Download B2B Diabetes

Back to Basics: Endocrinology
Diabetes, Obesity, Metabolic Syndrome
Dr. Amel Arnaout
[email protected]
Which of the following statements is
true?
A.
B.
C.
D.
E.
Type 1 diabetes is not diagnosed after age 50
Type 2 diabetes is more strongly inherited than
type 1 diabetes.
The incidence and prevalence of DM-1 is on
the rise
Gestational diabetes does not increase the risk
of developing diabetes in the future.
People with type 2 diabetes never get DKA
Answer

B and C
Diabetes in Canada: Prevalence of Diagnosed
Diabetes by age and sex
Prevalence of diagnosed diabetes among individuals aged ≥ 1 year, by age group
and sex, 2008/09
Overall Prevalence
30
Females
6.4%
Males
7.2%
Total
6.8%
Prevalence (%)
25
20
15
10
5
0
Age group (years) 1-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Canada
Prevalence increased with age. The sharpest increase occurred after age 40 years.
The highest prevalence was in the 75-79 year age group.
Public Health Agency of Canada. Diabetes in Canada: Facts and figures from a public health perspective. Ottawa, 2011.
Classification of Diabetes
Type
Definition
Type 1 Diabetes
Diabetes due to pancreatic beta destruction and prone
to ketosis
Type 2 diabetes
Diabetes that ranges from insulin resistance with
relative insulin deficiency to a predominant secretory
defect with insulin resistance
Gestational
Diabetes
Mellitus
Glucose intolerance with onset or first recognition in
pregnancy
Other types
Variety of uncommon diseases, genetic forms, or
diabetes associated with drug use.
TYPE 1 Diabetes
TYPE 2 Diabetes
10%
90%
Pathogenesis
Beta cell destruction
(usually autoimmune)
Insulin resistance, relative
insulin deficiency
Endogenous insulin
secretion
Low or absent
Variable
Need for insulin
therapy
Required for survival
Required in <50%, to improve
control rather than for survival
Age of onset
Often <30 (but can
occur at any age)
Often >40 but even in kids
Body habitus
Usually lean
Often obese
Genetic component
Smaller
Very large
Symptoms at onset
Acute, severe
Often mild, slow onset
Ketoacidosis
Yes
Rare
Proportion of diabetes
cases
Long-term
No
complications present at
dx?
Retinopathy ~20%, CVD
relatively common
The pathophysiology of T2DM includes
three main defects
Islet
α-cell produces excess
glucagon
Pancreas
β-cell produces
less insulin
1. Insulin deficiency
Excess
glucagon
Diminished
insulin
Hyperglycemia
Diminished
insulin
Muscle and fat
Liver
2. Excess glucose output
3. Insulin resistance
Diabetes mellitus - complications
Diabetic
Retinopathy
Stroke
Leading cause of
blindness in
working-age adults1
Cardiovascular
Disease
Diabetic
Nephropathy
Leading cause of
end-stage renal
disease2
Diabetic Neuropathy
Leading cause of nontraumatic lower
extremity amputations5
1. Fong DS et al. Diabetes Care 2003; 26(Suppl 1):S99-S102. 2. Molitch ME et al. Diabetes Care 2003; 26
(Suppl 1):S94-S98. 3. Kannel WB et al. Am J Heart 1990; 120:672-6. 4. Gray RP and Yudkin JS. In: Textbook of
Diabetes. 1997. 5. Mayfield JA, et al. Diabetes Care 2003; 26(Suppl 1):S78-S79.
Diabetes Complications:
Macrovascular



DM is a major risk factor for cardiac disease
Acute MI occurs 15-20 years earlier in those
with DM
Heart disease accounts for approximately 50%
of all deaths among people with diabetes in
industrialized countries
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:
Cardiovascular disease

Several large epidemiological studies have found
a strong relationship between
glucose level and subsequent coronary events, even
at ‘pre-diabetes’ levels (IGT and IFG)
 glucose levels that are only modestly elevated place
patients at risk.

REF: Coutiho M. et al Diabetes Care 1999;22:233-240.
& DECODE Study Group. Arch Intern Med 2001;161:397-404.
Diabetes Complications:
Peripheral vascular disease (Macro and microvascular
disease)

Diabetes….
Is the leading cause of non traumatic amputation
 Increases the risk of amputation by 20 fold


those living in the north or in low income neighborhoods
and those with poor access to physician services are at
particular risk for amputation.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:
Microvascular – Retinopathy
Diabetes
 Is a leading cause of adult-onset blindness
 Prevalence of diabetic retinopathy is ~ 70% in
persons with type 1 and 40% with person with
type 2 diabetes.
REF: Diabetes in Ontario, An ICES Practice Atlas, 2002
Diabetes Complications:
Microvascular - Nephropathy

Diabetes
Is the leading cause of ESRD
 Increases the risk of developing ESRD by up to 13fold

Refs: Meltzer S, et al CMAJ 1998; 159 (8 suppl):S1-S29, &
Parchman ML, et al Medical Care 2002; 40(2):137-144.
DM-2 Risk Factors
Modifiable Risk Factors
Physical
Activity
 Obesity
Diet
&
Non-Modifiable Risk Factors
Ethnicity
Family
History
Age
Diabetes Risk Factors:
Modifiable
Obesity:
Relative Risk For Developing DM
Relative Risk
40
30
20
10
0
<23 23-25 25-30 30-35 <35
BMI = wt/(ht)2
Source: Choi B, Shi F. Diabetologia 2001, 44:1221-1231.
The Epidemic:
Ethnic Groups at High Risk for DM
Aboriginal
Latino
South Asian
Asian
African Descent
Prevention strategies

Primary Prevention


Secondary Prevention


Prevent diabetes through reduction of modifiable
risk factors in general population
Screening those at high-risk for diabetes
Tertiary Prevention

Upon diagnosis of diabetes, prevention of
complications morbidity, and mortality
REF: Diabetes Blueprint
Primary Prevention Model

Goal


Target


General population & high-risk groups
Messages


Reducing modifiable risk factors for diabetes
Healthy lifestyle choices
Current Delivery Models of Primary Prevention


Population Health
Primary Care
Primary Prevention Model:
Population Health – National
CDS
Health Canada
NADA
REF: Health Canada
Secondary Prevention

Goal


Target


High-risk individuals and groups
Messages


Early identification of those with dysglycemia
Diabetes awareness
Current delivery model of secondary prevention
relies on primary care
Secondary Prevention:
Is It Effective?

Yes….

Patients diagnosed with IGT can be prevented from
progressing to type 2 diabetes
58% reduction with lifestyle changes (DPP, DPS)
 30% reduction with medication (DPP, Stop NIDDM)

Tertiary Prevention:
Is it Effective?

Yes…

Strong evidence for tertiary prevention particularly
for microvascular disease
DCCT, UKPDS
 And for macrovascular as legacy effect (UKPDS and
EDIC follow up studies)


How to translate this evidence into practice?
Tertiary Prevention

Goals
Glucose, blood pressure, and lipid control to reduce
the development of complications
 Complication screening for early identification and
management

OBESITY
Why are Obesity and Type 2 DM
Increasing in Frequency?

More sedentary lifestyles

Worldwide changes in urbanization and nutrition

Aging population due to demographic growth rates (baby
boomers) and increased life expectancy
www.who.int and www.idf.org accessed March 16, 2006
Obesity





The most common metabolic condition in
industrialized nations
Statistics Canada: 48% of Canadians between ages 2064 yr are overweight (BMI>25), about 25% are obese
Associated with dyslipidemia, impaired glucose
tolerance and insulin resistance
Risk factor for developing metabolic syndrome, type 2
Dm, cardiovascular disease
Huge economic costs
METABOLIC
SYNDROME
Metabolic Syndrome
A constellation of risk factors
 Significantly increased CVD risks
 Significantly increased risks for type 2
diabetes
Definition of Metabolic Syndrome – need central obesity plus 2
others for diagnosis
Clinical Features of the Metabolic
Syndrome






Abdominal obesity
Hyperglycemia
Atherogenic dyslipidemia
Hypertension
Proinflammatory state
Prothrombotic state
Metabolic Syndrome




A common condition associated with increased
cardiovascular disease risks
Treatment is aimed at lifestyle modification to
achieve desirable body weight and reduce
abdominal obesity
Multiple medical therapy may be required to
achieve metabolic targets (lipids, glucose and BP)
Lifestyle modification benefits everyone!
DIABETES
Diagnosis of Diabetes
2013
FPG ≥7.0 mmol/L
Fasting = no caloric intake for at least 8 hours
or
A1C ≥6.5% (in adults)
Using a standardized, validated assay, in the absence of factors that affect the
accuracy of the A1C and not for suspected type 1 diabetes
or
2hPG in a 75-g OGTT ≥11.1 mmol/L
or
Random PG ≥11.1 mmol/L
Random= any time of the day, without regard to the interval since the last meal
2hPG = 2-hour plasma glucose; FPG = fasting plasma glucose; OGTT = oral glucose tolerance test; PG = plasma glucose
Diagnosis of Prediabetes*
2013
Test
Result
Prediabetes Category
Fasting Plasma
Glucose
(mmol/L)
6.1 - 6.9
Impaired fasting glucose
(IFG)
7.8 – 11.0
Impaired glucose tolerance
(IGT)
6.0 - 6.4
Prediabetes
2-hr Plasma Glucose in
a 75-g Oral Glucose
Tolerance Test (mmol/L)
Glycated
Hemoglobin
(A1C) (%)
* Prediabetes = IFG, IGT or A1C 6.0 - 6.4%  high risk of developing T2DM
Fasting Glucose (mmol/L)
Definitions of Impaired Fasting Glucose (IFG)
and Impaired Glucose Tolerance (IGT) and
Diabetes
8.5
Diabetes
7.5
6.9
6.5
6.1
5.6*
5.5
4.5
IFG
IFG + IGT
Normal
Glucose
IGT
3.5
3
4
6
8
7.8
10
12
14
11.1
2-h Post-load Glucose (mmol/L)
* 1. ADA Diabetes Care 2006;29(Suppl 1):S47,2. CDA Can J Diabetes 2003;27(Suppl 2):S7,
3.WHO 1999 NDC/NCS.99.2 accessed Mar 2 2006 from www.who.int
Recognize pitfalls of A1C:
conditions that can affect
value
Factors affecting
A1C
Increased A1C
Decreased A1C
Erythropoiesis
B12/Fe deficiency
Decreased erythropoiesis
Use of EPO, Fe, or B12
Reticulocytosis
Chronic liver Dx
Altered
hemoglobin
Variable Change in
A1C
Fetal hemoglobin
Hemoglobinopathies
Methemoglobin
Altered glycation
Chronic renal failure
(use of EPO decreases
A1C)
ASA, vitamin C/E
Hemoglobinopathies
↑ erythrocyte pH
Erythrocyte
destruction
Splenectomy
Hemoglobinopathies
Chronic renal failure
Splenomegaly
Rheumatoid arthritis
HAART meds, Ribavirin
Dapsone
Assays
Hyperbilirubinemia
Carbamylated Hb
ETOH
Chronic opiates
Hypertriglyceridemia
Pros and Cons of Diagnostic Tests
Test
Advantages
Disadvantages
FPG
Established standard
Fast and easy
Single Sample
Sample not stable
Day-to-day variability
Inconvenient to fast
Glucose homeostasis in single time point
2hPG in
75 g
OGTT
Established standard
Sample not stable
Day-to-day variability
Inconvenient, Unpalatable
Cost
A1C
Convenient
Single sample
Low day-to-day variability
Reflects long term [glucose]
$$$
Affected by medical conditions, aging,
ethnicity
Standardized, validated assay required
Not used for age <18, pregnant women
or suspected T1DM
Treatment of Diabetes –
Target A1C
Individualizing A1C2013Targets
Consider 7.1-8.5% if:
which must be
balanced against
the risk of
hypoglycemia
DCCT
n=1441 T1DM
Intensive
(≥ 3
injections/day
or CSII)
vs
Conventional
(1-2 injections
per day)
Reduction in Retinopathy
Primary Prevention
Secondary Intervention
76% RRR
54% RRR
(95% CI 62-85%)
(95% CI 39-66%)
RRR = relative risk reduction CI = confidence interval
The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-986.
MI, stroke or CV death
DCCT/EDIC: Early intensive therapy reduced the risk of
nonfatal MI, stroke or death from CVD
0.12
0.10
57% risk reduction
(P=0.02; 95% CI: 12–79%)
0.08
0.06
Conventional
treatment
0.04
0.02
Intensive
treatment
0.00
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21
Years since entry
DCCT/EDIC Study Research Group. N Engl J Med 2005;353:2643–2653.
UKPDS: N = 3867 T2DM
9
Conventional
7.9%
A1C (%)
8
Intensive
7.0%
7
6
0 0
3
UKPDS Study Group. Lancet 1998:352:837-53.
6
9
12
15
Legacy Effect of Earlier Glucose
Control
After median 8.5 years post-trial follow-up
Aggregate Endpoint
1997
2007
Any diabetes related endpoint
RRR:
P:
12%
0.029
9%
0.040
Microvascular disease
RRR:
P:
25%
0.0099
24%
0.001
Myocardial infarction
RRR:
P:
16%
0.052
15%
0.014
All-cause mortality
RRR:
P:
6%
0.44
13%
0.007
Holman R, et al. N Engl J Med 2008;359.
Therapeutic strategies for
the management of type
2 diabetes.
AT DIAGNOSIS OF TYPE 2 DIABETES
Start lifestyle intervention (nutrition therapy and physical activity) +/- Metformin
L
I
F
E
S
T
Y
L
E
A1C <8.5%
If not at glycemic
target (2-3 mos)
Start / Increase
metformin
A1C 8.5%
Symptomatic hyperglycemia with
metabolic decompensation
Start metformin immediately
Consider initial combination with
another antihyperglycemic agent
Initiate
insulin +/metformin
If not at glycemic targets
Add an agent best suited to the individual:
Patient Characteristics
Degree of hyperglycemia
Risk of hypoglycemia
Overweight or obesity
Comorbidities (renal, cardiac, hepatic)
Preferences & access to treatment
Other
Agent Characteristics
BG lowering efficacy and durability
Risk of inducing hypoglycemia
Effect on weight
Contraindications & side-effects
Cost and coverage
Other
2013
See next page…
Oral Medications to
Treat Type 2 Diabetes
Major Classes of Medications
1. Drugs that sensitize the
body to insulin and/or
control hepatic glucose
production
Thiazolidinediones
Biguanides
2. Drugs that stimulate the
pancreas to make more
insulin
Sulfonylureas
Meglitinides
3. Drugs that slow the
absorption of starches
Alpha-glucosidase
inhibitors
Newer Classes of Medications
Incretins



Derived from gut hormone GLP-1
Glucagon like peptide 1
Two subtypes:


GLP-1 agonist : liraglutide, expand tide
DPPIV inhibitors : sitagliptin, saxagliptin, linagliptin
SGLT2 inhibitors





Canagloflozin, dapagloflozin and empagloflozin
Inhibit 30-50% renal reabsorption of glucose
Promotes glycosuria, improves blood glucose and causes
weight loss
May have cardiovascular benefits (EMPA-REG): CAD and
CHF
Side effects: genital urinary infections, normoglycemic DKA
GLP-1 Effects in Humans: Understanding
Glucoregulatory Role of Incretins
Adapted from Flint A, et al. J Chin Invest. 1998;101:515-520; Larsson H, et al. Acta
Physiol Scand. 1997;160:413-422; Nauck MA, et al. Diabetologia. 1996;39:1546-1553;
Drucker DJ. Diabetes. 1998;47:159-169.
Thiazolidinediones


Thiazolidinediones decrease insulin resistance by making muscle
and adipose cells more sensitive to insulin. They also suppress
hepatic glucose production.
Efficacy




Other Effects





Decrease fasting plasma glucose ~1.9-2.2 mmol/L
Reduce A1C ~0.5-1.0%
6 weeks for maximum effect
Weight gain, edema
Hypoglycemia (if taken with insulin or agents that stimulate insulin release)
Contraindicated in patients with abnormal liver function or CHF
Improves HDL cholesterol and plasma triglycerides; usually LDL neutral
Medications in this Class: pioglitazone (Actos), rosiglitazone
(Avandia),
Biguanides


Biguanides decrease hepatic glucose production and increase
insulin-mediated peripheral glucose uptake.
Efficacy



Other Effects







Decrease fasting plasma glucose 3.3-3.9 mmol/L
Reduce A1C 1.0-2.0%
Diarrhea and abdominal discomfort
Risk of Lactic acidosis in those at risk (renal failure, CHF)
Cause small decrease in LDL cholesterol level and triglycerides
No specific effect on blood pressure
No weight gain, with possible modest weight loss
Contraindicated in patients with impaired renal function (eGFR<33 ml/min)
Medications in this Class: metformin (Glucophage), metformin
hydrochloride extended release (Glumetza)
Sulfonylureas


Sulfonylureas increase endogenous insulin secretion
Efficacy



Other Effects





Decrease fasting plasma glucose 3.3-3.9 mmol/L
Reduce A1C by 1.0-2.0%
Hypoglycemia
Weight gain
No specific effect on plasma lipids or blood pressure
Generally the least expensive class of medication
Medications in this Class:

glyburide (DiaBeta), glimepiride (Amaryl), gliclizide (Diamicron)
Meglitinides


Meglitinides stimulate insulin secretion (rapidly and for a
short duration) in the presence of glucose.
Efficacy




Other Effects





Decreases peak postprandial glucose
Decreases plasma glucose 3.3-3.9 mmol/L
Reduce A1C 1.0-2.0%
Hypoglycemia (although may be less than with sulfonylureas if patient has a
variable eating schedule)
Weight gain
No significant effect on plasma lipid levels
Safe at higher levels of serum Cr than sulfonylureas
Medications in this Class: repaglinide (Gluconorm),
nateglinide (Starlix)
Alpha-glucosidase Inhibitors


Alpha-glucosidase inhibitors block the enzymes that
digest starches in the small intestine
Efficacy




Other Effects





Decrease peak postprandial glucose 2.2-2.8 mmol/L
Decrease fasting plasma glucose 1.4-1.7 mmol/L
Decrease A1C 0.5-1.0%
Flatulence or abdominal discomfort
No specific effect on lipids or blood pressure
No weight gain
Contraindicated in patients with inflammatory bowel disease or
cirrhosis
Medications in this Class: acarbose (Glucobay)
2013
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Copyright © 2013 Canadian Diabetes Association
Insulin Therapy
Types of Insulin
Insulin Type (trade name)
Onset
Peak
Duration
10 - 15 min
10 - 15 min
10 - 15 min
1 - 1.5 h
1 - 1.5 h
1-2h
3-5h
3-5h
3.5 - 4.75 h
30 min
2-3h
6.5 h
1-3h
5-8h
Up to 18 h
90 min
Not
applicable
Up to 24 h
(glargine 24 h,
detemir 16 - 24 h)
Bolus (prandial) Insulins
Rapid-acting insulin analogues (clear):
• Insulin aspart (NovoRapid®)
• Insulin glulisine (Apidra™)
• Insulin lispro (Humalog®)
Short-acting insulins (clear):
• Insulin regular (Humulin®-R)
• Insulin regular (Novolin®geToronto)
Basal Insulins
Intermediate-acting insulins (cloudy):
• Insulin NPH (Humulin®-N)
• Insulin NPH (Novolin®ge NPH)
Long-acting basal insulin analogues
(clear)
• Insulin detemir (Levemir®)
• Insulin glargine (Lantus®)
Types of Insulin (continued)
Insulin Type (trade name)
Time action profile
Premixed Insulins
Premixed regular insulin – NPH (cloudy):
• 30% insulin regular/ 70% insulin NPH
(Humulin® 30/70)
• 30% insulin regular/ 70% insulin NPH
(Novolin®ge 30/70)
• 40% insulin regular/ 60% insulin NPH
(Novolin®ge 40/60)
• 50% insulin regular/ 50% insulin NPH
(Novolin®ge 50/50)
Premixed insulin analogues (cloudy):
• 30% Insulin aspart/70% insulin aspart protamine
crystals (NovoMix® 30)
• 25% insulin lispro / 75% insulin lispro protamine
(Humalog® Mix25®)
• 50% insulin lispro / 50% insulin lispro protamine
(Humalog® Mix50®)
A single vial or cartridge contains a
fixed ratio of insulin
(% of rapid-acting or short-acting
insulin to % of intermediate-acting
insulin)
Normal Pancreatic Function
Basal: Beta cells secrete
small amounts of insulin
throughout the day.
Bolus: At mealtime, insulin
is rapidly released in
response to food.
Bolus Insulin
Basal Insulin
Meal
•
Meal
Meal
Expected insulin changes during the day for
individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.
Action Profiles of Bolus & Basal
Insulins
lispro/aspart 4–6 hours
regular 6-10 hours


BOLUS INSULINS
BASAL INSULINS
NPH 12–20 hours
detemir ~ 6-23 hours (dose dependant)
glargine ~ 20-26 hours
Hours
Note: action curves are approximations for illustrative purposes. Actual patient response will vary.
Mayfield, JA.. et al, Amer. Fam. Phys.; Aug. 2004, 70(3): 491
Plank, J. et.al. Diabetes Care, May 2005; 28(5): 1107-12
Therapy Compared to Normal Physiology
Basal needs: NPH
Bolus needs: Regular
Meal
•
•
Meal
Meal
Expected insulin changes during the day
for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data
Mayfield, JA. et al., Amer. Fam. Phys.; Aug. 2004, 70(3): 489-500
Multiple Daily Injections (MDI) –
Strive to Mimic Normal Physiology
MDI insulin therapy addresses:
Basal needs: Glargine, Detemir
Bolus needs: Lispro, Aspart
Meal
•
•
Meal
Meal
Expected insulin changes during the day
for individuals with a healthy pancreas.
*Insulin effect images are theoretical representations and are not derived from clinical trial data.
Insulin Regimens
Type 2

Usually – a single bedtime injection of basal
insulin added to OAD.

Occasionally - twice daily injections of basal
insulin with OAD.

Twice daily injection of “pre-mixed” insulin

Intensive insulin – basal/bolus (THE ONLY
RECOMMENDED OPTION FOR DM TYPE 1)

40% basal/20% mealtime with each meal
Case 1
55
year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%
On metformin, glyburide,


Breakfast
Lunch
Dinner
Bedtime
9.5
7.5
7.1
7.0
Is this patient well controlled?
Does this patient require insulin?
Case 1 - Bedtime Insulin
55
year old, 84 kg, BMI 29, T2DM 5 yrs, A1C = 8.5%
On metformin, glyburide,
Breakfast



Lunch
-
Dinner
-
Bedtime
NPH, Glargine or
Detemir - 10 units
Start with 10 units1, or use 0.1- 0.2 units/kg and titrate2
Ex. 84 kg X 0.1 = 8 units OR 84 kg X 0.2 = 17 units
Continue metformin, glyburide. Continuing TZD would be
off-label in Canada
1 Riddle et.al., Diabetes Care, 2003, 26(11):3080-86
2 CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S135
Hypoglycemia – Recognition

Hypoglycemia = development of symptoms or a plasma glucose
<4.0 mmol/L.
Symptoms of hypoglycemia
Autonomic
Trembling
Palpitations
Sweating
Anxiety
Neuroglycopenic
Hunger
Nausea
Tingling
Difficulty concentrating
Vision changes
Difficulty speaking
Headache
Dizziness
Confusion
Weakness
Drowsiness
Tiredness
Severity of hypoglycemia
Mild: Autonomic symptoms are present. The individual is able to self-treat.
Moderate: Autonomic and neuroglycopenic symptoms are present. The
individual is able to self-treat.
Severe: Individual requires assistance of another person. Unconsciousness may
occur. Plasma glucose is typically <2.8 mmol/L.
CDA 2003 CPG, Can J Diabetes 27(Suppl 2):S43
Diabetic ketoacidosis
Diagnostic criteria

Hyperglycemia


Metabolic acidosis (increased anion gap)



Glucose >11.1 mmol/l; usually > 15 mmol/l
pH < 7.35
decreased bicarbonate <15 (best estimation with venous)
Positive serum ketones

Urine ketones: may be absent in early stages
Insulin deficiency


Decreased peripheral glucose utilization
increased glucose production


liver - gluconeogenesis (from aminoacids, glycerol),
glycogenolysis
increased ketogenesis

increased lipolysis in adipocytes - provides free fatty
acids for ketones and glycerol for gluconeogenesis
1
Clinical features



Hyperglycemia: thirst, polyuria, circulatory
collapse
Ketosis: “acetone breath’
Acidosis/ compensatory respiratory alkalosis:
tachypnea
Consequences of DKA

Hyperglycemia

osmotic diuresis



hyperosmolar state


dehydration
loss of K, Na, HCO3 in urine
increase free water into blood hyponatremia, cerebral
dehydration  decreased level of consciousness
acidosis


compensatory respiratory alkalosis
K shifts (hyperkalemia)
Laboratory Calculations for
diagnosis and treatment

Serum osmolality


serum Na



for each 3-4 mmol/l increase in glucose, Na should decrease
by 1
anion gap


2(Na + K) + glucose +BUN
Na -(Cl+HCO3)
compensation for metabolic acidosis
If suspect other causes for acidosis; meausre serum
lactate and salicylate
Treatment

GOAL:
replace volume loss (with normal saline)
 stop ketone production (with insulin)
 replace K loss (K initially high but falls rapidly with
treatment)
 lower serum glucose
*Need to correct INSULIN DEFICIENCY
*Look for precipitating cause and treat


Fluid




NS 1L per hour first 2 hours, then 1L over 4 hrs
NS until glucose < 15
then D5/NS or D5 depending if still replacing volume
insulin
intravenous
 50 units regular in 500 normal saline (0.1U/ml)
 Bolus 0.1 unit per kg body weight (IM/IV)
 Infusion 0.1 unit/kg/hour
 Glucoscans q1h, adjust IV rate and IV D5
* Do not stop insulin infusion until acidosis/ AG corrected



bicarbonate generally avoided
potassium

start when K 3.3-5.5, 20 mmol/L (hold insulin if K is
<3.3 and give 40 meq/h
Hyperosmolar non-ketotic state





Severe hyperglycemia generally in DM type 2
dehydration
serum hyperosmolality
lack of significant ketosis (still some circulating insulin)
* takes less insulin to prevent ketosis than to stop
hyperglycemia




Stressor - increased insulin resistance
relative insulin deficiency
increased glucose production, decreased
utilization
reduced renal excretion of glucose

secondary to renal disease, aging kidneys
Treatment of HONK




Correct increased serum osmolality
Blood glucose will fall in response to fluid
repletion
If Na>155 mmol/L, start 0.45% NS as initial
fluid
Insulin infusion only if persistent hyperglycemia
after fluid replete
SCREENING AND PREVENTION
OF COMPLICATIONS
Who Should Receive Statins?
2013




≥40 yrs old or
Macrovascular disease or
Microvascular disease or
DM >15 yrs duration and age >30 years
Among women with childbearing potential, statins should only
be used in the presence of proper preconception counseling &
reliable contraception. Stop statins prior to conception.
Who Should Receive ACEi or ARB
Therapy?
2013

≥55 years of age or

Macrovascular disease or

Microvascular disease
At doses that have shown vascular protection [perindopril 8
mg daily (EUROPA), ramipril 10 mg daily (HOPE), telmisartan 80 mg
daily (ONTARGET)]
Among women with childbearing potential, ACEi or ARB should only
be used in the presence of proper preconception counseling & reliable
contraception. Stop ACEi or ARB either prior to conception or
immediately upon detection of pregnancy
EUROPA Investigators, Lancet 2003;362(9386):782-788.
HOPE study investigators. Lancet. 2000;355:253-59.
ONTARGET study investigators. NEJM. 2008:358:1547-59