drug use.
SEMT RECOMMENDATIONS FOR ACUTE HYPERGLYCEM‹C CRISES
1. Unit-specific standard treatment protocol should be applied to the patients with DKA. A similar treatment protocol should
be applied to patients with HHS, but insulin dose should be adjusted carefully according to PG levels (Class D,
evidence-based consensus).
2. Overall infusion rate in the first 4 hours should not be less than average of 500 mL/h in DKA [Class B, Level 2 evidence (1)].
Fluid replacement is administered faster in patients with shock (1-2 L/h) (Class D, evidence-based consensus). In HHS fluid
administration should be tailored to the patient's needs (Class D, evidence-based consensus).
3. Patients with DKA should receive short-acting insulin with i.v. infusion at a rate of 0.1 IU/kg/h [Class B, Level 2 evidence (2,3)].
Insulin infusion should be continued until ketosis [Class B, Level 2 evidence (4)] and anion gap disappears (Class D,
evidence-based consensus).
4. When PG levels are under 200-250 mg/dL dextrose infusion should be initiated to prevent hypoglycemia (Class D,
evidence-based consensus).
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REFERENCES
1. Adrogue HJ, Barrero J, Eknoyan G. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. JAMA 1989;262:2108-13.
2. Heber D, Molitch ME, Sperling MA. Low-dose continuous insulin therapy for diabetic ketoacidosis. Prospective comparison with “conventional” insulin
therapy. Arch Intern Med 1977;137:1377-80.
3. Butkiewicz EK, Leibson CL, O’Brien PC, et al. Insulin therapy for diabetic ketoacidosis. Bolus insulin injection versus continuous insulin infusion. Diabetes Care
1995;18:1187-90.
4. Umpierrez GE, Latif K, Stoever J, et al. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with
diabetic ketoacidosis. Am J Med 2004;117:291-6.
12.4 HYPOGLYCEMIA
The risk of hypoglycemia is the most important obstacle in front of strict glycemic control in the treatment of diabetes. It is unavoidable
that patients treated with insulin experience severe hypoglycemia several times a year. Therefore, the patient treated with insulin and
the family members should be trained about symptoms, prevention and treatment of hypoglycemia.
12.4.1 Diagnosis and Clinical Findings
The diagnosis of hypoglycemia can be made based on ‘Whipple's triad’ (PG <50 mg/dL, a low PG measured at the time of the
symptoms, and relief of symptoms when the glucose is raised to normal).
But many diabetic patients feel the symptoms when PG level is greater than 50 mg/dL, and need treatment. It is particularly seen in
individuals with poor glycemic control, and remained hyperglycemic for a long time.
In the ADA/Endocrine Society 2009 Diabetes Guidelines, hypoglycemia is defined as any PG level <70 mg/dL.
Acute hypoglycemia symptoms
Divided into two main groups as adrenergic and neuroglycopenic symptoms.
1. Adrenergic symptoms
The following symptoms appear as a consequence of mechanisms involving autonomic nervous system and adrenal medulla activation;
• Trembling
• Cold sweating
• Anxiety
• Nausea
• Palpitation
• Hunger
2. Neuroglycopenic signs and symptoms
Below listed symptoms and signs appear as a consequence of reduced glucose delivery to the cerebral cortex.
• Dizziness
• Headache
• Lack of concentration
• Difficulty in speaking
• Weakness
• Confusion
Classification
Hypoglycemia happens in three stages, mild, moderate and severe.
• The patient can self-treat mild to moderate hypoglycemia.
• The difference of moderate hypoglycemia from the mild hypoglycemia is to affect the patient's activities significantly.
• Severe hypoglycemia needs getting help from the outside, requires parenteral treatment, and often causes coma or seizures.
12.4.2 Predisposing Factors
The main cause of hypoglycemia is the absolute or relative insulin excess. Main reasons are:
• Insulin/OAD overdose (high dose administration of insulin and OADs either accidentally or deliberately, and mismatch of the
timing of exercise and meals).
• Increase in insulin bioavailability (accelerated absorption in exercise, anti-insulin antibodies, chronic renal failure)
• Increase in insulin sensitivity (counterregulatory hormone deficiency, weight loss, increase in physical activity, postpartum period,
menstruation)
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• Inadequate nutrition (light and late meals, anorexia nervosa, gastroparesis, lactation, and inadequate food intake during exercise)
• Alcohol and drug use (drugs that increase the impact of sulfonylureas, cause counterregulation, and increase insulin secretion)
• Recurrent severe hypoglycemic attacks may cause morbidity in various organs outlined below especially in the elderly and
pediatric patients:
1. Brain: Psychological (cognitive function disorder, automatism, behavior or personality disorders) and neurological (coma, convulsion,
focal involvement, hemiplegia, ataxia, choreoathetosis, decortication) disorders
2. Heart: Myocardial infarction, arrhythmias
3. Eye: Vitreous hemorrhage, deterioration of proliferative retinopathy
4. Other: Traffic, home or work accidents, hypothermia
12.4.3 Treatment and Prevention
1. If the patient is conscious and able to swallow
• 20 g glucose (preferably 3-4 glucose tablet/gel, 4-5 cube-sugar, or 150-200 mL fruit juice or lemonade) is administered via
oral route.
• Fat-containing products such as chocolate and wafer should not be used.
• If there isn’t any meal in the patient’s program within 1 hour after hypoglycemic attack he should take a snack containing
15-20 g complex carbohydrates.
2. If the patient is unconscious or unable to swallow/chew oral carbohydrates
• Parenteral treatment should be given.
• Glucagon injection: Especially in patients with type 1 diabetes who developed severe hypoglycemia 1 mg glucagon
administration by relatives, can be life saving; it can be applied by i.v., i.m. or even s.c routes.
• In hospital conditions i.v. 75-100 mL 20% (or 150-200 mL 10%) dextrose is applied.
3. Prevention
• All causes should be reviewed after each hypoglycemic attack, and education should be repeated if necessary.
• Especially elderly patients with type 2 diabetes and hypoglycemia due to the use of long-acting conventional sulfonylureas
must be monitored in hospital for a period of 24-48 hours.
• Hypoglycemia unawareness: Long-term diabetes, tight glycemic control, heavy alcohol intake, and recurrent nocturnal
hypoglycemias may mask the prodromal symptoms of hypoglycemia. Therefore, strict glycemic control should not be
attempted in children and elderly patients, and patients with advanced nephropathy or autonomic neuropathy.
SEMT RECOMMENDATIONS FOR HYPOGLYCEMIAS
Mild to moderate hypoglycemia should be treated with 15 g orally administered carbohydrate (4 cube-sugars, or 150 mL fruit juice
or lemonade) [Class B, Level 2 evidence (1)]. If PG level is still <80 mg/dL after 15 minutes, another 15 g carbohydrate should be given
(Class D, evidence-based consensus).
1. Severe hypoglycemia should be treated with 20 g orally administered carbohydrate (5 cube-sugars, or 200 mL fruit juice
or lemonade), and if PG level is still <80 mg/dL, another 15 g carbohydrate should be given (Class D, evidence-based consensus).
2. All unconscious patients over 5 years of age and with severe hypoglycemia should get a s.c. or i.m. injection of glucagon
at home by one of the family members, and emergency medical care should be asked (Class D, evidence-based consensus).
3. The relatives of patients with high risk of hypoglycemia should be taught how to apply glucagon injection (Class D,
evidence-based consensus).
4. Unconscious patient with severe hypoglycemia should be treated with 10-25 g glucose via i.v. route (20-50 mL 50%
dextrose within 1 to 3 minutes or 50-150 mL 20% dextrose within 5-10 minutes) (Class D, evidence-based consensus).5.
The meals and snacks should be given at scheduled times to prevent recurrent hypoglycemia. If the next meal is an hour
or more away, a snack consisting of 15 g carbohydrate and protein should be eaten (Class D, evidence-based
consensus).
REFERENCE
1.
Slama G, Traynard PY, Desplanque N, et al. The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Arch Intern Med 1990;150:589-93.
13
CHRONIC COMPLICATIONS OF DIABETES
13.1 MACROVASCULAR DISEASE (ACCELERATED ATHEROSCLEROSIS)
Coronary artery disease (CAD), stroke and peripheral arterial disease are covered under the title of ‘Macrovascular Diseases’ and in
general it is referred as ‘cardiovascular diseases (CVD)’.
CVD is the leading cause of morbidity and mortality in individuals with diabetes. The risk of CAD is 2-4 times higher particularly in type
2 diabetes patients compared to non-diabetic individuals. Mortality estimates due to macrovascular events vary between 60-75%.
Atherosclerosis occurs at a much younger age in patients with diabetes, and has multisegmental character and diffuse nature.
13.1.1 Risk Factors
CAD is an independent risk factor for diabetes.
Also HT, dyslipidemia, smoking, family history (<55 year old men and <65 year old women have CVD in first degree relatives) and
obesity (particularly central obesity) are other important risk factors.
Patients with diabetes with the following characteristics should be considered at high risk for CAD:
Men aged ≤45 year old, women aged ≤50 year old
Men <45 year old and women <50 year old with one of the following risk factors;
- Macrovascular disease (e.g. silent myocardial infarction or ischemia, evidence of peripheral arterial disease, carotid arterial
disease or cerebrovascular accident)
- Microvascular disease (especially nephropathy and retinopathy)
- Multiple additional risk factors (a family history of premature coronary or cerebrovascular disease in a first-degree relative)
- Extreme level of a single risk factor (e.g. LDL-cholesterol >200 mg/dL or systolic BP >180 mm Hg)
- Long duration of diabetes (>15 years) with age over 40 years.
SEMT RECOMMENDATIONS FOR CHRONIC COMPLICATIONS
1. Men aged ≥45 years, women aged ≥50 years with diabetes are at increased risk for CAD [Class B, Level 2 evidence (1)].
2. Also men <45 year old and women <50 year old with microvascular complications, multiple additional risk factors for CAD,
extreme level of a single risk factor and long duration of diabetes are at increased risk for macrovascular disease (Class D,
evidence-based consensus).
3. The patients with primary diagnosis of diabetes must be evaluated periodically with ECG, echocardiography and exercise
(stress) test, if necessary, for CAD (Class D, evidence-based consensus). Patients with positive results and known CAD
should be referred to a cardiology unit.
4. In contrast, patients with primary diagnosis of CAD should be investigated for FPG, OGTT, fasting lipid profile and A1C, if
necessary, and normoglycemia must be provided in patients with ACS (acute coronary syndrome) or myocardial infarction;
and patients with IGT, diabetes or metabolic syndrome should be referred to consultation with a cardiologist.
5. The patients with CAD along with known diabetes should be investigated for nephropathy and other complications, and
optimal glycemic target should be obtained without increasing the risk of hypoglycemia.
6. Glycemic control, as well as multifactorial approach (life-style modification, lipid and BP control, use of antiaggregant drugs,
and abstain from harmful factors such as tobacco) should be adopted to reduce the risk of CAD in type 2 diabetes.
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REFERENCE
1. Booth GL, Kapral MK, Fung K, et al. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic
people: a population-based retrospective cohort study. Lancet 2006;368:29-36.
13.1.2 Coronary Artery Disease Screening
CV history (dyspnea, chest pain), life style derangements (smoking, sedentary lifestyle, unbalanced diet), long duration of diabetes,
impotence, abdominal obesity, lipid profile, blood pressure, peripheral arterial disease, glycemic control level, retinopathy, ECG, ACR
on first morning urine and eGFR should be taken into account to determine the patients at high risk for CAD.
SEMT RECOMMENDATIONS FOR SCREENING OF CORONARY ARTERY DISEASE
1. A baseline resting ECG should be performed in individuals >40 years of age, with duration of diabetes >15 years, and with
HT (Class D, evidence-based consensus).
• A repeat testing ECG should be performed every 2 years in people considered at high risk for CAD (Class D,
evidence-based consensus).
2. Persons with diabetes should undergo investigation for CAD by exercise ECG stress testing as the initial test in the presence
of the following (Class D, evidence-based consensus):
• Typical or atypical cardiac symptoms (e.g. unexplained dyspnea, chest discomfort) [Class C, Level 3 evidence (1)].
• Resting abnormalities on ECG [Class D, evidence-based consensus].
• Peripheral arterial disease (abnormal ankle-brachial ratio) [Class D, Level 4 evidence (2)].
• Carotid bruits [Class D, evidence-based consensus].
• Transient ischemic attack (Class D, evidence-based consensus).
• Stroke [Class D, evidence-based consensus].
3. Pharmacologic stress echocardiography (e.g. dypiridamole) or nuclear myocardial imaging should be used in individuals
with left bundle branch block or ST-T abnormalities (Class D, evidence-based consensus).
• In addition, individuals who require stress testing and are unable to exercise due to obesity, sedentary lifestyle, neuropathy,
peripheral arterial disease and diabetic foot¬ should undergo pharmacologic stress echocardiography or nuclear
imaging [Class C, Level 3 evidence (3)].
4. Individuals with diabetes who demonstrate ischemia at low exercise capacity on stress testing should be referred to a
cardiac specialist (Class D, evidence-based consensus).
REFERENCES
1. Zellweger MJ, Hachamovitch R, Kang X, et al. Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients.
Eur Heart J 2004;25:543-50.
2. Bacci S, Villella M, Villella A, et al. Screening for silent myocardial ischemia in type 2 diabetic patients with additional atherogenic risk factors: applicability
and accuracy of the exercise stress test. Eur J Endocrinol 2002;147:649-54.
3. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol 2004;11:171-85.
13.1.3 Clinical Findings
Some of the following clinical features can be seen together:
Classic anginal symptoms (chest, left arm, shoulder and jaw pain, dyspnea, and cold sweating)
Myocardial infarction: The likelihood of silent myocardial infarction is greater in patients with diabetes.
Dyslipidemia: Diabetes is considered as the equivalent of primary CVD.
HT: The goal of BP should be <130/80 mmHg in patients with diabetes.
Peripheral vascular disease
Cerebrovascular disease
Half of the patients, admitted to the intensive care unit because of ACS, are diagnosed as IGT or new onset diabetes. The algorithm to
be followed during the investigation of the either disease in patients with diabetes or CAD can be seen in Figure 13.1.
Recommendations
Asymptomatic patients should be treated according to the 10-year CVD risk.
Glycemic targets should be tried to achieve in diabetic patients with CAD. The results of recent trials such as ACCORD, ADVANCE and
VA-DT have shown that intensive glucose lowering in type 2 diabetes does not reduce major CV events, in contrast it can increase
macrovascular event and mortality risk if hypoglycemia occurs (as shown in ACCORD-2007 and VA-DT-2008). Therefore, strict glycemic
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Chronic Complications of Diabetes
control should not be targeted in type 2 diabetic patients with advanced age, long-term diabetes, comorbidities and at high risk of
hypoglycemia.
Metformin is contraindicated in severe congestive heart failure. TZDs should not be used in patients with congestive heart failure,
severe coronary insufficiency, or who are at risk of edema, and in patients using intensive insulin unless the benefits of therapy are
believed to outweigh the risk.
β-blockers should be added to the treatment of patients with prior myocardial infarction or undergoing surgery.
DM and/or CAD
Main diagnosis CAD±DM
Main diagnosis DM±CAD
No known CAD
Perform ECG, Echo
and Exercise testing
If normal,
monitor
fKnown CAD
Refer to cardiology consultation if ECG, Echo and Exercise
testing have positive results
No known DM
Measure FPG, OGTT, A1C, and
Lipid profile. Attain normoglycemia if there is MI/ACS.
Abnormal
Refer to cardiology consultation.
Treat invasive and non-invasive
ischemia.
If normal,
monitor
Known DM
Research nephropathy.
Refer to consultation for
diabetes if A1C >6.5%.
New diagnosis
Refer to consultation for
diabetes if there is
DM/IGT±MS
Figure 13.1 Screening Algorithms in Patients with Diabetes and Coronary Artery Disease
DM: Diabetes mellitus, CAD: Coronary artery disease, Echo: Echocardiography, FPG: Fasting plasma glucose,
OGTT; Oral glucose tolerance test, A1C; Glycosylated HbA1C, MI; Myocardial infarction,
ACS; Acute coronary syndrome, IGT; Impaired glucose tolerance, MS; Metabolic syndrome
13.1.4 Cardiovascular Protection in Patients with Diabetes
SEMT RECOMMENDATIONS FOR PREVENTION OF CARDIOVASCULAR DISEASES
1. The priority should be given to reduce CV risk by comprehensive and multifaceted approach in the prevention of diabetes
complications [For all diabetic patients: Class D, evidence-based consensus; for type 2 diabetes patients over 40 years of
age with microalbuminuria: Class A, Level 1A evidence (1)].
2. The approaches followed to reduce CV risk in all patients with diabetes are outlined below:
• Lifestyle modifications (Maintenance of appropriate body weight, healthy diet, regular physical activity, smoking cessation)
• Optimal BP control
• Optimal glycemic control
3. Accompanied risk factors should be treated.
• The goal of BP should be <130/80 mmHg in patients with diabetes. ACE-I or ARB should be preferred for the treatment of HT.
• Lipid disorders in diabetic patients should be treated more aggressively compared to non-diabetic individuals. The target
for patients with diabetes is an LDL-cholesterol <100 mg/dL (in diabetic patients with prior CVD 70 mg/dL), HDLcholesterol >40 mg/dL in men and >50 mg/dL in women, and triglyceride <150 mg/dL. Statins should be used primarily in
lipid lowering therapy.
4. Individuals at high risk of CV mortality should receive pharmacologic vascular protective measures such as ACE-I or ARB
therapy [For patients with vascular disease: Class A, Level 1A evidence (2,3); for patients at high risk: Class B, Level 1A
evidence (2,3)].
5. Low-dose aspirin therapy (80-150 mg/day) may be considered in patients with stable CVD (Class D, evidence based consensus).
6. Clopidogrel (75 mg/day) may be considered in people unable to tolerate aspirin (Class D, evidence based consensus).
7. The decision to prescribe antiplatelet therapy for primary prevention of CV events, however, should be based on individual
clinical judgment (Class D, evidence based consensus).
REFERENCES
1. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.
2. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes
mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253-9.
3. The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008385;15:1547-59.
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13.2 MICROVASCULAR COMPLICATIONS
13.2.1 Retinopathy
Diabetic retinopathy is a leading cause of adult blindness.
Screening
1. Retinopathy screening should be performed yearly, starting at puberty or 5 years after diagnosis in type 1 diabetes.
2. Retinopathy screening should be performed in all individuals at diagnosis of type 2 diabetes, and the patients who at baseline
had no diabetic retinopathy, or had mild retinopathy should be rescreened annually, who had advanced retinopathy in every 3
to 6 months.
Clinical evaluation
A fundus examination is performed by indirect ophthalmoscopy through dilated pupil.
1. Non-proliferative retinopathy: Microaneurysms and hard exudates.
2. Pre-proliferative: Exudates, bleedings, IRMA (Intraretinal microvascular abnormalities)
3. Proliferative retinopathy: Newly formed fragile capillaries replace with less functional blood vessels in the retinal circulation.
Patients with neovascularization are at greater risk of developing retinal detachment and hemorrhage.
4. Macula edema is one of the leading causes of blindness along with tractional retinal detachment due to proliferative
retinopathy, and neovascular glaucoma.
The guidelines in assessment of diabetic retinopathy in adult patients is summarized in Table 13.1.
Prevention and treatment
Optimal BP and glycemic control should be achieved.
People with abnormal lipid levels should be considered at high risk for retinopathy.
Laser photocoagulation, vitrectomy, and pharmacologic intervention with anti-vascular endothelial growth factor (anti-VEGF) agents
can be considered.
Table 13.1 Diabetic retinopathy assessment in patients with type 2 diabetes
Routine follow-up methods
Referral to ophthalmologist
Urgent ophthalmology
consultation needed
Fundus examination
I. If maculopathy is present
The following cases must
- At the time of diagnosis
- Exudates or retinal thickening within one
be examined immediately
- Then annually
Routine visual acuity tests should be performed.
Alternatively, diabetic retinopathy can be
screened through retinal
photographs taken by experienced
professionals using compatible devices.
disc diameter from the center of the fovea
- Ring-shaped exudates or group
by an ophthalmologist:
Sudden vision loss
of exudates within macula(*)
- Visual acuity of 6/12 or less due to aneurysm or bleeding
within one disc diameter from the center of the fovea
II. If pre-proliferative retinopathy findings are present:(**)
Venous beading
- Venous ring or reduplication-Intraretinal
Rubeosis iridis
Pre-retinal and vitreous
hemorrhage
Retinal detachment
Neovascularization.
microvascular abnormalities (IRMA)
- Multiple deep-round or spot bleedings
III. Any unexplained drop in visual acuity
(*)
Macula has been described as the circle with the center of fovea, and with the diameter between the temporal edge of the optic disk and the fovea
Cotton wool spots do not indicate preproliferative retinopathy
(**)
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SEMT RECOMMENDATIONS FOR DIABETIC RETINOPATHY
1. In individuals with type 1 diabetes, screening for retinopathy should be performed starting at puberty or 5 years after the
onset of diabetes [Class A, Level 1 evidence (1-3)], and in individuals with type 2 diabetes at the time of diagnosis (Class A,
Level 1 evidence) and then annually [Class A, Level 1 evidence (2,4)]
2. To prevent the onset and delay the progression of diabetic retinopathy, people with diabetes should be treated to achieve
optimal control of blood glucose and BP [For glycemia: Class A, Level 1A evidence (5); for BP: Class A, Level 1A evidence (5)].
3. Patients with severe retinopathy (preproliferative or proliferative) should be assessed by an ophthalmologist [Class D,
evidence-based consensus].
4. Laser photocoagulation, vitrectomy and pharmacologic intervention should be considered in sight-threatening retinopathy
[For laser and vitrectomy: Class A, Level 1 evidence (6-8); for pharmacologic interventions: Class B, Level 2 evidence (9)].
REFERENCES
1. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IX. Four-year incidence and progression of diabetic
retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1989;107:237-43.
2. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at
diagnosis is less than 30 years. Arch Ophthalmol. 1984;102:520-6.
3. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. X. Four-year incidence and progression of diabetic
retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol 1989;107:244-9.
4. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. VII. Diabetic nonproliferative retinal lesions. Ophthalmology
1987;94:1389-1400.
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
6. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study
report number 1. Arch Ophthalmol 1985;103:1796-806.
7. The Diabetic Retinopathy Study Research Group. Photocoagulation treatment Study findings. Ophthalmology 1978;85:82-106.
8. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a
randomized trial: Diabetic Retinopathy Study report 5. Arch Ophthalmol 1990;108:958-64.
9. Cunningham ET Jr, Adamis AP, Altaweel M, et al. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor
aptamer, for diabetic macular edema. Ophthalmology 2005;112:1747-57.
13.2.2 Nephropathy
Nephropathy is one of the leading causes of morbidity and mortality in adults with diabetes.
Screening
To investigate the early nephropathy in adults, microalbuminuria and eGFR should be assessed together.
Serum creatinine is measured and GFR is estimated (eGFR) using MDRD or Cockcroft formulas. (Microalbuminuria assessment and
eGFR calculation have been previously described in the chapter for guidelines of standard care in diabetic patients).
Diabetic nephropathy screening:
Screening should be performed annually in adults with type 1 diabetes of >5 years’ duration.
Individuals with type 2 diabetes should be screened at diagnosis of diabetes and yearly thereafter.
Screening should be delayed when causes of transient albuminuria or low eGFR are present (e.g. uncontrolled HT, urinary tract
infection, hypovolemia).
Staging
Diabetic nephropathy is the most important cause of end-stage renal disease. Chronic renal failure in patients with diabetes is
assessed as in non-diabetic patients according to the following GFR stages based on kidney damage determined by urine and blood
tests, imaging and/or pathological assessments.
Stage 1: eGFR ≥90 mL/min/1.73 m2: normal/high GFR and kidney damage
Stage 2: eGFR 60-89 mL/min/1.73 m2: mildly decreased GFR and kidney damage
Stage 3: eGFR 30-59 mL/min/1.73 m2: moderately decreased GFR and kidney damage
Stage 4: eGFR 15-29 mL/min/1.73 m2: severely decreased GFR and kidney damage
Stage 5: eGFR <15 mL/min/1.73 m2 or dialysis: end-stage renal disease.
Serum creatinine levels should be measured to calculate albumin:creatinine ratio (ACR) in a first morning (spot) urine sample as well
as eGFR in every 3-6 months in diabetic patients with chronic renal failure.
Clinical findings
Diabetic nephropathy is characterized by HT, edema, proteinuria and renal failure.
The patient reaching end-stage renal failure requires renal replacement treatment. Renal transplantation is treatment of choice for
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Chronic Complications of Diabetes
73
young and middle age patients (<65 years of age) whereas elderly patients should be treated with hemodialysis, or with ambulatory
peritoneal dialysis at home.
Prevention and treatment
Glycemia control: In patients with type 1 and type 2 diabetes optimal glucose control should be assessed to prevent or delay
nephropathy. The progression of renal damage in diabetes can be slowed through intensive glycemic control.
Microalbuminuria: In people with persistent increased ACR (≥30 mg/g creatinine) with or without HT, an ACE-I or an ARB would be
preferred for prevention of renal disease progression.
Individuals starting therapy with an ACE-I or an ARB should be monitored within 1 to 2 weeks of initiation or titration of treatment for
serum creatinine and potassium levels.
Renal failure: The use of thiazide-like diuretics should be considered in individuals with CKD (chronic kidney disease) and
diabetes for control of sodium and water retention, HT or hyperkalemia. Alternatively, furosemide can be substituted for or added to
thiazide-like diuretics for individuals who fail monotherapy with thiazide-like diuretics or who have severe sodium and water retention
or hyperkalemia.
Consideration should be given to stopping ACE-I, ARB and/or diuretic therapy during times of acute illness such as febrile illness or
diarrhea, especially when intravascular volume contraction is present or suspected.
Women should avoid becoming pregnant when receiving ACE-I or ARB therapy, as the use of medications has been associated with
adverse fetal outcomes, and if pregnancy is planning the medication should be stopped two months before conception.
Evaluation of kidney damage in adult patients with diabetes is summarized in Figure 13.2.
A referral to a nephrologist should be considered in the following situations:
• Progressive loss of kidney function
• eGFR <30 mL/min,
• ACR >300 mg/g creatinine
• Uncontrolled HT
• Hyperkalemia or a >30% increase in serum creatinine within three months of starting an ACE-I or an ARB.
When no transient causes of albuminuria or low eGFR are present, and when acute renal
failure or nondiabetic kidney disease is not suspected
Type 1 diabetes: Annually in individuals with duration of diabetes >5 years
Type 2 diabetes: At diagnosis of diabetes and annually thereafter
Measure ACR on morning spot urine and serum creatinine for eGFR
eGFR ≤60 mL/min or ACR increased?
No
Yes
Measure serum creatinine and calculate eGFR in 3 months, then measure urine
ACR 2 times over the next 3 months.
No
Yes
At 3 months eGFR ≤60 mL/min or ACR increased?
No evidence of diabetic
nephropathy
Rescreen in 1 year
Diabetic nephropathy diagnosed
Order routine urine dipstick and microscopic
tests
No
Diabetic nephropathy
Suspicion of nondiabetic renal disease
(based on clinical findings
or laboratory tests)?
Yes
Refer to nephrologist
Figure 13.2 Evaluation of kidney damage in adult patients with diabetes
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Chronic Complications of Diabetes
Turk JEM 2010; 14: Suppl 68-78
SEMT RECOMMENDATIONS FOR DIABETIC KIDNEY DISEASE
1. The best possible glycemic control should be instituted in people with type 1 or type 2 diabetes for the prevention of onset
and delay in progression to CKD [Class A, Level 1A evidence (1-3)].
2. In adults, screening for CKD in diabetes should be conducted using ACR and eGFR [Class D, evidence-based consensus].
Screening should be performed:
• Annually in adults with type 1 diabetes of >5 years’ duration.
• At diagnosis of diabetes and yearly thereafter in individuals with type 2 diabetes [Class D, evidence-based consensus].
3. People with diabetes and CKD should have a random urine ACR and serum creatinine for calculated eGFR at least every 3
to 6 months [Class D, evidence-based consensus].
4. Adults with diabetes and persistent albuminuria should receive an ACE-I or an ARB to delay the progression of CKD, even
in the absence of HT [for ACE-I use in type 1 and type 2 diabetes, and for ARB use in type 2 diabetes: Class A, Level 1A
evidence (4-11); for ARB use in type 1 diabetes Class D, evidence-based consensus].
5. People with diabetes on an ACE-I or an ARB should have their serum creatinine and potassium levels checked [Class D,
evidence-based consensus].
6. The use of thiazide-like diuretics and/or furosemide should be considered in individuals with CKD and diabetes [Class D,
evidence-based consensus].
7. Consideration should be given to stopping ACE-I, ARB and/or diuretic therapy when intravascular volume contraction is
suspected [Class D, evidence-based consensus].
8. Women should avoid becoming pregnant when receiving ACE-I or ARB therapy [Class D, evidence-based consensus].
9. A referral to a nephrologist should be considered if eGFR is <30 mL/min or ACR is >300 mg/g creatinine, or the individual
is unable to achieve BP targets or if the patient has hyperkalemia or a >30% increase in serum creatinine after starting an
ACE-I or ARB [Class D, evidence-based consensus].
REFERENCES
1. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 1993;341:1306-9.
2. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy
in the Diabetes Control and Complications Trial. Kidney Int 1995;47:1703-20.
3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
4. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl
J Med 1993;329:1456-62.
5. Strippoli GF, Craig MC, Schena FP, et al. Role of blood pressure targets and specific antihypertensive agents used to prevent diabetic nephropathy and delay
its progression. J Am Soc Nephrol 2006;17(suppl 2):S153-S155.
6. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N
Engl J Med 2001;345:861-9.
7. Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes.
N Engl J Med 2001;345:870-8.
8. Laffel LM, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM
patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med 1995;99:497-504.
9. ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensinconverting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134:370-9.
10. Ravid M, Savin H, Jutrin I, et al. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in
normotensive type II diabetic patients. Ann Int Med 1993;118:577-81.
11. Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients
with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002;106:672-8.
13.2.3 Neuropathy
Neuropathy may affect any system of the body. Distal symmetrical sensory disorder of the lower-extremity is the major cause of foot
amputation with infection and ischemia. In recent years it is recommended to conduct screening for neuropathy annually in adults with
type 1 diabetes of 5 years duration, and at diagnosis of diabetes and yearly thereafter in individuals with type 2 diabetes.
A. Peripheral polyneuropathy
1. Distal polyneuropathy
The most common presentation is a progressive distal polyneuropathy.
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75
Unsteadiness of the gait, ataxic gait, muscle weakness in hands and feet
It is associated with loss of proprioception and tactile hypoesthesia
There is also loss of pain and heat sensation
Abnormal changes in tactile sensory (allodynia, pain) may progress to the sensory loss
Stocking glove distribution of sensory loss with a distal to proximal gradient is typical.
Diabetic polyneuropathy causes contact-induced discomfort, superficial burning, dull aching, deep aching pains, and jabbing pain
especially at nights.
Foot ulcers, infections and neuro-osteoarthropathy (Charcot foot: characterized by bone erosions, undetected recurrent fractures, foot
edema due to bone demineralization disorders, increase of heat and deformities) may develop. Proper foot care can reduce the risk.
Sometimes it is asymptomatic. When symptomatic it may show a self-limiting or a progressive clinical course.
2. Focal neuropathies
Focal neuropathy usually has a sudden onset and shows a spontaneous regression within a few weeks or months.
Third cranial nerve paralysis: It is characterized by unilateral eye pain, diplopia and ptosis.
Radiculopathy: Diabetic radiculopathy involving the nerve roots causes thoracic, abdominal and truncal pain with band-style spread.
Plexopathy: Diabetic plexopathy typically affects the lumbosacral plexus and brachial plexus and causes pain spreading to extremities.
Treatment of neuropathy
Immediate and accurate diagnosis is needed.
Treatment should be directed at symptoms
Painful neuropathies should be treated with non-specific analgesics initially, specific pain treatment should be performed in
non-responsive cases (Table 13.2).
Table 13.2 Management of neuropathic pain in diabetes
Class
Example
Recommended doses(*)
Tricyclic antidepressants
Amitriptyline
10-75 mg at night
Nortriptyline
25-75 mg at night
Imipramine
25-75 mg at night
Anticonvulsants
Gabapentin
3x300-1200 mg
Carbamazepine
3x200-400 mg
Pregabalin
3x100 mg(**)
Duloxetine
1x60-120 mg
Alpha lipoic acid(**)
Thioctacid ampoule
600-1200 i.v. infusion
Substance-P inhibitor
Capsaicin cream
5-Hydroxytryptamine and
Norepinephrine reuptake inhibitors
0.025-0.075%
externally 1 to 3 times per day
Isosorbide dinitrate(**)
Isosorbide topical cream
Externally 1 to 2 times per day
(*)
Dose response is variable. The therapy is started at the lowest dosage and titrated gradually
Not available in our country
(**)
Treatment algorithm of pain neuropathy is shown in Figure 13.3. It has been known for many years that alpha lipoic acid may
partially improve subjective findings, such as paresthesia, burning, pricking, and numbness. However, the oral form of alpha lipoic acid
is not useful in the treatment of neuropathic pain. On the other hand, small pilot studies using parenteral form of this drug, which is not
available in our country, have been proposed some beneficial effects in the pain relief.
Prevention
Optimum glycemic control should be achieved.
Foot care should not be neglected.
76
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Chronic Complications of Diabetes
Examine the symptoms of neuropathy once in a year
If symptoms of neuropathy are present:
Patients should be informed about reasons and prognosis of neuropathy, and that the pain may be
relieved in time.
Patients should be informed about the importance of optimal glycemic control and
treatment options and their consent should be obtained. Psychological consequences of neuropathy
should be considered, and if necessary, psychological support should be provided.
Inadequate pain control
Treatment should be;
• started with a tricyclic antidepressant drug.
• given at the most appropriate time for pain control.
• carried out with low doses should be titrated upward slowly.
Inadequate pain control
• The cheapest one among Duloxetine, Gabapentin or
Pregabalin should be chosen.
• The maximum tolerated dose should be achieved.
• The medication should be stopped if insufficient in pain control.
• Switch to another drug should be considered if dose titration is
not possible because of side effects.
Inadequate pain control
Opium analgesics can be tried.
Inadequate pain control
If pain is under
control
The patient should be referred to specialist experienced in chronic
pain therapy (with the consent of the patient).
If pain is relieved the dose should be decreased or
stopped (with the consent of the patient).
Figure 13.3 Treatment of neuropathic pain in adult patients with diabetes
SEMT RECOMMENDATIONS FOR PERIPHERAL NEUROPATHY
1. In people with type 1 diabetes, annual screening for peripheral neuropathy should commence after 5 years’ postpubertal
duration of diabetes. In people with type 2 diabetes, screening should begin at diagnosis of diabetes and occur annually
thereafter. [Class D, evidence-based consensus].
2. Screening for peripheral neuropathy should be conducted by assessing loss of sensitivity to the 10-g monofilament or loss
of sensitivity to vibration at the dorsum of the great toe [Class A, Level 1 evidence (1)].
3. People with diabetes should be treated with intensified glycemic control to prevent onset and delay progression of
neuropathy [For type 1 diabetes Class A, Level 1A evidence, (2, 3); for type 2 diabetes Class B, Level 2 evidence (4)].
4. For the relief of painful peripheral neuropathy:
• Antidepressants [Class A, Level 1A evidence (5,6)],
• Anticonvulsants [Class A, Level 1A evidence (7-10)], and
• Opioid analgesics [Class A, Level 1A evidence (9)] should be considered alone or in combination.
REFERENCES
1. Perkins BA, Olaleye D, Zinman B, et al. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250-6.
2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of
long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86.
3. Reichard P, Berglund B, Britz A, et al. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes
mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years. J Intern Med 1991;230:101-8.
4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-53.
5. Rowbotham MC, Goli V, Kunz NR, et al. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled
study. Pain 2004;110:697-706.
6. Raskin J, Smith TR, Wong K, et al. Duloxetine versus routine care in the long-term management of diabetic peripheral neuropathic pain. J Palliat Med
2006;9:29-40.
7. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a
randomized controlled trial. JAMA1998;280:1831-6.
8. Richter RW, Portenoy R, Sharma U, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 2005;6:253-60.
9. Gilron I, Bailey JM, Tu D, et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324-34.
10. Dogra S, Beydoun S, Mazzola J, et al. Oxcarbazepine in painful diabetic neuropathy: a randomized, placebo-controlled study. Eur J Pain 2005;9:543-54.
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77
B. Autonomous polyneuropathy
• Orthostatic hypotension
• Cardiac denervation syndrome:
- It affects CV reflexes.
- Heart becomes hypersensitive to catecholamine.
- Dysrhythmia (mostly tachycardia)
- Exercise intolerance
- Silent (painless) myocardial infarction
- Sudden death
• Gastrointestinal neuropathy
- Delayed gastric emptying (Gastroparesis)
- Motility is reduced (swallowing difficulty, quick full feeling, nausea-vomiting)
- Delayed absorption of food (Brittle diabetes: Episodes of hypoglycemia or hyperglycemia which constantly disrupt
regulation of diabetes.
- Constipation (colonic atony)
- Nocturnal diarrhea
- Cholecystitis, biliary sludge (gallbladder atony)
• Genitourinary neuropathy
- Erectile dysfunction
- Retrograde ejaculation and infertility
- Sexual arousal difficulties and dyspareunia in women
- Bladder dysfunction (incontinence due to neurogenic bladder, infection)
• Hypoglycemia unawareness
- Counterregulatory hormone (epinephrine, glucagon) responses to hypoglycemia are blunted.
- Autonomous sudomotor dysfunction
- Uncontrolled hypohidrosis in extremities
- Gustatory sweating (central hyperhidrosis): Sweating on the forehead, face, and neck occurring soon after ingesting food.
The approach to autonomous neuropathy in diabetic patients is summarized in Table 13.3.
Table 13.3 The approach to autonomous neuropathy in diabetic patients
Involved system
Treatment approach
Suggestions
Gastroparesis
- Impaired glucose control due to
hypo- and hyperglycemia
-Unexplained stomach bloating and vomiting
- Metoclopramid
- Domperidone
- Erythromicin
- Suspicion in the differential diagnosis
- In case of continuous and severe
vomiting patient
should be referred to a gastroenterologist.
- Necessary assessments
should be performed.
- Patients should be informed about
contributing factors and treatment options
- Phosphodiesterase-5 inhibitors should
be given unless there is some
contraindication to their use.
If a phosphodiesterase-5 inhibitor is
insufficient the next step will be:
- Medical treatment
- Surgical treatment
- Patient should be referred to a
specialist for psychological support.
Sympathetic nervous system
damage must be considered
Intestinal autonomic neuropathy
Further investigations and
specific treatment should be applied
Erectile dysfunction
- Diabetic men should be examined once in a year
Hypoglycemia unawareness
The absence of hypoglycemic symptoms
Nocturnal diarrhea
Unexplained diarrhea especially at night
Neurogenic bladder
Impaired bladder emptying
Autonomic neuropathy involving the bladder
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Turk JEM 2010; 14: Suppl 68-78
Erectile dysfunction
SEMT approach and recommendations on this issue are summarized below:
SEMT RECOMMENDATIONS FOR ERECTILE DYSFUNCTION
1. Adult males with diabetes should be regularly screened for erectile dysfunction along with sexual function history (Class D,
evidence-based consensus).
2. A phosphodiesterase-5 inhibitor is recommended as first-line therapy for treating erectile dysfunction in men with diabetes
[Class A, Level 1A evidence (1-8)].
3. Referral to a specialist in erectile dysfunction should be considered for eugonadal men who do not respond to
phosphodiesterase-5 inhibitors, or for whom the use of phosphodiesterase-5 inhibitors is contraindicated (Class D,
evidence-based consensus).
4. Men with diabetes and erectile dysfunction who do not respond to phosphodiesterase-5 inhibitors should be investigated
for hypogonadism [Class D, Level 4 evidence (9-12)].
5. Men with diabetes and retrograde ejaculation who desire fertility should be referred to a specialist experienced in the
treatment of ejaculatory dysfunction (Class D, evidence-based consensus).
REFERENCES
1. Fonseca V, Seftel A, Denne J, et al. Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil
clinical trials. Diabetologia 2004;47:1914-23.
2. Rendell MS, Rajfer J, Wicker PA, et al. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. JAMA 1999;281:421-6.
3. Boulton AJM, Selam J-L, Sweeney M, et al. Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus. Diabetologia
2001;44:1296-301.
4. Goldstein I, Young JM, Fischer J, et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: a
multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003;26:777-83.
5. Sáenz de Tejada I, Anglin G, Knight JR, et al. Effects of tadalafil on erectile dysfunction in men with diabetes. Diabetes Care 2002;25:2159-64.
6. Carson CC, Lue TF. Phosphodiesterase type 5 inhibitors for erectile dysfunction. BJU Int 2005;96:257-80.
7. Briganti A, Salonia A, Gallina A, et al. Drug insight: oral phosphodiesterase type 5 inhibitors for erectile dysfunction. Nat Clin Pract Urol 2005;2:239-47.
8. DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton
Consensus Panel. Am J Cardiol 2000;86:175-81.
9. Dhindsa S, Prabhakar S, Sethi M, et al. Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol Metab 2004;89:5462-68.
10. Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging
Male 2003;6:1-7.
11. Shabsigh R, Kaufman JM, Steidle C, et al. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile
dysfunction who do not respond to sildenafil alone. J Urol 2004;172:658-63.
12. Kalinchenko SY, Kozlov GI, Gontcharov NP, et al. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients
failing on sildenafil citrate therapy alone. Aging Male 2003;6:94-9.
14
DIABETIC FOOT ULCERS
Patient with diabetes is at risk of developing diabetic foot ulcers by 12-15% throughout his life.
• Foot problems are a major cause of morbidity and mortality in people with diabetes and contribute to decreased quality of life, and
increased healthcare costs, and results in the high rate of lower extremity amputations.
• Forty to 60% of non-traumatic foot amputations are related to diabetes.
• The average duration of hospital stay of a diabetic patient with foot ulcer is at least 50% longer than a patient without an ulcer.
14.1 CAUSES OF DIABETIC FOOT ULCERS
Risk factors for development of diabetic foot ulcers include peripheral neuropathy, peripheral vascular disease, and foot traumas. Also
motor and autonomic deficits contribute to the development of the ulcer.
Diabetic foot ulcers are classified as neuropathic, ischemic and neuro-ischemic ulcers.
The most common diabetic foot ulcers are neuropathic ulcers. Ulcers develop in feet with loss of pain and pressure sensations, and
with loss of thermal and deep sensorial sensations after trauma. Motor neuropathy causes atrophy and weakness of intrinsic foot
muscles and increased pressure fields due to flexion deformity of digits (for example, under metatarsal heads and under toes).
Post-traumatic ischemic ulcers develop in tissues with poor perfusion.
Also restriction of joint movement, poor foot care and foot deformities increase risks for the development of foot ulcers.
Neuropathic bone fractures and joint disease, defined as Charcot foot (neuro-osteoarthropathy), is one of the most destructive foot
complications of diabetes. Charcot foot should be considered in a patient presents with the typical foot deformity (rocker bottom) where
the foot is warm, red, swollen, usually painless with medial arch collapse and large ulcers under the foot, and should be distinguished
from the infection to avoid misdiagnosis and inappropriate treatment. Given that neuro-osteoarthropathy always requires a specific
expertise the patient should be referred to a diabetic foot center.
14.2 CLASSIFICATION
Although there are many classifications of foot ulcers, none of them has internationally recognized. The Wagner-Meggitt classification
classifies wounds by the depth of ulceration and extent of gangrene (Table 14.1).
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Diabetic Foot Ulcers
Table 14.1 Wagner classification of diabetic foot ulcers
Grade 0
Intact skin with bone protrusion and/or callus formation (foot at risk for ulcer).
Grade 1
Superficial ulcer involving the full skin thickness but not deep underlying tissues.
Grade 2
Deep ulcer, penetrating down to tendon, bones, ligaments and joints.
Grade 3
Deep ulcer with abscess formation and/or osteomyelitis.
Grade 4
Localized gangrene involving toes and/or metatarsal bones.
Grade 5
Extensive gangrene involving the heel and/or whole foot which requires amputation.
Wagner FW. Foot Ankle 1981;2:64.
The diabetic foot infections have been classified as mild (limited with subcutaneous tissue), moderate (extensive and involving
underlying tissues) and severe (findings of systemic infection and metabolic disorders) ulcers in 2004 the guidelines by the Council
composed of Infectious Diseases Society of America (IDSA) and International Working Group on the Diabetic Foot (IWGDF).
Table 14.2 shows the diabetic foot ulcer classification based on widely accepted University of Texas ulcer classification system.
Table 14.2 University of texas ulcer classification system
Stage
Grade
A
B
C
D
0
Pre- or post-ulcerative
lesion (completely epithelialized)
1
Superficial ulcer (not involving
tendon, capsule or bone)
No infection or ischemia
Infection exists
but no ischemia
Infection exists
but no ischemia
Both infection
and ischemia exist
No infection or ischemia
Infection exists
but no ischemia
Infection exists
but no ischemia
Both infection
and ischemia exist
2
Deep ulcer
(penetrating to tendon
or capsule, but not involving
bone or joint)to bone/joint)
No infection or ischemia
Infection exists
but no ischemia
Infection exists
but no ischemia
Both infection
and ischemia exist
3
Ulcer
(penetrating to
No infection or ischemia
Infection exists but no
ischemia
Infection exists
but no ischemia
Both infection
and ischemia exist
Wagner FW. Foot Ankle 1981;2:64.
14.3 CLINICAL FINDINGS
Patients with skin lesion that persists for longer than two weeks should be referred to a specialist ¬experienced in the treatment of
diabetic foot.
Priority assessment is to distinguish if the ulcer is ischemic or neuropathic.
The duration, width, depth and smell of the ulcer, the presence of osteomyelitis, and the previous treatment should be considered to
evaluate ulcers in diabetic patients.
The physician should perform sensory examination, examination of peripheral pulses and ankle-brachial pressure index and a
duplex scanning to distinguish a neuropathic ulcer from a vascular disease.
Magnetic resonance angiography (MRA) or conventional angiography can be used for treatment planning.
Tissue oxygen supply is crucial for wound healing, and it is not possible to reach a treatment success unless tissue perfusion is restored.
Infection is clinically evident in the presence of at least two clinical signs of inflammation (erythema, locally increased temperature,
tenderness, pain and induration) or purulent secretion.
The findings related to ischemia or neuropathy can mimic infection. Evidence of infection in a wound is indicated by a putrid smell.
Diabetic foot infection is generally does not cause systemic findings, such as fever and leukocytosis. Existence of such findings
indicates the severity of clinical course.
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81
14.3.1 First Intervention
When diabetic foot infection is first detected the wound should be cleaned, necrotic and gangrenous material should be removed, and
the presence of foreign body and the contact of wound with the bone should be investigated with a blunt-tipped sterile probe.
Deep tissue samples are sent for culture at this stage. Aspiration culture is taken in the presence of a pouch.
Superficial swab culture is not recommended because they reflect colonization. Culture material in superficial wounds can be
obtained by curettage or biopsy.
14.3.2 Laboratory Examination
Complete blood count, basic biochemical tests and serum markers of inflammation (erythrocyte sedimentation rate and C-reactive
protein (CRP) are useful for follow-up and treatment modification.
Direct radiographs provide important information in terms of foreign bodies, flatulence and osteomyelitis.
MRI may be necessary to evaluate the deep tissue infections, abscesses and osteomyelitis.
The most important pathogenic microorganisms in diabetic foot wounds are gram positive cocci (especially Staphylococcus aureus),
β-hemolytic streptococcus (especially group B) and coagulase-negative staphylococci. Gram-positive cocci often cause monomicrobial
infections, however they may occur in chronic ulcers or previously treated wounds in the form of mixed infections. Although anaerobic
bacteria are rarely detected in wounds, they can be observed in mixed infections especially in ischemic and gangrenous wounds.
Pseudomonas and Enterococcus strains are often colonizing agents.
14.3.3 Osteomyelitis
Diagnosis and treatment of osteomyelitis is difficult. Osteomyelitis is often present when the bone is clinically exposed or palpated
with a probe. Osteomyelitis is diagnosed in at least 20% of infected foot ulcers.
Erythrocyte sedimentation rate of >70 mm/h supports the presence of osteomyelitis, but this test has a low sensitivity.
Plain radiographic evidence of osteomyelitis lags behind the bone infection by at least two weeks.
Radio-labeled nuclear imaging techniques such as radio-labeled three-phase leukocyte scintigraphy have greater sensitivity than
plain radiographs, but relatively less specific and have lower accuracy compared with MRI.
The gold standard for the diagnosis of osteomyelitis is to examine the bone biopsies histopathologically and microbiologically. A
tissue sample for culturing should be obtained at least 48 hours following antibiotic discontinuation.
The clinical approach to a diabetic foot ulcer is shown in Figure 14.1.
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Diabetic Foot Ulcers
• Education
• Risk assessment
• The importance of preventive foot care
Low risk
(Both sensory nerve functions
and peripheral pulses are
normal)
Providing education and skill
development
Increased risk
Impaired sensory function,
no distal pulses; or other risk
factors are present.
Examination
• Skin appearance
• Deformities
• Appropriate footwear
• Examination of sensory nerve function with 10-g
monofilament and a non-traumatic pin-prick
• Peripheral circulation and distal pulses
High risk (Impaired sensory
function, no distal pulses; or
history of deformity, skin
changes or ulcers)
Evaluation of other risk factors
(Deformity, smoking, glycemic control, foot care, selection of
appropriate footwear)
Foot ulcer is present
Urgent referral if there is infection
(The treatment of diabetic foot
in accordance with current
guidelines)
Patients with known or suspected Charcot neuro-osteoarthropathy should be referred immediately to a multidisciplinary foot care team!
Figure 14.1 The clinical approach to patients with diabetic foot problems
14.4 TREATMENT
Management of foot ulceration requires wound care, antibiotic treatment, reducing plantar pressure, and tight glycemic control.
All patients with lower extremity ulcer benefit from evidence-based treatments that reduce the risk of atherosclerotic artery disease.
These treatments include smoking cessation, diet, anti-hyperlipidemic drug therapy to achieve target LDL-cholesterol levels,
anti-platelet drug therapy, and optimal glycemic control and HT control.
Diabetic foot ulcers should be evaluated with a multidisciplinary approach. Patients should be evaluated by endocrinologist,
infectious disease specialist, orthopedic specialist, plastic surgeon, vascular surgery specialist, physiotherapist, dietitian and diabetic
foot nurse, and the treatment should be planned.
The duration of hospital stay, amputation rates and treatment costs are reduced with multidisciplinary approach. The treatment of
diabetic foot should be conducted in cooperation with the primary care physician and the internist.
The initial antibiotic preference should include both aerobic and anaerobic spectrum.
14.4.1 Antibiotic Treatment
Antibiotic therapy is modified in accordance with the clinical response, culture results and antibiotic sensitivity during follow-up.
Local antibiotic resistance patterns must be taken into consideration in the selection of treatment (e.g. Methicillin-resistant
staphylococcus aureus: MRSA).
Hepatic and renal functions and any drug allergy history affect antibiotic choice and doses.
While severe infections are treated with intravenous therapy, patients with mild infections can be treated with oral antibiotic therapy.
In the presence of osteomyelitis long-term treatment (4-6 weeks) with the agents that can penetrate into the bone (e.g. quinolones)
has been shown to provide remission.
The mild wounds other than osteomyelitis are treated approximately 2 weeks with antibiotics.
There is a lack of sufficient clinical data to show that some antibiotics penetrate better to the bones in diabetic foot osteomyelitis.
There is not enough evidence to show that topical antibiotics are effective, however topical applications may be considered in mild
superficial wounds.
Some antiseptic preparations may distort tissue healing.
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83
There is not enough data upon the use of larvae in the treatment of osteomyelitis.
The wound is regularly cleaned with isotonic sodium chloride solution.
The main aim of the surgery is to debride infected and necrotic tissues until the level to obtain granulation tissue for secondary recovery.
14.4.2 Wound Care
Surgically debrided ulcer should be monitored regularly. Because the wound is infected very quickly to become a life-threatening
systemic disease.
The bone infections usually originated by direct invasion from the adjacent soft tissue to the bone and become chronic. Therefore the
most definitive treatment is surgical resection of infected and necrotic bone.
Surgical techniques such as free tissue transfer can produce excellent results.
There is not enough data to support routine use of growth factors.
Peripheral artery disease in a diabetic patient typically affects arteries between the knee and ankle.
The standard treatment of ischemic and neuro-ischemic ulcer is autogenous tissue (saphenous vein) and femoro-distal by-pass graft.
14.4.3 Revascularization
A prosthetic graft can be used if a suitable autogenous tissue is not available. The incidence of infections is greatly increased when
a prosthetic graft, rather than autogenous tissue, is implanted.
Conventional angioplasty cannot be applied to the vascular disease with distal and diffuse calcification in diabetic patients with
ischemic ulcers. The methods such as stenting, endarterectomy and subintimal angioplasty can be used in these patients successfully.
The ulcer does not heal unless mechanical loads are removed even though adequate circulation is restored.
Increased load and pressure on the wound cause continuous injury.
14.4.4 Removal of the Pressure
Off-loading measures such as bed rest, crutch-assisted gait, total contact casts, Scotch cast boot and special orthopedic devices
protect the ulcers from pressure and contribute to healing.
The patient Charcot foot is treated with an empirical treatment. In these patients bed resting is required until the skin temperature
returns to normal values. Ankle support shoes and shoes with padded insock should be used. Bisphosphonates can be given. Decision
for surgery requires careful assessment.
14.4.5 Supporting Treatments
The new techniques performing intermittent or continuous negative pressure on the wound may promote a-moist wound healing
environment, facilitate removal of bacteria, and help increase the cell division and subsequent formation of granulation tissue (e.g.
vacuum-assisted closure: VAC device).
Chemical debridement can be managed by special wound dressings.
Hyperbaric oxygen therapy can accelerate wound healing in selected cases with relatively controlled infection, if there is an
adequate perfused capillary bed in the wound area (transcutaneous oxygen pressure >40 mmHg).
14.5 PREVENTION OF RECURRENCE
The recurrence rate of ulcer is 28% at 12 months rising to 100% at 40 months.
Therefore patients with a history of diabetic ulcers or at high-risk should be monitored regularly in special diabetic foot clinics.
Patients with a foot ulceration or ischemia should be evaluated in every 1-2 weeks.
Patients should be informed about the risk of recurrence of foot ulceration.
All diabetic patients should be educated, and especially the patients with loss of pain sensation should be informed how to avoid
from mechanical, thermal and chemical traumas.
Assessment of the feet should be a part of the physical examination on each visit.
Patients should be explained the principles of ulcer treatment, symptoms of infection and the importance of regular foot care.
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Regular foot care, education, hygienic practices and appropriate footwear may result in 50% reduction in ulcer formation.
It is important to lower the pressure on foot to lesser than the threshold pressure predicting ulceration in preventing formation and
recurrence of ulcers.
Patients should not wear the shoes causing ulcer, and choose appropriate footwear according to their deformity and activity level.
There is not enough evidence to support the success and reliability of protective surgical techniques such as Achilles tendon
lengthening and metatarsal head resection in diabetic foot.
SEMT RECOMMENDATIONS FOR DIABETIC FOOT ULCERS
1. All people with diabetes should be instructed on proper foot care and the training should be repeated periodically (Class
D, evidence-based consensus).
2. Foot examination should be performed at every visit, including distal pulses (Class D, evidence-based consensus).
3. Individuals who develop a foot ulcer should be managed by a multidisciplinary healthcare team (Class D, evidence-based
consensus).
15
DIABETES MANAGEMENT IN SPECIAL SITUATIONS
Operations, pregnancy, infection and drug use due to concomitant diseases, and the problems arising from social life (traveling,
driving and habits) can disrupt glycemic regulation in diabetic patients.
The treatment and follow-up protocols which should be performed in special situations are summarized below.
15.1 SURGERY AND DIABETES
15.1.1 Preparation for Surgery in Patients with Diabetes
Patients with diabetes often require surgical procedures besides the general causes for peripheral vascular disease, diabetic foot,
vitrectomy, cataract, and arteriovenous (AV) fistula for end-stage renal disease. Diabetes regulation is an important problem in patients
undergoing surgical procedures. The patient undergoing to surgery may experience problems summarized in four main topics as
follows beside the risks associated with surgery:
1. Hyperglycemia and ketosis
Surgery invokes a stress response with release of counter-regulatory hormones. Counter-regulatory hormone secretion impairs insulin
sensitivity and inhibits insulin secretion especially in patients with insulin deficiency. These changes will accelerate the catabolism and
lead to rapid hyperglycemia and ketosis.
2. Hypoglycemia
Perioperative fasting, a long-acting insulin or OAD given before the operation (e.g. chlorpropamide and glibenclamide) may cause
hypoglycemia. Because the patient under anesthesia or sedation cannot feel warning signs of hypoglycemia or cannot seek help
extremely serious consequences may occur. Therefore, it is necessary to avoid the risk of hypoglycemia in patients, especially in
elderly patients, undergoing to surgery.
3. Perioperative complications
Infection and myocardial infarction are common complications in diabetic patients undergoing to surgery.
4. Suboptimal metabolic control
Negligence of protocols or only partially adherence to protocols during surgery, insufficient follow-up blood glucose levels and
ignorance of obvious deviations of glycemia may lead to problems.
The goal is to maintain blood glucose levels within a target range (e.g., 100 to 125 mg/dL) during the perioperative period.
Recommended target blood glucose levels for patients prone to develop diabetic complications including nephropathy and severe
autonomic neuropathy are in the range of 120 to 180 mg/dL.
A simple and secure protocol should be developed to regulate diabetic patients during surgery, and this protocol should be adapted
by all members of the team (Table 15.1). The protocols in patients treated with insulin and in those who are not using insulin to ensure
glycemia regulation during surgery are different:
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Table 15.1 The preparation protocol for surgery in patients with type 1 and type 2 diabetes
1. Glycemic control should be provided in the preoperative period
• A short-acting agent should be used instead of a long-acting sulfonylurea a few days before minor surgery in patients with type 2 diabetes.
• Patients undergoing to major surgical procedure are hospitalized 2-3 days before surgery, and a short-acting insulin is used in patients with
type 2 diabetes.
2. A consultation with the anesthesiologist is arranged.
3. Operations should be planned in the morning if possible.
4. Patients should not have breakfast and should not take sulfonylurea or insulin in the operation morning.
5. Type 2 diabetic patients not using insulin, undergoing to a minor surgical procedure, is monitored by measuring blood glucose levels in every 2 hours in
the operation day, and routine OAD treatment is started with the first meal after surgery.
6. All patients with type 1 diabetes as well as type 2 diabetic patients, undergoing to major surgical procedures, should receive glucose-insulin-potassium
(GIK) infusion.
GIK solution(*) is prepared as a mixture of 500 mL 5% dextrose, 10 IU short-acting insulin and 10 mmol K (1 ampoule of 7.5% KCl).
• The infusion is started at 08:00-09:00 am in the day of surgery.
• The infusion rate is started at 100 mL/h.
• The infusion is renewed in every 5 hours.
• Blood glucose levels are measured in every 1 to 2 hours and the infusion rate is adjusted to keep the level between 100-125 mg/dL(**).
7. GIK infusion is maintained until oral intake is adequate, then routine treatment is initiated. If the infusion is continued for longer than 24 hours Na+ and K+
must be controlled.
(*)
GIK solution can be prepared as a mixture of 10% dextrose, 15 IU insulin and 10 mmol K+.
Target BG levels should be between 120-180 mg/dL in patients at high risk of hypoglycemia.
(**)
A. Non-insulin treated type 2 diabetic patients
Short-acting agents should be used instead of long-acting sulfonylureas a few days before surgery to reduce the risk of
hypoglycemia.
Many patients with well-controlled diabetes are monitored closely for blood glucose levels during minor surgical procedures.
The patients with uncontrolled diabetes or undergoing major surgical procedures should be monitored and treated as patients
treated with insulin.
B. Type 1 diabetic patients or insulin-treated type 2 diabetic patients
Both insulin and glucose should be given in a continuous infusion during surgery. Glucose and insulin infusions during surgery
reduce the metabolic disturbances and improve the success of surgery.
Although glucose and insulin can be given through separate veins, they can also be given together as a glucose-insulin-potassium
(GIK) infusion to avoid hypokalemia.
15.1.2 GIK Infusion
Glucose and insulin is supplied in the same route in this widely used, practical and safe method. 10 IU short-acting insulin and
10 mmol KCl (1 ampoule of 7.5% KCl) are added to 500 mL 5% dextrose. The insulin infusion rate is determined by blood glucose
levels according to the following protocol (Table 15.2).
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Table 15.2 GIK infusion protocol
Blood glucose level (mg/dL)
≥280
279-220
219-180
179-120
119-80
<80
Infusion rate (mL/h)
140
120
100
80
60
Infusion is interrupted for 2 h
GIK: Glucose-insulin-potassium solution
Alternatively a mixture of 500 mL 10% dextrose, 20 IU short-acting insulin and 10 mmol K may be prepared for patients at risk for fluid
overload. The infusion rate is decreased by 50% of the original protocol, and adjusted according to blood glucose levels, thus fluid
loading could be avoided.
15.1.3 Glucose and InsulinIinfusions Given by Separate Veins
Glucose is administered in 5% dextrose in water at the rate of 100 mL/h, and insulin is given to keep blood glucose levels in the range
of 100-125 mg/dL (between 120-180 mg/dL in patients at high risk of hypoglycemia) at a rate of 2-4 IU/h. Insulin solution is prepared
with 250 IU short-acting insulin within 500 mL saline solution. Insulin infusion should be given from the set of 5% dextrose rather than
directly by intravenous route (Table 15.3). 10% rather than 5% dextrose solution can be chosen in patients at risk for fluid overload.
Table 15.3 Perioperative insulin and glucose infusion protocol given by separate routes
Blood glucose levels (mg/dL)
≤70
71-100
101-150
151-200
201-250
251-300
>300
Insulin infusion
5% dextrose
(mL/h)
(IU/h)
1.0
2.0
3.0
4.0
6.0
8.0
12.0
0.5
1.0
1.5
2.0
3.0
4.0
6.0
15.1.4 Regulation of Glycemia in Specific Surgical Procedures
Insulin requirement changes during surgery in patients with different clinical conditions (Table 15.4).
Table 15.4 Perioperative insulin requirements in different clinical
conditions
Clinical condition
Normal weight
Obese
Liver disease
Steroid users
Sepsis
Cardiopulmonary problems
Insulin (IU /1 g glucose)
0.25-0.35
0.40
0.40-0.60
0.40-0.50
0.50-0.70
0.90-1.20
150
125
100
75
50
0
0
(mL/h)
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Glycemic regulation during open heart surgery
Glucose-rich solutions and inotropic agents given during cardiopulmonary bypass surgery, and hypothermia significantly increases
insulin requirements.
These patients may not be adequately controlled with GIK solution.
Glucose and insulin should be given through separate veins and blood glucose levels should be checked more frequently (e.g. in
every half an hour).
Glucose infusion rate should be kept low during the operation, but immediately converted to the conventional doses after the operation.
According to the literature, patients who received glucose, insulin and potassium during cardiac surgery had less need
for inotropic agents, required a shorter duration of mechanical ventilation, had a shorter hospital stay and had a lower risk of atrial
fibrillation compared to the patients who did not receive this treatment.
Laparoscopic abdominal surgery
Metabolic disorders and insulin resistance that may occur during these types of procedures (e.g. cholecystectomy) are similar to
those seen in open surgeries.
Therefore, surgery preparation guidelines should be strictly adhered and similar protocols should be used.
Cesarean section
Pregnant women with diabetes who require insulin are suggested to receive glucose and insulin in separate routes during delivery.
GIK protocol is safe and reliable in women who undergo an elective section.
GIK solution is prepared with 15-20 IU short-acting insulin within 500 mL 10% dextrose, and the infusion rate is determined by blood
glucose levels.
The α-adrenergic agonists which are used to delay labor and dexamethasone, used to accelerate fetal lung maturation, may
increase insulin requirements.
Upon delivery of placenta the insulin requirement decreases. Therefore, GIK infusion is stopped and blood glucose monitoring is
continued.
After delivery the insulin dose is decreased by half or one-third of the original dose and GIK infusion is reinitiated.
The pre-pregnancy s.c. insulin doses can be given again as oral intake is adequate.
15.2 PATIENTS UNDER TOTAL PARENTERAL NUTRITION THERAPY
Some diabetic patients may need TPN therapy in the postoperative period. TPN can cause serious metabolic problems if not properly
monitored or adjusted.
In this case, the therapy should be initiated with continuous insulin infusion and hourly blood glucose measurements.
Since TPN solution contains a very high concentration of glucose, glucose infusion is not necessary.
Initially, insulin infusion and TPN solution should be administered by different routes.
Once the insulin dose becomes stable by hourly blood glucose measurements (usually after 12-24 hours), total insulin dose given in
the last 24 hours can be added to the TPN solution.
From this point blood glucose levels should be measured every 2-4 hours.
The insulin dosage can be >100 IU/24 h according to the metabolic status and insulin resistance of the patient.
15.3 PREGNANCY AND DIABETES
The compliance with follow-up and treatment protocols in practice is necessary to minimize the risk of fetal and maternal
complications in women with pregestational diabetes, or women with GDM. The principles of diagnosis and treatment in
uncomplicated diabetic pregnancies are summarized in Table 15.5.
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Table 15.5 Principles of follow-up and treatment for pregnant women with diabetes without complication
Follow-up
White Class B-C
• SMBG is required 4 – 7 times a day at home.
• The patient is examined every 2 weeks up to 34 weeks and every week after that.
• The second level ultrasonography is performed at 20 weeks and then repeated every 4 – 6 weeks.
• A1C is measured every month.
• Fetal movements are evaluated.
• A non-stress test is carried out at 32 and 34 weeks.
• Fundus is examined every trimester.
• Microalbuminuria is checked with a 24 hour urine sample every trimester.
White Class D-FR
• In addition to the above, ECG, and uric acid, transaminases, fibrinogen and fibrin degradation products levels are measured in each trimester.
Insulin treatment
• The basal-bolus insulin regimen is used in the therapy of both pregestational (type 1 and type 2) diabetic patients and GDM cases with
FPG>95 mg/dL, 1 h PG>140 mg/dL and 2 h PG>120 mg/dL.
• A regular insulin is given 3 times a day before meals, and NPH insulin at night.
NPH may be administered in two doses (morning and evening or noon and night) in patients who are inadequately controlled.
Delivery time
• In White A and B patients, if glycemia is well regulated delivery is planned in ≤42 weeks.
•I n White C-FR patients, delivery should be planned in term or when lung maturity has been completed.
Delivery
• GIK is infused based on blood glucose levels. An NaCl 0.9% is also infused if needed.
15.3.1 Gestational Period
Glycemic control targets
Targets for venous PG levels measured by glucose oxidase method and A1C goals are summarized below:
Fasting (FPG) ≤95 mg/dL
1 h postprandial PG levels 100-140 mg/dL (preferably 100-120 mg/dL)
2 h PG 90-120 mg/dL
A1C ≤6.5% (preferably <6.0%).
Treatment
A. The principles of medical nutrition therapy (MNT)
Daily caloric requirements
Calories are calculated according to ideal body weight.
24 kcal/kg for obese diabetic patients
A diet of 30 kcal/kg ideal body weight in the first trimester, with an increase to 35 kcal/kg ideal body weight in the second trimester
in non-obese patients
Food components
The food components in total daily caloric requirements should be calculated as follows:
Carbohydrates: 45-50% (≥200 g/day)
Proteins: 18-20% (1-1.5 g/kg/day)
Fats: 30-35% (40-60 g/day)
In addition, pregnant women need sufficient vitamin and mineral intakes:
Iron: 18 mg/day
Folic acid: 400-800 mg/day
Calcium: 1200 mg/day
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Number of meals
Pregnant women should have a meal planning in 7 parts in a distribution of 3 main meals and 4 snacks. Daily calorie intake should
be distributed as follows:
Main meals: 3/18 in the morning, 4/18 at noon, and 4/18 in the evening
2/18 in each snack
1/18 at bedtime snack
The rate of weight gain
1-2 kg in the first trimester
250-500 g per week in the second and third trimesters
Total weight gain during pregnancy should not exceed 10-12 kg.
B. Principles of medical treatment
Gestational diabetes
1. Insulin should be initiated if FPG >105 mg/dL and/or 1 h PG levels >140 mg/dL despite two weeks of dietary treatment (insulin
therapy may be initiated in patients with FPG >95 mg/dL and trained against the risk of hypoglycemia).
2. If FPG is 105-120 mg/dL, and 1 h PG levels are 120-160 mg/dL, 0.3-0.4 IU/kg/day intermediate acting NPH insulin can be given as a
single dose at night.
3. If FPG >120 mg/dL, and 1 h PG levels >200 mg/dL, 0.7 IU/kg/day mixed insulin (short acting + NPH) can be given in two doses.
4. Basal-bolus insulin therapy should be implemented as early as possible in patients with symptoms of hyperglycemia or who
cannot be controlled with the therapy mentioned above.
5. Dosage adjustment is done according to the results of SMBG at least 3 days per week for 4-7 times a day.
SEMT RECOMMENDATIONS FOR MANAGEMENT OF GESTATIONAL DIABETES
1. Women with GDM should achieve the following glycemic targets:
o Fasting and preprandial PG ≤95 mg/dL
o 1 h postprandial PG (PPG) 100-140 mg/dL
o 2 h PPG 90-120 mg/dL
o A1C ≤6.5% (preferably <6.0%)
• SMBG should be undertaken at least 3 times per day, 4-7 times a day (both pre- and postprandial and at night) to achieve
glycemic targets and improve pregnancy outcomes [Class C, Level 3 evidence (1)].
• 1-h PPG levels should be preferred in postprandial monitoring (Class D, evidence based consensus).
• Nutrition counseling should be received from a dietitian who is a part of the diabetes health care team during pregnancy and
postpartum period [in pregnancy: Class C, Level 3 evidence (2); postpartum period: Class D, evidence based consensus].
• Recommendations for weight gain during pregnancy should be based on pregravid BMI [Class D, evidence based consensus].
• Ketosis should be avoided during pregnancy [Class C, Level 3 evidence (3)].
2. Insulin treatment should be initiated in women with GDM who cannot achieve adequate glycemic control despite two-week
dietary treatment (Class D, evidence based consensus).
• Insulin regimen should be individualized to achieve glycemic targets, with consideration given to intensive insulin therapy
[Grade A, Level 1A evidence (4)].
3. As women who have had GDM are defined at high risk of developing subsequent type 2 diabetes, a standard OGTT (with
75-g glucose) should be performed between 6 weeks and 6 months postpartum [Class D, evidence based consensus].
4. Women with previous GDM should follow the screening and prevention guidelines for other high-risk groups for type 2
diabetes [Class D, evidence based consensus].
• They should be rescreened for type 2 diabetes when planning another pregnancy [Class D, evidence based consensus].
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REFERENCES
1. Nachum Z, Ben-Shlomo I, Weiner E, et al. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomized controlled trial.
BMJ 1999;319:1223-7.
2. Langer O, Conway DL, Berkus MD, et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134-8.
3. Bertini AM, Silva JC, Taborda W, et al. Perinatal outcomes and the use of oral hypoglycemic agents. J Perinat Med 2005; 33:519-23.
4. Jacobson GF, Ramos GA, Ching JY, et al. Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care
organization. Am J Obstet Gynecol 2005;193:118-24.
Pregestational diabetes
In patients with insulin requirement of ≥0.8 IU/kg/day, insulin is applied 3-5 times a day according to basal-bolus insulin regimen.
There is no consensus about the use of rapid-acting insulin analogues (lispro, aspart) in pregnancy. However, an increasing
number of clinical studies reported successful results because these insulins provide physiological insulinemia, and they were taken
to category B in pregnancy.
Similarly the use of insulin pump provides a more physiological insulinemia in trained and motivated patients.
SEMT RECOMMENDATIONS FOR MANAGEMENT OF PREGESTAT‹ONAL DIABETES
1. Women with type 1 or type 2 diabetes of reproductive age should:
• Use a reliable birth control method if sexually active and not desire pregnancy [Class D, evidence based consensus].
• Be counseled about the necessity of pregnancy planning, including the importance of good glycemic control and the
need to stop potentially embryopathic drugs prior to pregnancy [Class D, evidence based consensus].
2. Before attempting to become pregnant, women with type 1 or type 2 diabetes should:
• Receive preconception counseling regarding optimal diabetes management and nutrition, preferably in consultation with
an interdisciplinary pregnancy team, to optimize maternal and neonatal outcomes [Class C, Level 3 evidence (1-3)].
• Strive to attain a preconception glycemic control (optimal A1C should be ≤6.5%, if the patient is not at high risk of
hypoglycemia A1C target can be 6.0%) to minimize the risk of:
o Spontaneous abortions [For type 1 diabetes: Class C, Level 3 evidence (4); for type 2 diabetes: Class D, evidence
based consensus]
o Congenital malformations [Class C, Level 3 evidence (1-6)]
o Pre-eclampsia [Class C, Level 3 evidence (7,8)]
o Progression of retinopathy in pregnancy [For type 1 diabetes: Class A, Level 1A evidence (9); for type 2 diabetes:
Class D, evidence based consensus].
• The women attempting to become pregnant should be supplemented with 5 mg/day folic acid at least 3 months
preconception and continuing until at least 12 weeks postconception. From 12 weeks postconception and throughout the
pregnancy, the first 6 weeks postpartum and as long as breastfeeding continues, supplementation should consist of 0.4
to 1.0 mg/day folic acid [Class D, evidence based consensus].
• The medications considered to be potentially embryopathic, including any from the following classes should be discontinued:
o ACE-Is and ARBs [Class C, Level 3 evidence (10)]. In the presence of HT, these may be replaced with antihypertensive
agents that are known to be safe in pregnancy such as calcium channel blockers, beta-blockers, labetolol,
hydralazine and methyldopa [Class D, evidence based consensus].
o Statins [Class D, Level 4 evidence (11)].
• Women planning pregnancy should undergo an ophthalmologic evaluation by a specialist. Repeat assessments should
be performed during the first trimester, as needed during the rest of the pregnancy and within the first year postpartum
[For type 1 diabetes: Class A, Level 1 evidence (9-12); for type 2 diabetes: Class D, evidence based consensus].
• Women attempting to become pregnant should be screened for nephropathy [Class D, evidence based consensus]. If
microalbuminuria or overt nephropathy is found, glycemic and BP control should be optimized to minimize maternal and
fetal complications and to delay progression of nephropathy [Class C, Level 3 evidence (13,14)].
3. Women with type 2 diabetes who are planning pregnancy or become pregnant should:
• Switch from OADs to insulin [Class D, evidence based consensus].
• In the setting of PCOS metformin can be safely used for ovulation induction [Class D, evidence based consensus].
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• The safety of metformin beyond ovulation induction in women with type 2 diabetes remains unknown [Class D, evidence
based consensus].
• Receive an individualized insulin regimen to achieve glycemic targets, with consideration given to intensive insulin therapy
[Class A, Level 1 evidence (15)].
4. Pregnant women with type 1 or type 2 diabetes should:
• Strive to achieve target glucose values:
o Fasting/preprandial PG ≤95 mg/dL
o 1 h PPG 100-140 mg/dL
o 2 h PPG 90-120 mg/dL
o A1C ≤6.5% (preferably 6.0%)
• Perform SMBG at least 3 days and 4-7 times a day (pre- and postprandial and at night) to achieve glycemic targets and
improve pregnancy outcomes [Class C, Level 3 evidence (1)].
• 1 h PPG should be preferred in postprandial monitoring (Class D, evidence based consensus).
• Receive nutrition counseling from a dietitian who is a part of the diabetes health care team during pregnancy and
postpartum period [in pregnancy: Class C, Level 3 evidence (3); postpartum period: Class D, evidence based consensus].
• Weight gain during pregnancy should be based on pregravid BMI [Class D, evidence based consensus].
• Ketosis should be avoided during pregnancy [Class C, Level 3 evidence (16)].
• Pregnant women with type 1 diabetes should receive intensive insulin therapy with multiple daily injections or an insulin
pump [Class A, Level 1A evidence (15,17)].
• Pregnant women with type 1 diabetes should be screened for postpartum thyroiditis with TSH levels at 6 weeks
postpartum [Class D, evidence based consensus].
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2.
3.
4.
5.
6.
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8.
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Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis.
QJM 2001;94:435-44.
Kitzmiller JL, Gavin LA, Gin GD, et al. Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 1991;265:731-6.
McElvy SS, Miodovnik M, Rosenn B, et al. A focused preconceptional and early pregnancy program in women with type 1 diabetes reduces perinatal
mortality and malformation rates to general population levels. J Matern Fetal Med 2000;9:14-20.
Jovanovic L, Knopp RH, Kim H, et al. Elevated pregnancy losses at high and low extremes of maternal glucose in early normal and diabetic pregnancy:
evidence for a protective adaptation in diabetes. Diabetes Care 2005;28:1113-7.
Suhonen L, Hiilesmaa V, Teramo K. Glycaemic control during early pregnancy and fetal malformations in women with type I diabetes mellitus. Diabetologia
2000;43:79-82.
Guerin A, Nisenbaum R, Ray JG. Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care 2007;30:1920-5.
Hiilesmaa V, Suhonen L, Teramo K. Glycaemic control is associated with pre-eclampsia but not with pregnancy-induced hypertension in women with type
I diabetes mellitus. Diabetologia 2000;43:1534-9.
Hsu CD, Tan HY, Hong SF, et al. Strategies for reducing the frequency of preeclampsia in pregnancies with insulin-dependent diabetes mellitus. Am J
Perinatol 1996;13:265-8.
The Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and
Complications Trial. Diabetes Care 2000;23:1084-91.
Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med
2006;354:2443-51.
Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 2004;350:1579-82.
The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch
Ophthalmol 1998;116:874-86.
Ekbom P, Damm P, Feldt-Rasmussen B, et al. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001;24:1739-44.
Reece EA, Leguizamon G, Homko C. Stringent controls in diabetic 180 mg/dl nephropathy associated with optimization of pregnancy outcomes. J Matern
Fetal Med 1998;7:213-6.
Nachum Z, Ben-Shlomo I, Weiner E, et al. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomized controlled trial.
BMJ 1999;319:1223-7.
Rizzo T, Metzger BE, Burns WJ, et al. Correlations between antepartum maternal metabolism and child intelligence. N Engl J Med 1991;325:911-16.
The Diabetes Control and Complications Trial Research Group. Pregnancy outcomes in the Diabetes Control and Complications Trial. Am J Obstet Gynecol
1996;174:1343-53.
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15.3.2 Delivery
Preferably delivery by the vaginal route at 38 weeks is recommended.
The delivery must take place in pregestational diabetics classified as C-FR in White classification when fetal pulmonary maturation
has completed.
Glycemic levels during labor are followed in accordance with GIK infusion protocol. (GIK infusion has been described under the
heading of ‘Diabetes and surgery’ previously. See Chapter 15.1).
GIK protocol is continued until normal oral intake can be resumed.
Women can switch to preconception insulin therapy when oral intake is adequate.
15.3.3 Postnatal Period
After delivery the need for insulin is reduced.
The treatment is rearranged by taking into consideration therapeutic doses before pregnancy.
Lactation should be started as soon as possible and CH should be increased 50g/day in daily energy requirements.
If glycemic targets are not achieved using lifestyle modifications in pregestational type 2 diabetic patients and postpartum GDM
cases insulin therapy should be continued during lactation period.
15.4 TREATMENT OF HYPERGLYCEMIA IN INTENSIVE CARE UNIT
Hyperglycemia in patients with previously known diabetes or newly onset diabetes who are monitored in medical and surgical
intensive care units is one of the key factors determining morbidity and mortality. Although previous studies have been reported good
results with intensive insulin therapy in patients monitored in the coronary care unit due to acute myocardial infarction, subsequent
studies revealed contradictory results. But as a result of new meta-analyses including the NICE-SUGAR study published in 2009, and
similar studies, tight glycemic goals have been adopted to avoid hypoglycemia that may increase the risk of mortality. The revised SEMT
approach is summarized below in light of recently published ADA/EASD consensus on this issue.
SEMT RECOMMENDATIONS FOR MANAGEMENT OF HYPERGLYCEMIA IN INTENSIVE CARE UNIT PATIENTS
1. Provided that their medical conditions, dietary intake and glycemic control are acceptable, patients with diabetes should be
maintained on their prehospitalization regimens [Class D, evidence based consensus].
2. In critically ill patients:
• Insulin therapy should be initiated for treatment of persistent hyperglycemia, starting at a threshold of 180 mg/dL (Class
D, evidence based consensus).
• Intravenous insulin infusion is the preferred method for achieving and maintaining glycemic control in critically ill patients
[Class D, evidence based consensus].
• Glycemic levels should be maintained between 140-180 mg/dL in critically ill patients using insulin [Class A, Level 1A
evidence (1)].
• Validated insulin infusion protocols with demonstrated safety and efficacy, and with low risk of hypoglycemia are
recommended (Class D, evidence based consensus).
• In patients on i.v. insulin therapy, frequent glucose monitoring is essential to minimize the risk of hypoglycemia and to
achieve optimal glucose control (Class D, evidence based consensus).
• To maintain intraoperative glycemic levels between 100 and 180 mg/dL for patients with diabetes undergoing coronary
artery bypass surgery, a continuous i.v. insulin infusion alone [Class C, Level 3 evidence (2-5)] or with the addition of
glucose and potassium [Class B, Level 2 evidence (6)].
3. Non-critically ill patients (Class D, evidence based consensus):
• For the majority of noncritical ill patients, premeal PG target should generally be <140 mg/dL in conjunction with random
PG levels <180 mg/dL, provided these targets can be safely achieved.
• In patients already in tight glucose control, lower glycemia levels can be achieved.
• Less stringent targets may be appropriate in terminally ill patients or in patients with severe comorbidities.
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• A proactive approach that may include s.c. basal-bolus insulin along with correction-doses is preferred over the “sliding
scale” reactive approach using only a short- or a rapid-acting insulin after hyperglycemia has occurred [Class D,
evidence based consensus].
• Non-insulin antihyperglycemic agents are not appropriate in most hospitalized patients who require therapy for
hyperglycemia.
• Clinical judgment and ongoing assessment of clinical status must be incorporated into day-to-day decisions regarding
treatment of hyperglycemia.
4. Safety [Class B, Level 2 evidence (7,8)].
• Overtreatment and undertreatment of hyperglycemia represent major safety concerns.
• In hospitalized patients the therapy should be conducted with an appropriate protocol and trained staff to ensure the safe
and effective implementation of this therapy and to minimize the likelihood of hypoglycemia.
• Caution is required in interpreting results of point of care glucose meters in patients with anemia, polycythemia, hypoper
fusion, or use of some medications.
5. Cost [Class A, Level 1A evidence (9,10)].
• Appropriate inpatient management of hyperglycemia is cost-effective.
6. Discharge planning
• Preparation for discharge should begin at the time of hospital admission.
• Discharge planning, patient education, and clear communication with outpatient providers are critical for ensuring a safe
and successful transition to outpatient glycemic management.
7. Other issues [Class B, Level 2 evidence (8)].
• Hyperglycemia is a common complication of corticosteroid therapy. A reasonable approach is to institute glucose
monitoring for at least 48 h in all patients receiving high-dose glucocorticoid therapy and to initiate insulin therapy as appropriate.
• In patients who are receiving continuous enteral or parenteral nutrition, glucose monitoring is optimally performed every
4-6 h. More frequent BG testing, ranging from every 30 min to every 2 h, is required for patients receiving i.v. insulin infusions.
REFERENCES
1. The NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med
2009;360:1283-97.
2. Furnary AP, Zerr KJ, Grunkemeier GL, et al. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients
after cardiac surgical procedures. Ann Thorac Surg 1999;67:352-60.
3. Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass
grafting. J Thorac Cardiovasc Surg 2003;125:1007-21.
4. Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland
Diabetic Project. Endocr Pract 2004;10(Suppl. 2):21–33.
5. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001;345:1359-67.
6. Lazar HL, Chipkin SR, Fitzgerald CA, et al. Tight glycaemic control in diabetic coronary artery bypass graft patients improves perioperative outcomes and
decreases recurrent ischemic events. Circulation 2004;109:1497-502.
7. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA 2008;300:933–44.
8. Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement
on Inpatient Glycemic Control. Diabetes Care 2009;32:1119-31, and Endocrine Practice 2009;15:1-15.
9. Krinsley JS, Jones RL. Cost analysis of intensive glycemic control in critically ill adult patients. Chest 2006;129:644–50.
10. Van den Berghe G, Wouters PJ, Kesteloot K, et al. Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients. Crit Care
Med 2006;34:612-6.
15.5 TREATMENT OF CORTICOSTEROID RELATED HYPERGLYCEMIA
Certain drugs, commonly used today may cause hyperglycemia in people without diabetes or may impair glycemic control in patients
with previously known diabetes (Table 15.6). Glucocorticoids are the most well-known of these drugs.
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Table 15.6 Drugs that cause hyperglycemia
Strong effect
Glucocorticoids
Oral contraceptives
High-dose estrogen preparations
Levonorgestrel (combined)
Drugs containing high dose (>5 mg/day) thiazide diuretics
β2-adrenoceptor antagonists
B2-adrenoceptor agonists
Salbutamol
Ritodrine
Atypical antipsychotics
Clozapine
Olanzapine
HIV protease inhibitors
Indinavir
Nelfinavir
Other hyperglycemic agents
Pentamidine
Streptozotocin
Diazoxide
Cyclosporin
Tacrolimus
Light effect
Oral contraceptives
Drugs containing low dose (≤2.5 mg/day) thiazide diuretics
Loop diuretics
ACE-I
Calcium channel blockers
α1-antagonists
Growth hormone
Somatostatin analogues
SSRI
ACE-I: Angiotensin converting enzyme inhibitors, SSRI: Selective serotonin re-uptake inhibitors
Glucocorticoids reduce the peripheral and partly hepatic insulin sensitivity by affecting post-receptor mechanisms.
High-dose prednisolone (≥30 mg/day) impairs glycemic regulation in known diabetics, and increases short-acting insulin
requirement. Insulin resistance and hyperglycemia, occurred in patients using prednisolone over the physiological doses (>7.5
mg/day) may return to normal after discontinuation of medication.
Almost 14-28% of people without diabetes develop IGT or diabetes with glucocorticoid use. Insulin response to glucose decreases in OGTT.
In diabetes induced by glucocorticoids, an OAD or more favorably insulin should be used.
Patients receiving high dose glucocorticoid therapy should initiate insulin.
The insulin dose should be increased (by ~50%) in diabetic patients under insulin treatment.
SEMT RECOMMENDATIONS FOR GLUCOCORTICOID INDUCED HYPERGLYCEMIA
1. FPG is relatively normal in diabetics using glucocorticoid, whereas postprandial glycemia is high in the afternoon and in
the evening (Class D, evidence based consensus).
2. A short/rapid-acting insulin should be preferred in hyperglycemia related to the use of high dose glucocorticoids. Basal
insulin may be required in patients using single-dose steroid (Class D, evidence based consensus).
3. The insulin dose can be increased by 50% in patients under insulin treatment (Class D, evidence based consensus).
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15.6 DIABETES IN THE ELDERLY
Older population with diabetes is growing with prolonged life expectancy in our country and diabetes care and treatment of this group
constitutes problem. The relevant approach and recommendations by SEMT are summarized below.
SEMT RECOMMENDATIONS FOR MANAGEMENT OF DIABETES IN THE ELDERLY
1. Similar to other risk groups, in elderly individuals with IGT, a structured program of lifestyle modification that includes
moderate weight loss and regular physical activity should be considered to reduce the risk of type 2 diabetes [Class A, Level
1A evidence (1)].
2. Otherwise healthy elderly people with diabetes should be treated to achieve the same glycemic, BP and lipid targets as
younger people with diabetes [Class D, evidence based consensus].
• In people with multiple comorbidities, restricted functional capacity or limited life expectancy, the goals should be
less stringent [Class D, evidence based consensus].
3. Elderly people with diabetes living in the nursing house should be referred for interdisciplinary interventions [Class D,
evidence based consensus].
4. Mild aerobic (and if necessary endurance exercise may benefit elderly people with type 2 diabetes and should be
recommended for those individuals in whom it is not contraindicated [Class B, Level 2 evidence (2,3-5)].
• In elderly people with type 2 diabetes, sulfonylureas should be used with caution because the risk of hypoglycemia
increases exponentially with age [Class D, Level 4 evidence (6)].
• In general, initial doses of sulfonylureas in the elderly should be half those used for younger people, and doses
should be increased more slowly or switched to glinides [Class D, evidence based consensus].
• Gliclazide [Class B, Level 2 evidence (7,8)] and glimepiride [Class C, Level 3 evidence (9)] are the preferred
sulfonylureas, as they are associated with a reduced frequency of hypoglycemic events.
• Glinides (repaglinide and nateglinide) should be considered in patients with irregular eating habits [Class D,
evidence based consensus].
5. In elderly people, the use of premixed insulins and prefilled insulin pens should be considered to reduce dose errors, and
to potentially improve glycemic control [Class B, Level 2 evidence (10-12)].
REFERENCES
1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med
2002;346:393-403.
2. Tessier D, Ménard J, Fülöp T, et al. Effects of aerobic physical exercise in the elderly with type 2 diabetes mellitus. Arch Gerontol Geriatr 2000;31:121-32.
3. Ligtenberg PC, Hoekstra JBL, Bol E, et al. Effects of physical training on metabolic control in elderly type 2 diabetes mellitus patients. Clin Sci (Lond).
1997;93:127-35.
4. Dunstan DW, Daly RM, Owen N, et al. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes. Diabetes Care
2002;25:1729-36.
5. Castaneda C, Layne JE, Munoz-Orians L, et al. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with
type 2 diabetes. Diabetes Care 2002;25:2335-41.
6. Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycaemia: a report on 57 cases. Diabetologia 1983;24: 412-7.
7. Tessier D, Dawson K, Tétrault JP, et al. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Diabet Med. 1994;11:974-80.
8. Schernthaner G, Grimaldi A, Di Mario U, et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients.
Eur J Clin Invest 2004;34:535-42.
9. Holstein A, Plaschke A, Egberts EH. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.
Diabetes Metab Res Rev 2001;17:467-73.
10. Coscelli C, Calabrese G, Fedele D, et al. Use of premixed insulin among the elderly. Reduction of errors in patient preparation of mixtures. Diabetes Care
1992;15:1628-30.
11. Corsi A, Torre E, Coronel GA, et al. Pre-filled insulin pen in newly insulin-treated diabetic patients over 60 years old. Diab Nutr Metab 1997;10:78-81.
12. Coscelli C, Lostia S, Lunetta M, et al. Safety, efficacy, acceptability of a pre-filled insulin pen in diabetic patients over 60 years old. Diabetes Res Clin Pract
1995;28:173-7.
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15.7 DIABETES AND TRAVELING
Diabetes is not an obstacle to travel. But the changes in eating habits and physical activity increase, or going beyond the routine
application in medical treatment may affect the glycemic levels.
Diabetic patient using insulin should have an identity card stating he/she has diabetes.
Insulin vials or cartridges, insulin pen or syringes and pen needles as well as insulin cooler, glucometer, sufficient quantities of lancets
and glucose measurement strips, and additional battery should be packed in travel bag.
The patient should have adequate amount of sugarless liquid and water. Also fruit juice, sugar cubes or glucose tablets and biscuits
should be kept in the bag to use in case of hypoglycemia.
Diabetes handbag should not be put in the check-in luggage as there is a risk of the luggage being lost.
Prior to travel, particularly by air, the physician should be informed about the travel planning (departure time, travel length, meal time,
offered food and arrival time) and necessary treatment changes should be learned.
Flight crew should be informed, extra CHs should be kept, and patient should be vigilant against the delay.
Insulin doses should be adjusted during long distance flights.
Glucose levels should be measured every 3-4 hours throughout the journey, especially in time zone changes, and the treatment
should be continued to keep the level of glycemia between 120-180 mg/dL.
15.7.1 Travel of Patients with Type 1 Diabetes and Patients with Type 2 Diabetes Using Insulin
1. When patient travels from north to south (or vice versa) there will not be time zone difference and there will not be a big change in
times of meals and insulin injections.
2. As in going west the days are longer
• Before flight: Normal insulin dose is taken.
• During flight: Additional insulin is applied if the flight is longer than 8 hours.
• On arrival: The next dose is applied at the scheduled time according to a new local time.
3. As in going east the days are shorter
• Before flight: Normal insulin dose is decreased
• During flight: Additional insulin is applied if necessary due to measured glucose levels.
• On arrival: The next dose is applied at the scheduled time according to a new local time.
15.7.2 Travel of Non-Insulin Dependent Type 2 Diabetic Ratients
These patients should be advised to use short-acting agents (glinides) in long journeys.
15.8 IMMUNIZATION IN PATIENTS WITH DIABETES
International authorities such as ADA, WHO and The Centers for Disease Control and Prevention’s Advisory Committee on
Immunization Practices (http://www.cdc.gov/vaccines/recs/) recommend influenza and pneumococcal vaccination for all patients
with diabetes. The relevant SEMT recommendations are summarized below.
SEMT RECOMMENDATIONS FOR VACCINATION IN PATIENTS WITH DIABETES
1. Childhood routine immunization program should be continued in children with type 1 diabetes (Class D, evidence based consensus)
2. Individuals with diabetes are at high risk for complications and mortality related to influenza and pneumococcal infection
[Class C, Level 3 evidence (1,2)].
3. People with diabetes should receive an annual influenza vaccine to reduce the risk of complications associated with
influenza epidemics [Class B, Level 2 evidence (3)].
4. Influenza vaccine in early September each year is highly protective for people with diabetes.
5. As people with diabetes are at least as susceptible to pneumococcal infection as other people with chronic diseases, the use
of the pneumococcal vaccine once in lifetime should be encouraged [Class D, Level 4 evidence (4)].
6. Pneumococcal revaccination is recommended for individuals ?65 years of age if the original vaccine was administered when
they were <65 years of age and >5 years earlier (Class D, evidence based consensus).
7. Pneumococcal vaccine should be repeated in patients with immunosuppression, nephrotic syndrome, chronic renal failure
and transplantation (Class D, evidence based consensus).
8. People with diabetes should take place within all social protection and eradication programs (Class D, evidence based consensus).
9. Patients with diabetes who will travel to endemic areas are recommended to receive required vaccination according to the
destination.
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REFERENCES
1. Colquhoun AJ, Nicholson KG, Botha JL, et al. Effectiveness of influenza vaccine in reducing hospital admissions in people with diabetes. Epidemiol Infect
1997;119:335–41.
2. American Diabetes Association: Influenza and pneumococcal immunization in diabetes (Position Statement). Diabetes Care 2004;27(Suppl.1):S111–S113.
3. Heymann AD, Shapiro Y, Chodick G, et al. Reduced hospitalizations and death associated with influenza vaccination among patients with and without
diabetes. Diabetes Care 2004;27:2581-4.
4. Bolan G, Broome CV, Facklam RR, et al. Pneumococcal vaccine efficacy in selected populations in the United States. Ann Intern Med 1986;104:1-6.
15.9 MANAGEMENT OF DIABETES DURING NATURAL DISASTERS
The SEMT approach on this issue is summarized below (Class D, evidence based consensus).
SEMT RECOMMENDATIONS FOR MANAGEMENT OF DIABETES DURING NATURAL DISASTERS
• People with diabetes should make a portable diabetes disaster kit to use in the event of a flood, earthquake or other
natural disaster in case of hypoglycemic and hyperglycaemic emergencies (DKA and HHS), and the contents should be
checked at least twice a year in terms of the amounts and expiration dates.
• Since our country lies on an earthquake zone, nurseries, schools, caring homes, and all institutions employing or caring
people with diabetes should be required to keep such disaster kit.
• Disaster kits in these institutions should include adequate amount of insulin vials (short- and long-acting insulins), insulin
syringes, glucagon vials, glucometer and blood glucose strips, urine ketone strips, i.v. solutions (10% dextrose, 0.9% NaCl)
and some certain OADs (sulphonylureas, metformin).
• In the same way, people with diabetes and their relatives or responsible care-providers should prepare a small emergency
kit with currently used drugs and insulins to use in hypo-and hyperglycemia emergencies and should store it in a place
known by household.
15.10 DIABETES AND RELIGIOUS TASKS
People with chronic diseases like diabetes may experience some negative issues in fulfilling their religious duties. The items below
summarize the issues which should be considered during fasting and pilgrimage by patients belonging to the religion of Islam.
Similarly patients belonging to Christianity and Judaism can fulfill their religious duties by consulting their physicians, and as their health
status requires.
15.10.1 Hajj Mission
The general rules of travelling that diabetics have to follow are valid for pilgrimage. SEMT approach in this issue is summarized below
(Class D, evidence based consensus).
SEMT RECOMMENDATIONS FOR HAJJ MISSION
• Elderly diabetic patients with complications should interview their health condition with their physicians before going to
pilgrimage, and fulfill this task if their health status is appropriate.
• Diabetic patients going to Hajj should receive vaccinations recommended for diabetic patients.
• All diabetic patients should increase the frequency of SMBG during the pilgrimage duties.
• Especially in the summer, hot environments may cause unexpected hypoglycemia in diabetics using insulin. Therefore,
patients are required to carry sugar and fruit juice with them.
• Fluid intake should be increased, and direct sunlight exposure should be avoided.
• Since physical activity is increased while performing his/her duties during pilgrimage, patient with diabetes should be alert
against the risk of hypoglycemia, and insulin/OAD dose adjustments should be performed, if necessary.
• Diabetic patient should wear proper footwear during the collective worship in crowded environments (circumambulation of
the Kaaba), and should avoid to walk barefoot or wearing slippers since it may increase the risk of injury and infection.
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15.10.2 Diabetes and Fasting
Although some small studies carried out in some Islamic countries have reported that fasting does not impair metabolic control in
patients on diet or OAD therapy, but other studies do not support these findings.
SEMT approach in this issue is summarized below (Class D, evidence based consensus).
SEMT RECOMMENDATIONS FOR FASTING
• Ramadan fasting may be hazardous in patients with type 1 and type 2 diabetes because it may lead to severe hypo
glycemia, and hyperglycemia after the meals taken after sunset and before dawn, and also it might disrupt fluid and
electrolyte balance.
• Fasting should be strictly prohibited in patients with type 1 and type 2 diabetes on basal-bolus insulin therapy.
• Training sessions should be arranged for patients for information before Ramadan, and if necessary, support from religious
authority should be provided.
15.11 DIABETES CARE FOR PEOPLE LIVING IN SPECIAL SETTINGS
15.11.1 Diabetic Patients Living in Orphanages, Nursing Homes or Prisons
SEMT recommendations regarding care and therapy of diabetic patients living in orphanages, nursing homes or prisons are
summarized below (Class D, evidence based consensus).
SEMT RECOMMENDATIONS FOR PEOPLE WITH DIABETES LIVING IN SPECIAL SETTINGS
1. Medical history of the people with diabetes who are admitted to institutions (prison, detention center, orphanage or
nursing home) should be questioned by the doctors or nurses, and physical examination should be performed immediately.
2. When the patients on insulin therapy first arrived to institution glycemic levels should be measured in 1-2 hours.
3. Pharmacological treatment and MNT of patients should be continued without interruption without changing the insulinmeal timing, and physical activity opportunities as well as snack meals should be provided.
4. Institution staff should be informed about the symptoms and treatment of hypo-and hyperglycemia, and be taught to inject
glucagon if needed.
5. When PG level is measured <50 mg/dL or >350 mg/dL on-duty personnel should inform the physician and refer the patient
to hospital immediately.
6. Patient should be referred to a hospital containing a diabetes unit for periodic screening for diabetes complications.
7. Insulin and OAD should be provided, glycemic monitoring should be performed at an appropriate frequency, necessary
material for SMBG should be provided, and the patient should be referred to hospital every 3-6 months for A1C measurement.
8. Discharge report should include the patient’s history of diabetes and treatment in details.
9. Residents of prisons or nursing homes without known diabetes should be reviewed in terms of risk factors for diabetes and
should undergo diabetes screening.
15.11.2 Diabetes At Workplace
The number of individuals with diabetes at various business lines is increasing with the increase of people with diabetes and better
care opportunities. To reduce the problems faced in workplace by individuals with diabetes, some issues have to be taken into
consideration. SEMT recommendations in this issue are summarized below (Class D, evidence based consensus).
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SEMT RECOMMENDATIONS FOR MANAGEMENT OF DIABETES IN THE WORKPLACE
1. Health authorities and civil organizations working in the field of diabetes should inform the employers about breaking
prejudice and negative discriminations directed against diabetic patients at stages of employment and workplace safety.
2. People with diabetes, when applying for a new job, must be considered on an individual basis with medical history, disease
stage, drugs, and special circumstances of this new job.
3. If there are doubts raised from diabetes in terms of employment eligibility to work, the situation should be evaluated by
a physician expert in diabetes treatment.
4. Whether the business environment and job pose a risk for people with diabetes should be evaluated in an objective
manner, and protective measures and positive discrimination should be implemented, if necessary.
5. People with well-controlled diabetes without serious complications can do all kinds of works. But working in some jobs that
require special attention (working at high altitude, use of firearms, use of heavy construction machinery, driving of heavy
vehicles and public transport, and guarding) may be risky for the people experiencing recurrent severe hypoglycemia.
6. People with diabetes should be provided appropriate care opportunities for productive work (main meals and snacks
consistent with MNT, physical activity arrangements, SMBG, treatment options).
7. Especially the patients on intensive insulin therapy should avoid working in different shifts.
8. The physician in the workplace should collaborate with the doctor treating the diabetic patient.
16
TREATMENT OF HYPERTENSION IN DIABETES
Hypertension is twice as common in diabetics versus the general population. While the prevalence varies between 10-30% in type 1
diabetic patients, this rate is 40-50% at the time of diagnosis in type 2 diabetics.
HT is associated with the other components of metabolic syndrome in type 2 diabetes.
HT is usually an indicator of nephropathy in type 1 diabetes and may lead to the progression of renal pathology.
Other reasons of HT in patients with diabetes
Coincidental HT which occurs at the same time with diabetes and usually due to other reasons (such as essential HT, isolated
systolic HT, HT due to renal scar formation in patients with recurrent pyelonephritis)
HT due to diabetogenic and anti-hypertensive drugs (K+-depleting chlortalidone, high-dose thiazide diuretics, high dose β-blockers,
α-blocker/diuretic combinations, glucocorticoids that cause both HT and diabetes, and combined oral contraceptives)
Endocrine diseases (acromegaly, Cushing syndrome, pheochromocytoma)
Association of diabetes and HT
Central obesity
Atherogenic lipid profile (low HDL cholesterol, high triglyceride levels, increased small-dense LDL-cholesterol levels)
Hyperinsulinemia and insulin resistance
Endothelial dysfunction
Hyperuricemia
Increased markers of inflammation (e.g. CRP)
Loss of nocturnal BP reduction (non-dipping HT)
Left ventricular hypertrophy
Metabolic factors, such as CAD at an early age play a determining role.
Many guidelines about assessment of HT have been published over the past few years. HT guidelines have been revised based on
ALLHAT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial) results, described recently, and JNC-7 (Seventh
Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure) guidelines,
including the rules of approach to and prevention of HT in general population in accordance with the principles of evidence-based
medicine, have been published. BP classification has been determined by considering the age and CAD risk in this guideline, and each
10-20 mmHg increase has been reported to be associated with a doubling of CV risk. BP classification according to JNC-7 is given in Table 16.1.
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Table 16.1 JNC-7 Classification of hypertension
Systolic BP (mmHg)
Diastolic BP (mmHg)
<120
120-139
140-159
≥160
<80
80-89
90-99
≥100
Normal BP
Pre HT
Grade-1 HT
Grade-2 HT
BP: Blood pressure, HT: Hypertension."
"The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and
Treatment of High Blood Pressure (JNC-7). Hypertension 2003;42:1206-52.
After JNC, American Society of Hypertension (ASH), in its meeting in 2005, has proposed to take into account BP values with CV risk
factors and target organ damage in the new classification of HT (Table 16.2).
Table 16.2 New hypertension classification according to ASH 2005 recommendations
Classification
Normal
Descriptive category
Normal BP (sBP≤120,
Occasionally rising BP
dBP≤80 mmHg) or rarely higher, sBP 140-160, dBP 80-100 mmHg)
but no finding of CVD.
(or early signs of CVD
Cardiovascular risk
No or few
factors (age, gender,
lipids, BMI, smoking,
diabetes, family history)
Markers of early disease
No
(Microalbuminuria or BP
response to exercise/stress)
Target organ diseases
(Heart, arteries, kidney, eye) No
Grade 1
Grade 2
Grade 3
Continuous and obvious
high BP (sBP≥160,
dBP≥100 mmHg)
or advanced CVD
Various
Consistently high BP
(sBP 140-160,
dBP 80-100 mmHg)
or progressive CVD
Many
Usually present
Always present
Always present and in
progressive character
No
Early signs present
Obvious,
CVD present or not present
American Society of Hypertension Writing Group 14-18 May 2005, San Francisco, US.
BP: Blood pressure, sBP: Systolic blood pressure, dBP: Diastolic blood pressure, CVD: Cardiovascular disease, BMI: Body mass index.
Effective treatment of HT can prevent diabetes and complications.
According to evidence-based medicine recommendations for HT treatment in diabetes, goals have been transformed and 140/90
mmHg value in the 1990s declined to 130/80 mmHg.
United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that a 10 mmHg reduction in sBP was associated with a 24%
lower rate of complications related to diabetes, a 37% decline in the risk of microvascular complications, and a 14% lower risk of stroke.
However, in the same trial a 1% reduction in A1C was associated with a 24% lower rate of complications related to diabetes, a 35%
decline in the risk of microvascular complications, and a 16% lower risk of stroke.
16.1 CLINICAL ASSESSMENT OF HYPERTENSIVE PATIENTS WITH DIABETES
When a patient with diabetes is diagnosed with HT:
The degree of HT
Secondary causes of HT (renal, endocrine and drug-induced)
Tissue damage related to HT (left ventricular hypertrophy, CVD, heart failure, peripheral vascular disease, renal failure, and fundus
changes) should be investigated.
Also other risk factors associated with CVD such as smoking, hyperlipidemia, poor glycemic control, family history of CAD should be asked.
Standing or supine BP measurement, signs of left ventricular hypertrophy, heart failure, peripheral pulses (renal murmur and
radio-femoral delay) and signs of an underlying endocrine or renal disease should be sought in physical examination.
Laboratory investigations:
- ECG (left ventricular hypertrophy, ischemic changes, arrhythmias)
- Teleradiography (heart shadow size, left ventricular dilation)
- Fundus examination
- Urine analysis
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103
- Biochemical analyses (urea, creatinine, electrolytes, fasting lipid profile, A1C, uric acid)
- Microalbuminuria
- Echocardiography (left ventricular hypertrophy, ischemia-induced dyskinesia)
- Further evaluation (GFR, abdominal ultrasonography, urinary catecholamines and vanilmandelic acid, aldosterone, plasma renin
activity, cortisol, cardiac autonomic neuropathy tests etc.)
16.2 TREATMENT OF HYPERTENSION IN DIABETES
Hypertensive patients with diabetes should be encouraged to reach target BP values (≤130/80 mmHg). The lowest BP (≤120/70 mmHg)
as tolerated should be reached in appropriate cases if they are not at risk of severe hypotension.
Lifestyle interventions to reduce BP should be considered, including achieving and maintaining a healthy weight, doing exercise and
16.2.1 Non-pharmacological treatment
limiting salt, cigarette and alcohol intakes.
Patients with a sBP of 130-139 mmHg or dBP of 80-89 mmHg should be followed for maximum period of three months with lifestyle
and behavioral education.
Lifestyle changes must be planned and implemented primarily in the treatment process.
The relationship between HT, obesity and salt intake is well-known.
Weight loss and salt restriction can decrease BP. But there are no controlled trials documenting the roles of diet and exercise in the
treatment of HT.
However, it is recommended to increase the consumption of fresh vegetables, fruit and low fat products.
In the diet of hypertensive patient with diabetes, the recommended adequate intake for Na+ is 3.80-5.85 g/day and for K+ is >5.9 g/day.
There is not a clear-cut clinical trial documenting the support of Ca2+ and Mg2+ in hypertensive persons.
Dynamic activities at moderate intensity (walking, jogging, bicycling, swimming) are recommended ≥4 days a week for 30-60 minutes.
Weight loss is a crucial factor in lifestyle changes. Patients with HT, with BMI >25 kg/m2, should lose weight.
Waist circumference should be <102 cm in men and <88 cm in women (IDF definitions of waist circumference for European men <94
cm and women <80 cm).
Weight loss increases the effectiveness of pharmacological treatment.
Also in terms of stress factors, the use of relaxation techniques and reduced alcohol consumption (maximum 4 drinks/week for men
and 2 drinks/week for women) are recommended.
If target HT values cannot be reached despite lifestyle modifications and behavioral training, drug therapy should be initiated.
16.2.1 Non-pharmacological Treatment
If sBP ≥140 mmHg and dBP ≥90 mmHg, pharmacological treatment should be initiated concurrently with lifestyle recommendations.
The agents shown to be beneficial in pharmacological treatment of patients with diabetes and HT in controlled trials are ACE-I, ARB,
low dose thiazide diuretics, and β-blockers and calcium channel blockers in CAD patients.
All guidelines recommend life-style changes as initial treatment, then a renin angiotensin system (RAS) antagonist, ACE-I or ARB, in
patients with albuminuria.
In patients without albuminuria any of the options is reported to be useful.
Progression of clinical nephropathy can be slowed through the use of ACE-I, regardless of HT, in patients with type 1 diabetes.
In the presence of HT the progression of microalbuminuria can be delayed with ACE-I or ARB in type 2 diabetics.
In people with type 2 diabetes and HT, microalbuminuria or clinical renal failure (serum creatinine >1.5 mg/dL), ARBs may delay
progression to end-stage renal disease.
If a RAS system blocking agent cannot be tolerated, it can be substituted with another one.
A 24-h ambulatory BP monitoring is recommended in patients with suspicious white-coat HT.
In addition, β-blockers are recommended for patients with previous myocardial infarction or angina, and ACE-I or diuretics for those
with heart failure, and β-blocker + thiazide combinations should be monitored carefully because of the negative effects on metabolic control.
As the duration of HT gets longer, it becomes difficult to control BP. Patients with diabetes use a mean of 3.2 different types of drugs
to reach the target BP values in the treatment of HT. This has been shown in several studies.
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16.2.2 Pharmacological Treatment
Target BP should be 110-129/65-79 mmHg in pregnant women with chronic HT and diabetes.
While these values have long-term benefits to mother, lower values may have negative effect on fetal growth.
ACE-Is and ARBs are contraindicated in pregnancy as they can cause fetal injury.
Chronic use of diuretics may impair utero-placental perfusion by reducing maternal plasma volume.
Methyldopa, labetolol, diltiazem, clonidine and prazosin are safe and effective agents in pregnancy.
The advantages and disadvantages of drugs used to treat HT in diabetic patients are summarized in Table 16.3.
The algorithm of HT treatment in patients with diabetes based on JNC-7 guideline and ALLHAT study is outlined in Figure 16.1.
Table 16.3 Drug classes in treatment of hypertension in diabetes
Drug class
Advantage
Disadvantage
Diuretics
Cheap
Hyperglycemia, dyslipidemia, sexual dysfunction
β-blockers
Cheap; post-MI benefits have been shown.
May suppresses the symptoms of hypoglycemia; sexual
dysfunction
ACE-Is
Specific effects on nephropathy
Cough; hyperkalemia
ARBs
Specific effects on nephropathy
Expensive
CCBs
Effective
Edema
MI: Myocardial infarction; ACE-Is: Angiotensin converting enzyme inhibitors; ARBs: Angiotensin receptor blockers; CCBs: Calcium channel blockers.
Accordingly:
Concurrent with lifestyle modification dietary regulation is recommended as initial therapy in order to reach target BP values (<130/80
mmHg).
For persons with BP ≥130/80 mm Hg despite lifestyle interventions an ACE-I (or an ARB) is recommended.
Thiazide diuretics should be added if necessary.
The doses should be increased and additional antihypertensive drugs should be used and if target BP levels are not achieved with
standard-dose monotherapy.
If target BP (<130/80 mmHg) cannot be achieved
(If UAE >1g/24 h and renal failure present target BP should be <125/75 mmHg)
Initiate nonpharmacological treatment
Apply lifestyle modifications (weight loss, aerobic exercise, salt restriction, smoking cessation, alcohol restriction, diet rich in fiber, K and Ca).
Initiate pharmacological treatment
Add thiazide diuretics and continue non-pharmacological interventions.
Add a second antihypertensive drug (listed in alphabetical order as ABC)
(ACE-I/ARB, β-blocker, Ca-channel blocker)
Add a third drug
Increase drug doses
Figure 16.1 Antihypertensive treatment algorithm in patients with diabetes
BP; Blood pressure, UAE; Urinary albumin excretion
"The anti-hypertensive treatment algorithm based on JNC-7 and ALLHAT trial is modified from ‘Joslin’s Diabetes Mellitus 2005’." yaz.
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105
SEMT RECOMMENDATIONS THE TREATMENT OF HYPERTENSION IN DIABETES
1. BP should be measured at every diabetes outpatient visit for the assessment of HT (Class D, evidence-based consensus).
2. HT should be diagnosed in people with diabetes according to the current HT guidelines (Class D, evidence-based consensus).
3. Persons with diabetes and HT should be treated to attain sBP <130 mm Hg [Class C, Level 3 evidence (1-3)] and dBP
<80 mm Hg [Class B, Level 2 evidence (4,5)].
4. Lifestyle interventions to reduce BP (achieving and maintaining a healthy weight and limiting sodium and alcohol intake)
should be initiated concurrently with pharmacological interventions (Class D, evidence-based consensus).
5. For persons with diabetes and normal UAE and without chronic kidney disease, with BP ?130/80 mm Hg:
• Any of the following medications is recommended, with special consideration to ACE-Is and ARBs given their additional
renal benefits (Class D, evidence-based consensus]:
• ACE-I [Class A, Level 1A evidence (6)]
• ARB [Class A, Level 1A evidence (7); for non-left ventricular hypertrophy Class B, Level 2 evidence (7)]
• Dihydropyridine calcium channel blocker (DHP-CCB) [Class B, Level 2 evidence (8)]
• Thiazide-group diuretics [Class A, Level 1A evidence (8)]
• If the above drugs are contraindicated or cannot be tolerated, a cardioselective ‚-blocker [Class B, Level 2 evidence (5)]
or a non-DHP-CCB [Class B, Level 2 evidence (9)] can be substituted.
• Additional antihypertensive drugs should be used if target BP levels are not achieved with standard-dose monotherapy
[Class C, Level 3 evidence (5,8)].
• Add-on drugs should be chosen from the first-line choices listed above (Class D, evidence-based consensus].
• For people with diabetes and persistent albuminuria an ACE-I or an ARB is recommended as initial therapy [Class A,
Level 1A evidence (10-13)].
• If BP remains ≥130/80 mm Hg despite lifestyle interventions and the use of an ACE-I or an ARB, additional antihypertensive drugs
should be used to obtain target BP [Class D, evidence-based consensus].
6. For persons with diabetes and a normal UAE rate, without chronic kidney disease but with isolated systolic HT:
• An ACE-I [Class B, Level 2 evidence (6)]
• An ARB [Class B, Level 2 evidence (7)]
• A thiazide-group diuretic [Class B, Level 2 evidence (8,14)] or
• Alternatively a long-acting DHP-CCB [Class C, Level 3 evidence (15)] can be used.
7. Alpha-blockers are not recommended as first-line agents for the treatment of HT in persons with diabetes [Class A, Level
1A evidence (16)].
REFERENCES
1. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS
36): prospective observational study. BMJ 2000;321:412-19.
2. Orchard TJ, Forrest KY, Kuller LH, et al; Pittsburgh Epidemiology of Diabetes Complications Study. Lipid and blood pressure treatment goals for type 1
diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 2001;24:1053-9.
3. Schrier RW, Estacio RO, Esler A, et al. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and
strokes. Kidney Int 2002;61:1086-97.
4. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results
of the Hypertension Optimal Treatment (HOT) randomized trial. HOT Study Group. Lancet 1998;351:1755-62.
5. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS
38. BMJ 1998;317:703-13.
6. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes
mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253-9.
7. Lindholm LH, Ibsen H, Dahlof B, et al; LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For
Endpoint reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 2002;359:1004-10.
8. Whelton PK, Barzilay J, Cushman WC, et al; ALLHAT Collaborative Research Group. Clinical outcomes in antihypertensive treatment of type 2 diabetes,
impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch
Intern Med 2005;165:1401-9.
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Turk JEM 2010; 14: Suppl 101-6
9. Bakris GL, Gaxiola E, Messerli FH, et al; INVEST Investigators. Clinical outcomes in the diabetes cohort of the INternational VErapamil SR-Trandolapril study.
Hypertension 2004;44:637-42.
10. Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl
J Med 1993;329:1456-62.
11. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with
nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851-60.
12. Brenner BM, Cooper ME, de Zeeuw D, et al; RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2
diabetes and nephropathy. N Engl J Med 2001;345:861-9.
13. The ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 2001;134:370-9.
14. Curb JD, Pressel SL, Cutler JA, et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Cooperative Research Group. JAMA 1996;276:1886-92.
15. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. Systolic
Hypertension in Europe Trial Investigators. N Engl J Med 1999;340:677-84.
16. ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs. chlorthalidone: the
antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). JAMA 2000;283:1967-75.
17
TREATMENT OF DYSLIPIDEMIA IN DIABETES
All people with diabetes have an extremely high lifetime risk of CVD. Fasting lipid profile should be evaluated every year, and the
following lipid levels should be targeted:
LDL-cholesterol <100 mg/dL (70 mg/dL in diabetic patient with primary CV event)
Triglycerides <150 mg/dL
HDL-cholesterol >40 mg/dL in men, and >50 mg/dL in women
Especially in patients with high LDL-cholesterol levels other secondary causes of hyperlipidemia, such as hypothyroidism, should be
investigated.
MNT and other lifestyle modifications (reduction in intake of dietary saturated fats and cholesterol, weight loss, increase in physical
activity) are highly effective in the prevention and treatment of dyslipidemia in individuals with diabetes.
If target lipid levels cannot be reached despite MNT and lifestyle modifications for two months pharmacologic therapy should be
initiated.
Lifestyle interventions should be initiated concurrently with pharmacological intervention if LDL-cholesterol is >160 mg/dL or the patient's
CVD risk profile is high despite LDL-cholesterol of 130-159 mg/dL.
Evidence based lipid lowering treatment algorithm in adult patients with diabetes is summarized in Figure 17.1.
Age <40 yr-old and
poor CV risk profile
Age ≥40 yr-old and
low CV risk
Initiate Statin
Calculate CV risk
Age ≥40 yr-old and
normal-high CV risk
Isolated high TG
Search for poor glycemic
control and other secondary causes, if present treat.
If 10-yr CV risk is
>20%
If TG >500 mg/dL despite
good glycemic control, start
Statin or Fibrate.
Give Statin
If lifestyle change and
Fibrate are insufficient, add
high-dose Omega-3.
Target LDL-cholesterol <100 mg/dL or total
/HDL-cholesterol <4. If target cannot be
reached, increase Statin dose. If there is history
of CVD (LDL-cholesterol should be <70 mg/dL)
and UAE is high, use more powerful Statins or
Ezetimibe.
Reassess fasting lipid profile or
and modifiable risk factors within 3-6 months after Statin treatment has been started. Follow
treatment annually.
If CV risk is high and TG is
200-400 mg/dL despite
Statin, add Fibrate or Niacin.
Figure 17.1 Lipid lowering treatment in patients with diabetes
CV; Cardiovascular, TG; Triglycerides, LDL-cholesterol; Low density lipoprotein cholesterol, HDL-cholesterol; High density lipoprotein cholesterol
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SEMT RECOMMENDATIONS FOR THE TREATMENT OF DYSLIPIDEMIA IN DIABETES
1. People with type 1 or type 2 diabetes should be encouraged to adopt a healthy lifestyle (healthy eating habits, achieving
and maintaining a healthy weight, engaging in regular physical activity and smoking cessation) [Class D, evidence based consensus].
2. Fasting lipid levels (total cholesterol, HDL-cholesterol, triglyceride and calculated LDL-cholesterol) should be measured at the
time of diagnosis of diabetes and then annually. More frequent testing should be performed if treatment for dyslipidemia
is initiated [Class D, evidence based consensus].
3. Individuals at high risk of a CAD and ?40 years of age should be treated with a statin to achieve an LDL-cholesterol ≤70
mg/dL [Class A, Level 1 evidence (1,2), and Level 2 evidence (3)]. Clinical judgment should be used as to whether additional LDLcholesterol lowering is required for those with an on-treatment LDL-cholesterol of 70-100 mg/dL [Class D, evidence based
consensus].
4. The primary target of therapy is to decrease LDL-cholesterol levels [Class A, Level 1 evidence (1,2) and Level 2 evidence (3)];
the secondary target is to reduce total/HDL-cholesterol ratio (<4) [Class D, evidence based consensus].
5. If the total/HDL-cholesterol ratio is ?4.0, consider strategies to achieve a total/HDL-cholesterol ratio <4.0 such as improved
glycemic control, intensification of lifestyle modifications (weight loss, physical activity, smoking cessation) and, if necessary,
pharmacologic interventions [Class D, evidence based consensus].
6. If serum triglycerides levels are >500 mg/dL despite best efforts at optimal glycemic control and other lifestyle interventions
(e.g. weight loss, restriction of refined carbohydrates and alcohol), a fibrate should be prescribed to reduce the risk of pan
creatitis [Class D, evidence based consensus].
• For those with triglycerides of 400-800 mg/dL either a statin or a fibrate can be attempted as first line therapy
• If target lipid levels are not achieved after 3 to 6 months on monotherapy a second lipid lowering agent of a different
class (omega-3) can be added [Class D, evidence based consensus].
7. For individuals not at target despite optimally dosed first-line therapy, combination therapy can be considered:
• Statin plus ezetimibe [Class B, Level 2 evidence (4)].
• Statin plus fibrate [Class B, Level 2 evidence (5), Level 3 evidence (6)].
• Statin plus niacin [Class B, Level 2 evidence (7)].
8. Because of an increased risk of myalgia, myopathy and rhabdomyolysis, statins should not be used in combination with
fibrates (Class D, evidence based consensus).
9. Plasma apo B can be measured, at the physician’s discretion, in addition to LDL-cholesterol and triglyceride/HDL-cholesterol ratio, to
monitor adequacy of lipid-lowering therapy in the high-risk individual (Class D, evidence based consensus).
• Target apo B should be <0.9 g/L (Class D, evidence based consensus).
REFERENCES
1. Collins R, Armitage J, Parish S, et al; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin
in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003;361:2005-16.
2. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS Investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in
the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet 2004;364:685-96.
3. Shepherd J, Barter P, Carmena R, et al. Effect of lowering LDL-cholesterol substantially below currently recommended levels in patients with coronary heart
disease and diabetes: the Treating to New Targets (TNT) study. Diabetes Care 2006;29:1220-6.
4. Simons L, Tonkon M, Masana L, et al. Effects of ezetimibe added to on-going statin therapy on the lipid profile of hypercholesterolemic patients with
diabetes or metabolic syndrome. Curr Med Res Opin 2004;20:1437-45.
5. Athyros VG, Papageorgiou AA, Athyrou VV, et al. Atorvastatin and micronized fenofibrate alone and in combination in type 2 diabetes with combined
hyperlipidemia. Diabetes Care 2002;25:1198-202.
6. Durrington PN, Tuomilehto J, Hamann A, et al. Rosuvastatin and fenofibrate alone and in combination in type 2 diabetes patients with combined
hyperlipidaemia. Diabetes Res Clin Pract 2004;64:137-51.
7. Grundy SM, Vega GL, McGovern ME, et al; Diabetes Multicenter Research Group. Efficacy, safety, and tolerability of once-daily niacin for the treatment of
dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial. Arch Intern Med
2002;162:1568-76.
18
PREVENTION OF DIABETES
18.1 PREVENTION OF TYPE 1 DIABETES
Safe and effective preventive therapies for type 1 diabetes have not yet been identified according to evidence-based medicine trials.
The results of two major placebo-controlled, large-scale, multicentre and prospective trials have been published in 2003. A trial of
parenteral and oral insulin therapy in the US (DPT: Diabetes Prevention Trial), and that of nicotinamide therapy in Europe (ENDIT:
European Nicotinamide Diabetes Intervention Trial), to prevent type 1 diabetes could not achieve successful results. The absence of
effective prevention programs makes both family and general population screening for identification of prediabetic peoples ethically
questionable.
18.2 PREVENTION OF TYPE 2 DIABETES
The role of environmental factors in the development of type 2 diabetes is clear. Adoption of modern lifestyles has led to people
exercising fewer and changing their eating habits. In the last quarter of this century, consuming a diet rich in saturated fat, and poor
in fiber, including fast food and high-calorie meals has led to a rapid increase in the prevalence of diabetes.
Prevention of type 2 diabetes with lifestyle changes has gained more interest in recent years.
"Da Qing Diabetes and IGT" trial, published in 1997, has showed that type 2 diabetes risk can be reduced by approximately 40% with
diet and exercise in people with IGT in China.
Structured exercise and calorie restriction, assessed in the Finnish Diabetes Prevention Study (DPS) which was published in 2001, has
resulted in 58% risk reduction for type 2 diabetes in obese or overweight patients with IGT.
DPP study (Diabetes Prevention Program), conducted in the US and Canada with the results published in 2003, has been reported
that diabetes risk has been reduced by 58% with the intense life changes and by 31% with metformin in overweight or obese
individuals with IGT or IFG.
The importance of pharmacological prevention in prediabetic period has also been emphasized. In addition to metformin, acarbose
is also used in DPP.
In ‘The Study to Prevent Non-Insulin Dependent Diabetes (STOP-NIDDM)’ acarbose treatment was associated with a 32% reduction
in the progression of diabetes and also reduction in CV events in obese and overweight population with IGT in European countries and
Canada.
In TRIPOD study troglitazone has been associated with a decrease in type 2 diabetes risk in women with a history of GDM.
Also in the studies which were planned to reduce the problem of obesity (XENDOS) and CV problems (MICRO-HOPE) the progression
to type 2 diabetes was significantly less compared to placebo with Orlistat and Ramipril respectively in subgroups with IGT.
DREAM study (Diabetes REduction Assessment with ramipril and rosiglitazone Medication trial), where rosiglitazone and ramipril were
used in prediabetes period (IGT/IGF), documented that rosiglitazone could prevent the development of diabetes by 60%. However, the
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Prevention of Diabetes
long-term sustainability of this improvement could not be determined after cessation of the drug. Similarly, results of the NAVIGATOR
study (Nateglinide and Valsartan in Impaired Glucose TolerAnce Outcomes Research trial) have shown that nateglinide did not
diminish the risk of new onset diabetes. Therefore, future ongoing studies are hoped to bring greater clarity to this topic.
Table 18.1 demonstrates FINDRISK questionnaire which is developed to identify people at high risk for type 2 diabetes and which can
be easily applied in the social scale.
Table 18.1 Type 2 diabetes risk test (FINDRISK questionnaire)
1. Age
0 point
<45 year old
2 points:
45–54 year old
3 points:
55–64 year old
4 points:
>64 year old
2. Body mass index (BMI)
0 point:
<25 mg/m2
1 point:
25–30 kg/m2
3 points:
>30 kg/m2
3. Waist circumference
Men
Women
0 point:
<94 cm
<80 cm
3 points:
94-102 cm
80-88 cm
4 points:
>102 cm
>88 cm
4. Do you exercise at least 30 minutes a day?
0 point:
Yes
2 points:
No
5. How often do you consume fruit and vegetables?
0 point:
Everyday
2 points:
Not everyday
6. Have you ever used medication for hypertension or diagnosed with hypertension?
0 point:
No
2 points:
Yes
7. Have you ever been told previously (during check-up, illness or pregnancy) that you had high blood sugar or borderline level?
0 point:
No
5 points:
Yes
8. Has any of your family members have been diagnosed with diabetes?
0 point:
No
3 points:
Yes, paternal/maternal uncle/aunt, cousin or nephew-niece (second-degree relatives)
5 points:
Yes, biological parent, sibling or offspring (first-degree relatives)
Table 18.2 Evaluation of FINDRISK (diabetes risk score)
Total scores (points)
Risk rating
10-year risk
<7
7-11
12-14
15-20
>20
Low
Mild
Moderate
High
Very high
1% (1/100)
4% (1/25)
16% (1/6)
33% (1/3)
50% (1/2)
As a result; in light of our current knowledge lifestyle modification to prevent type 2 diabetes is accepted as a cheap and easy method
which can be applied in the social scale. Below three crucial issues related to prevention are summarized
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Prevention of Diabetes
111
Can the interventions, which were implemented to prevent the progression of IFG/IGT to diabetes, also prevent the development or
progression of microvascular complications, cardiometabolic risk factors (e.g. HT, hyperlipidemia) or CVDs associated with diabetes?
Although intensive lifestyle modifications have been shown to prevent or delay the development of diabetes, their effect on CVD risk
factors is mild. But whether they decrease the risk of CVDs is unknown. The effects of pharmacological interventions to prevent or delay
diabetes are even less effective on CVD risk factors.
Do we have enough data to propose specific initiatives for delay and prevention of the progression of IFG/IGT to diabetes?
For today lifestyle modification (approximately a 5% to 10% weight loss and 30 minutes per day moderate intensity physical activity)
is accepted as the most appropriate approach for IFG/IGT. Only metformin among pharmacological agents is an option that can be
used at this stage.
How often, by which method and to whom should the screening be done to prevent the negative consequences of IFG/IGT?
The cases in the risk groups should be identified (Table 17.1 and Table 17.2). The most effective way is to measure FPG and then to
investigate the presence of ‘IFG+IGT’ (combined glucose intolerance: CGI) by OGTT in another day. If CGI is present metformin should
be added to therapy together with lifestyle modifications (Table 18.3). The patients using metformin should be monitored twice in a year
with A1C, non-users should be reviewed once a year.
Table 18.3 Treatment recommendations in IFG, IGT or CGI (IFG+IGT)
Population
Treatment
People diagnosed with IFG or IGT
Lifestyle modification program (e.g. 5-10% weight loss and
30 min/day moderate intensity physical activity)
The people with any of the following risk
factors together with IFG+IGT (CGI)
- <60 years of age
- BMI ≥35 kg/m2
- History of diabetes in first degree relatives
- Hypertriglyceridemia
- Low HDL-cholesterol
- Hypertension
- A1C >6%
Metformin(*) can be initiated in these people concurrently
with lifestyle modification programs outlined above.
(*)
Metformin 850 mg tb bid
IFG: Impaired fasting glucose, IGT: Impaired glucose tolerance, CGI: Combined glucose intolerance, BMI: Body mass index, HDL-cholesterol: High-density lipoprotein cholesterol, A1C:
Glycosylated hemoglobin A1c.
SEMT RECOMMENDATIONS FOR PREVENTION OF DIABETES
1. A structured program of lifestyle modification that includes moderate weight loss and regular physical activity should be
implemented in individuals at high risk for diabetes [For IGT Class A, Level 1A evidence (1,2)] and For IFG [Class D, evidence
based consensus].
2. In individuals with IGT (especially with IGT+IFG), pharmacologic therapy (preferably Metformin, or Acarbose in tolerated
patients) should be considered. [For Metformin: Class A, Level 1A evidence (2); For Acarbose: Class A, Level 1A evidence (3)].
REFERENCES
1. Tuomilehto J, Lindström J, Eriksson JG, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among
subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343-50.
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20
ABBREVIATIONS
1 h PG; One hour plasma glucose level
2 h PG; Two hours plasma glucose level
3 h PG; Three hours plasma glucose level
A1C; Glycosylated hemoglobin A1C (HbA1c)
ACE/AACE; American College of Endocrinology and American Association of Clinical Endocrinologists
ACE-I; Angiotensin converting enzyme inhibitor
ACS ; Acute coronary syndrome
ADA; American Diabetes Association
ALLHAT; Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial
ALT; Alanine aminotransferase
Anti-GAD; Anti-glutamic acid decarboxylase antibody
Anti-TG ; Anti thyroglobulin antibody
Anti-TPO; Anti-thyroid peroxidase antibody
Anti-VEGF; Anti-vascular endothelial growth factor
ARB; Angiotensin receptor blocker
ARDS ; Adult respiratory distress syndrome
ASH; American Society of Hypertension
AV; Arteriovenous
BMI; Body mass index
BP; Blood pressure
CAD; Coronary artery disease
CGI; Combined glucose intolerance
CGMS ; Continuous glucose monitoring sensor
CH ; Carbohydrate
CH/I; Carbohydrate / insulin ratio
CPK; Creatine phosphokinase
CV ; Cardiovascular
CVD; Cardiovascular disease
CVP; Central venous pressure
DCCB ; Dihydropyridine calcium channel blocker (DHP-CCB)
DCCT; Diabetes Control and Complications Trial
DIC; Disseminated intravascular coagulation
DIDMOAD syndrome; Also known as Wolfram syndrome, refers to the combination of diabetes insipidus, diabetes mellitus, optic
atrophy and deafness
DKA; Diabetic ketoacidosis
DPP ; Diabetes Prevention Program
DPP-4; Dipeptidyl peptidase-4
DPS; Diabetes Prevention Study
116
Turk JEM 2010; 14: Suppl 116-8
Abbreviations
117
DREAM; Diabetes REduction Assessment with ramipril and rosiglitazone Medication trial
eGFR; Estimated glomerular filtration rate
EASD ; European Association for the Study of Diabetes
ECG; Electrocardiography
ENDIT; European Nicotinamide Diabetes Intervention Trial
FDA; Food and Drug Administration
FPG; Fasting plasma glucose level
GDM ; Gestational diabetes mellitus
GFR ; Glomerular filtration rate
GIK; Glucose-insulin-potassium solution
GLP-1 ; Glucagon like peptide-1
GLP-1 agonists ; Glucagon like peptide-1 agonists
HDL-cholesterol; High-density lipoprotein cholesterol
HHS; Hyperosmolar hyperglycemic state
HNF-1·; Hepatocyte nuclear factor-1·
HNF-1‚ ; Hepatocyte nuclear factor-1‚
HNF-4·; Hepatocyte nuclear factor-4·
h: hour
HT: Hypertension
IA2-β; Anti phogrin antibody
IA2 ; Anti-tyrosine phosphatase antibody
IAA ; Insulin autoantibody
ICA; Islet cell antibody
IDF; International Diabetes Federation
IDSA; Infectious Disease Society of America
IFCC ; International Federation of Clinical Chemistry
IFG ; Impaired fasting glucose
IGF-1 ; Insulin like growth factor-1
IGT; Impaired glucose tolerance
i.m.; Intramuscular
IPF-1; Insulin promoter factor-1
IRMA; Intraretinal microvascular anomalies
ISF; Insulin Sensitivity Factor
i.v.; Intravenous
IWGDF; International Working Group on the Diabetic Food
JNC-7; Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure
kcal; Kilocalorie
LDL-cholesterol; Low-density lipoprotein cholesterol
MDRD; Modification of Diet and Renal Disease
MI; Myocardial infarction
min ; minute
MNT; Medical nutrition therapy
MODY1-6 ; Maturity onset diabetes of the young 1-6
MR; Magnetic Resonance
MRSA; Methicillin-resistant Staphylococcus aureus
NAVIGATOR ; Nateglinide and Valsartan in Impaired Glucose Tolerance (IGT) Outcomes Research trial
Non-DCCB; Non-dihydropyridine calcium channel blocker (non-DHP-CCB)
NeuroD1 ; Neurogenic differentiation 1
118
Abbreviations
Turk JEM 2010; 14: Suppl 116-8
OAD; Oral antidiabetic drugs
OGTT ; Oral glucose tolerance test
PBG ; Postprandial Blood Glucose
PCOS ; Polycystic ovarian syndrome
PG; Plasma glucose level
RAS; Renin angiotensin system
RECORD; Rosiglitazone Evaluated for Cardiovascular Outcome and Regulation of Glycemia in Diabetes trial
s.c.; subcutaneous
STOP-NIDDM; Study to prevent NIDDM with acarbose
SMBG; Self monitoring of blood glucose
Sosm ; Serum osmolality
SSRI; Selective serotonine re-uptake inhibitors
TBW ; Total body water
TID ; Total insulin dose (daily)
UAE ; Urinary albumin excretion
UKPDS ; United Kingdom Prospective Diabetes Study
XENDOS ; XENical in the prevention of Diabetes in Obese Subjects
WHO: World Health Organization
21
REFERENCE RANGES OF LABORATORY TESTS
APPENDIX TABLE-1. Clinical biochemical tests(*)
Parameter
Sample type
SI unit
Traditional unit
Acetoacetate
P
<100 μmol/L
<1 mg/dL
Acid phosphatase
S
0.90 nkat/L
0-5.5 U/L
Albumin
S
35-55 g/L
3.5–5.5 g/L
Aldolase
S
0-100 nkat/L
0-6 dL
Alkaline phospatase (ALP)
S
0.5-2.0 nkat/L
30-120 U
Alpha-1-antitrypsin
S
0.8-2.1 g/L
85-213 mg/dL
Alpha-fetoprotein (AFP) (Adult)
S
<15 μg/L
<15 ng/mL
0-0.58 μkat/L
0-35 U/L
0-0.58 μkat/L
0-35 U/L
Aminotransferases
Aspartate (AST, SGOT)
Alanine (ALT, SGPT)
S
Ammonia (NH3)
P
6-47 μmol/L
10-80 μg/dL
Amylase
S
0.8-3.2 μkat/L
60-180 U/L
Angiotensin converting enzyme (ACE)
S
<670 nkat/L
<40 U/L
Anion gap
S
7-16 mmol/L
7-16 mmol/L
0.35-0.98
0.35-0.98
Apo B/Apo A-1
Apolipoprotein A-1 (Apo A-1)
S
1.2-2.4 g/L
119-240 mg/dL
Apolipoprotein B (Apo B)
S
0.52-1.63 g/L
52-163 mg/dL
21-28 mmol/L
21-30 mEq/L
Arterial blood gases
Bicarbonate (HCO3)
pCO2
4.7-5.9 kPa
35-45 mmHg
pH
A
7.38-7.44
7.38-7.44
pO2
11-13 kPa
80-100 mmHg
P: Plasma, S: Serum, U: Urine, C: Complete blood, A: Arterial blood, V: Venous blood.
119
120
Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-1. Clinical biochemical tests(*)
Parameter
Beta-2-microglobulin
Beta-hydroxybutyrate
Sample type
SI unit
Traditional unit
S
1.2-2.8 mg/L
1.2-2.8 mg/L
U
≤200 μg/L
≤200 μg/L
P
<300 μmol/L
<3 mg/dL
5.1-17 μmol/L
0.3-1.0 mg/dL
S
1.7-5.1 μmol/L
0.1-0.3 mg/dL
3.4-12 μmol/L
0.2-0.7 mg/dL
Bilirubin
Total
Direct
Indirect
Blood urea nitrogen (BUN)
S
3.6-7.1 mmol/L
10-20 mg/dL
Brain natriuretic peptide (BNP)
P
Values differ by age and gender.
Values differ by age and gender.
<167 ng/L
<167 ng/L
CA 125
S
0-35 kU/L
0-35 U/mL
CA 15-3
S
0-30 kU/L
0-30 U/mL
CA 19-9
S
0-37 kU/L
0-37 U/mL
CA 27-29
S
0-32 kU/L
0-32 U/mL
Calcium (Ca)
S
2.2-2.6 mmol/L
9-10.5 mg/dL
(Ionized calcium)
C
1.1-1.4 mmol/L
4.5-5.6 mg/dL
Carbon dioxide content (tCO2) (sea level)
P
21-30 mmol/L
21-30 mEq/L
Carbon dioxide pressure (pCO2) (sea level)
A
4.7-5.9 kPa
35-45 mmHg
Carbon monoxide content (CO)
C
Carcinoembryonic antigen (CEA)
S
0.0-3.4 μg/L
0.0-3.4 ng/mL
Ceruloplasmin
S
27-37 mg/L
27-37 ng/dL
Chloride (Cl)
S
98-106 mmol/L
98-106 mEq/L
Cholinesterase
S
5-12 kU/L
5-12 U/mL
Coproporphyrin (Type-I and Type-III)
U
150-460 μmol/day
100-300 μg/day
Calcium, ionized
P: Plasma, S: Serum, U: Urine, C: Complete blood, A: Arterial blood, V: Venous blood.
Symptoms occur with 20% saturation of Hb
Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-1. Clinical biochemical tests(*)
Parameter
C-peptide
Sample type
SI unit
Traditional unit
S
0.17-0.66 nmol/L
0.5-2.0 ng/mL
0.67-2.50 μkat/L
40-150 U/L
S
1.00-6.67 μkat/L
60-400 U/L
S
According to the method
According to the method
Creatine kinase (Total CK)
Women
Men
Creatine kinase, relative index =
[(ng/ml) (total CK U/L)]x100
Creatine kinase-MB (CK-MB)
S
0-7 μg/L
0-7 ng/mL
Creatinine
S
<133 μmol/L
<1.5 mg/dL
Erythropoietin
S
5-36 U/L
5-36 U/L
10-200 μg/L
10-200 ng/mL
S
15-400 μg/L
15-400 ng/mL
Ferritin
Women
Men
Free fatty acids (FFA)
P
0.28-0.89 mmol/L
<8-25 mg/dL
Gamma glutamyl transferase (GGT)
(non-esterified)
S
1-94 U/L
1-94 U/L
Glucose, 2-h postprandial
P
<6.7 mmol/L
<120 mg/dL
4.2-5.6 mmol/L
75-100 mg/dL
Glucose, fasting
Normal
Diabetes mellitus
P
>7.0 mmol/L
>125 mg/dL
Hemoglobin A1c (A1C)
C
0.038-0.064 fraction of Hb
3.8-5.6%
Homocysteine (Hcy)
P
4-12 μmol/L
4-12 μmol/L
U, 24-h
0-10 μmol/L
0-1.3 mg/day
Hydroxyproline
Iron (Fe)
S
9-27 μmol/L
50-150 μg/dL
Iron binding capacity
S
45-66 μmol/L
250-370 μg/dL
Iron binding saturation, total
S
0.2-0.45
20-45%
Ketone (Acetone)
S, U
Negative
Negative
Lactate
P, V
0.6-1.7 mmol/L
5-15 mg/dL
P: Plasma, S: Serum, U: Urine, C: Complete blood, A: Arterial blood, V: Venous blood.
121
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Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-1. Clinical biochemical tests(*)
Parameter
Lactate dehydrogenase (LDH)
Lactate dehydrogenase isoenzymes
Fraction 1 (in total)
Fraction 2
Fraction 3
Fraction 4
Fraction 5
Lipase
Lipid fractions (Adult)
HDL-cholesterol
Men
Women
LDL-cholesterol
Diabetes mellitus
Diabetes mellitus + CV event
Lipoprotein (a)
Magnesium (Mg)
Microalbuminuria (UAE)
24 h
Spot
(First morning urine sample)
Myoglobin
Men
Women
N-telopeptide (cross-linked), NTX
5’-Nucleotidase
Osmolarity
Osteocalcine
Oxygen content
(sea level)
Oxygen pressure (pO2)
Sample type
S
SI unit
1.7-3.2 μkat/L
Traditional unit
100-190 U/L
0.14-0.25
0.29-0.39
0.20-0.25
0.08-0.16
0.06-0.16
0-2.66 μkat/L
14-26%
29-39%
20-26%
8-16%
6-16%
0-160 U/L
>1.0 mmol/L
>1.3 mmol/L
<3.4 mmol/L
<2.6 mmol/L
<1.8 mmol/L
0-300 mg/L
0.8-1.2 mmol/L
<0.2 g/L or
≤0.031 g/24 h
>40 mg/dL
>50 mg/dL
<130 mg/dL
<100 mg/dL
<70 mg/dL
0-30 mg/dL
1.8-3 mg/dL
<20 mg/L or
≤30 mg/24 h
U
<30 mg albumin/
g creatinine
<30 mg albumin/
g creatinine
S
19-92 μg/L
12-76 μg/L
3-65 nmol/mmol creatinine
0.02-0.18 μkat/L
285-295 mmol/kg serum
300-900 mmol/kg
3.1-14 μg/mL
S
S
S, fasting
S
S
U
U
S
P
U
S
C, A
C, V, forearm
C
P: Plasma, S: Serum, U: Urine, C: Complete blood, A: Arterial blood, V: Venous blood.
11-13 kPa
3-65 nmol/mmol creatinine
0-11 U/L
285-295 mmol/kg serum
300-900 mmol/kg
3.1-14 ng/mL
17-21%
10-16%
80-100 mmHg
Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-1. Clinical biochemical tests(*)
Parameter
Oxygen saturation percentage (sea level)
Sample type
C, A
C, V, forearm
S
C
S
S
S
Parathyroid hormone-related peptide (PTHrP)
pH
Phosphorus, inorganic (P)
Potassium (K)
Prealbumin
Prostate-spesific antigen (PSA), total
Women
Men
<40 years of age
S
≥40 years of age
PSA, free,
Men, 45-75 years of age,
for 4-20 μg/mL PSA values
Protein fractions
Albumin
Globulin
Alpha-1
Alpha-2
Beta
Gamma
Protein, total
Pyruvate
Transferrin
Triglycerides
Troponin-I
Troponin-T
S
S
P, V
S
S
S
S
SI unit
0.97 mol/mol
0.60-0.85 mol/mol
<1.3 pmol/L
7.38-7.44
1.0-1.4 mmol/L
3.5-5 mmol/L
195-358 mg/L
Traditional unit
97%
60-85%
<1.3 pmol/L
3-4.5 mg/dL
3.5-5 mEq/L
19.5-35.8 mg/dL
<0.5 μg/L
<0.5 ng/mL
0-2.0 μg/L
0-2.0 ng/mL
0-4.0 μg/L
0-4.0 ng/mL
>0.25
(related to BPH)
>25%
(related to BPH)
35-55 g/L
20-35 g/L
2-4 g/L
5-9 g/L
6-11 g/L
7-17 g/L
55-80 g/L
60-170 μmol/L
2.3-3.9 g/L
<1.8 mmol/L
0-0.4 μg/L
0-0.1 μg/L
3.5-5.5 g/dL (50-60%)
2-3.5 g/dL (40-50%)
0.2-0.4 g/dL(4.2-7.2%)
0.5-0.9 g/dL (6.8-12%)
0.6-1.1 g/dL (9.3-15%)
0.7-1.7 g/dL (13-23%)
5.5-8 g/dL
0.5-1.5 mg/dL
230-390 mg/dL
<160 mg/dL
0-0.4 ng/mL
0-0.1 ng/mL
P: Plasma, S: Serum, U: Urine, C: Complete blood, A: Arterial blood, V: Venous blood; BPH: Benign prostatic hypertrophy.
APPENDIX TABLE-1. Clinical biochemical tests(*)
Parameter
Sample type
SI unit
Traditional unit
Uric acid
Men
150-480 μmol/L
2.5-8.0 mg/dL
Women
S
90-360 μmol/L
1.5-6.0 mg/dL
Urobilinogen
U
1.7-5.9 μmol/day
1-3.5 mg/day
Vasoactive intestinal polypeptide (VIP)
P
<75 ng/L
<75 pg/mL
P: Plasma, S: Serum, U: Urine, C: Complete blood, A: Arterial blood, V: Venous blood.
(*)
The conversion between the traditional standard (conventional) and international (SI) unit systems can be made according to the following formula: “mmol/L = (mg/dL x 10-1) /
Atom (or molecular) weigh”; “mg/dL = (mmol/L x Atomic (or molecular) weigh) / 10”
123
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Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-2. Tests of endocrinology and metabolism(*)
Test
Adrenocorticotropin hormone (ACTH)
Aldosterone (Adult)
Supine,
(normal Na diet)
Standing,
(normal Na diet)
Supine,
(low Na diet)
Random
(low Na diet)
Androstenedione (Adult)
C-peptide (Adult)
Dehydroepiandrosterone (DHEA) (Adult)
Men
Women
DHEA sulphate (Adult)
Men
Women (Premenauposal)
Women (Postmenauposal)
Deoxycorticosteron (DOC) (Adult)
11-Deoxycortisol
(Adult) (S content) (08:00 in the morning)
Dihydrotestosterone
Men
Women
Dopamine
Cortisol
Fasting, 08:00-Noon
Noon-20:00
20:00-08:00
Cortisol, free
P: Plasma, S: Serum, U: Urine, C: Complete blood.
Sample type
P
SI unit
1.3-16.7 pmol/L
Traditional unit
6-7.6 pg/mL
S, P
55-250 pmol/L
2-9 ng/dL
S, P
2-5 X supine value
S, P
2-5 X normal Na diet
U
6.38-58.25 nmol/day
2.3-21.0 μg/24-h
S
S, P
1.75-8.73 nmol/L
0.17-0.66 nmol/L
50-250 ng/dL
0.5-2.0 ng/mL
S
6.24-41.6 nmol/L
4.5-34 nmol/L
180-1250 ng/dL
130-980 ng/dL
S
S
100-6190 μg/L
120-5350 μg/L
300-2600 μg/L
61-576 nmol/L
10-619 μg/dL
12-535 μg/dL
30-260 μg/dL
2-19 ng/dL
S
0.34-4.56 nmol/L
12-158 ng/dL
S, P
1.03-2.92 nmol/L
0.14-0.76 nmol/L
<475 pmol/L
425-2610 nmol/day
30-85 ng/dL
4-22 ng/dL
<87 pg/mL
65-400 g/day
138-690 nmol/L
138-414 nmol/L
0-276 nmol/L
55-193 nmol/24 h
5-25 μg/dL
5-15 μg/dL
0-10 μg/dL
20-70 μg/24 h
P
U
S
U
Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-2. Tests of endocrinology and metabolism(*)
Test
Epinephrine (Adrenaline)
Supine (30 min)
Sitting
Standing (30 min)
Sample type
SI unit
Traditional unit
P
<273 pmol/L
<328 pmol/L
<4914 pmol/L
0-109 nmol/day
<50 pg/mL
<60 pg/mL
<900 pg/mL
0-20 μg/day
184-532 pmol/L
411-1626 pmol/L
184-885 pmol/L
217 pmol/L
184 pmol/L
<20-145 pg/mL
112-443 pg/mL
<20-241 pg/mL
<59 pg/mL
<20 pg/mL
55-555 pmol/L
55-740 pmol/L
55-204 pmol/L
55-240 pmol/L
1.5-15 pg/mL
1.5-20 pg/mL
1.5-5.5 pg/mL
1.5-6.5 pg/mL
3-20 IU/L
9-26 IU/L
18-153 IU/L
1-12 IU/L
3-20 U/L
9-26 U/L
18-153 U/L
1-12 U/L
6.9-107.5 pmol/L
416-1386 pmol/L
10.3-35 pmol/L
4.2-13
0.22-6.78 pmol/L
1.61-2.68 mmol/L
<100 ng/L
20-100 ng/L
0.5-17.0 μg/L
0.2-3.1 pg/mL
12-40 pg/mL
0.8-2.7 ng/dL
4.2-13
1.4-4.4 pg/mL
1.61-2.68 mmol/L
<100 pg/mL
20-100 pg/mL
0.5-17.0 ng/mL
U
Estradiol
Women
Follicular phase
Mid-cycle peak
Luteal phase
Postmenauposal
Men
Estrone
Women
Follicular phase
Luteal phase
Postmenauposal
Men
Follicle stimulating hormone (FSH)
Women
Follicular phase
Ovulation phase
Postmenauposal
Men
Free testosterone
(Adult, morning)
Women
Men
Free thyroxine (FT4)
Free thyroxine index (FTI)
Free triiodothyronine (FT3)
Fructosamine
Gastrin
Glucagon
Growth hormone (GH) (Resting)
P: Plasma, S: Serum, U: Urine, C: Complete blood.
S, P
S, P
S, P
S
S
S
S
S
S
P
S
125
126
Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-2. Tests of endocrinology and metabolism(*)
Test
Human chorionic gonadotropin
(HCG) (except pregnancy)
5-hydroxy-indole-acetic acid (5-HIAA)
17-Hydroxyprogesterone (Adult)
Men
Women
Follicular phase
Mid-cycle peak
Luteal phase
Postmenauposal
Insulin
17-Ketosteroids
Luteinizing hormone (LH)
Women
Follicular phase
Ovulation
Luteal phase
Postmenauposal
Men
Norepinephrine(Noradrenaline)
Supine (30 min)
Sitting
Standing (30 min)
Parathyroid hormone (PTH)
Progesterone
Women
Follicular
Mid-luteal phase
Men
Prolactin (PRL)
Women
Men
Renin (Adult, normal Na diet)
Supine
Standing
P: Plasma, S: Serum, U: Urine, C: Complete blood.
Sample type
SI unit
Traditional unit
S
U
<5 IU/L
10.5-36.6 μmol/day
<5 mIU/mL
2-7 mg/day
0.15 nmol/L
5-250 ng/dL
0.6-3 nmol/L
3-7.5 nmol/L
3-15 nmol/L
20-100 ng/dL
100-250 ng/dL
100-500 ng/dL
≤2.1 nmol/L
14.35-143.5 pmol/L
10-42 μmol/day
≤70 ng/dL
2-20 μU/mL
3-12 mg/day
2-15 U/L
22-105 U/L
0.6-19 U/L
16-64 U/L
2-12 U/L
89-473 nmol/day
650-2423 pmol/L
709-4019 pmol/L
739-4137 pmol/L
10-60 ng/L
2-15 U/L
22-105 U/L
0.6-19 U/L
16-64 U/L
2-12 U/L
15-80 μg/day
<110-410 pg/mL
120-680 pg/mL
125-700 pg/mL
10-60 pg/mL
<3.18 nmol/L
9.54-63.6 nmol/L
<3.18 nmol/L
<1.0 ng/mL
3-20 ng/mL
<1.0 ng/mL
0-20 μg/L
0-15 μg/L
1.9-25.9 ng/mL
1.6-23 ng/mL
(1-5)
(1-5)
0.3-3 ng/(ml/h)
1-9 ng/(ml/h)
S
S, P
U
S, P
U
P
P
P
S
S, P
S
P
Turk JEM 2010; 14: Suppl 119-27
Reference Ranges of Laboratory Tests
APPENDIX TABLE-2. Tests of endocrinology and metabolism(*)
Test
Serotonin
Sex hormone-binding globulin (SHBG) (Adult)
Men
Women
Somatomedin-C (IGF-1) (Adult)
16-24 years of age
25-39 years of age
40-54 years of age
>54 years of age
Somatostatin
Thyroglobulin
Thyroid hormone-binding index
(THBI or T3RU)
Thyroid stimulating hormone (TSH)
Thyroxine-binding globulin (TBG)
Total testosterone
(morning sample)
Women
Men
Total thyroxine (T4)
Total triiodothyronine (T3)
P: Plasma, S: Serum, U: Urine, C: Complete blood
Sample type
C
Platelet
SI unit
0.28-1.14 μmol/L
0.7-2.8 μmol/ platelet
Traditional unit
50-200 ng/mL
125-500 ng/109 platelet
13-71 nmol/L
18-114 nmol/L
S
P
S
182-780 μg/L
114-492 μg/L
90-360 μg/L
71-290 μg/L
<25 ng/L
0-60 μg/L
182-780 ng/mL
114-492 ng/mL
90-360 ng/mL
71-290 ng/mL
<25 pg/mL
0-60 ng/mL
S
S
S
0.83-1.17 molar ratio
0.5-4.7 mU/L
206-309 μg/L
0.83-1.17
0.5-4.7 μU/mL
16-24 μg/dL
S
0.21-2.98 nmol/L
9.36-37.10 nmol/L
58-140 nmol/L
0.92-2.78 nmol/L
6-86 ng/dL
270-1070 ng/dL
4.5-10.9 μg/dL
60-181 ng/dL
S
S
S
127
FORTHCOMING MEETINGS
9. Medikal-Cerrahi Endokrinoloji Mezuniyet Sonras› Kursu
2-5 Aral›k 2010, Antalya
14th Asia-Oceania Congress of Endocrinology (AOCE)
2-5 December 2010, Malesia
13th European Congress of Endocrinology ECE 2011
29 April-4 May 2011, the Netherland
18th European Obesity Congress
25-28 may, Istanbul Turkey
Endocrine Society Meeting
4-7 June 2011, Boston-USA
ADA 2011 Meeting
23-28 June 2011, San Diego - USA