Download Treatment of type 2 DM

Diabetes Mellitus
ADA
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American Diabetes Association
www.Diabetes.org
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DM is a group of metabolic disorders of fat,
carbohydrate & protein metabolism that results
from defect in insulin secretion, action or both
Signs & symptoms
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Polyuria
Polydipsia
Fatigue
Weight loss (in type 1)
Diagnosis
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Symptoms+ random glc ≥200 mg/dL
An FPG≥126 mg/dL(7 mmole/L) (at least 8 hr)
2 hr postprandial ≥ 200 mg/dL during OGTT
HbA1C ≥ 6.5%
Glycated Hemoglobin
A1C (%)
Mean Blood Glucose
NGSP
IFCC
mg/dl
7
5.3
170
8
6.3
205
9
7.3
240
10
8.4
275
11
9.5
310
12
10.6
345
National Glycohemoglobin Standardization Program
the International Federation for Clinical Chemistry
Hoelzel W. et al. Clin Chem 2004;50(1):161-174
Conversions
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Whole blood glucose (mg/dL) = plasma glucose
(mg/dL) ÷ 1.12
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Plasma glucose (mmol/L) = plasma glucose
(mg/dL) ÷ 18
Biochemical Index
ADA recommendations
HgA1C
<7%
FPG
80-130
PPG
<180
Methods of Monitoring Glycemic
Control
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SMBG and HbA1c levels continue to be the two primary
methods used to access glycemic control
Recently, continuous glucose monitoring (CGM) of interstitial
fluid has become available
Urine Ketone Testing
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For when glucose concentrations consistently > 300 mg/dL or
during acute illness, symptoms of ketoacidosis and pregnancy
Principles of type 1 DM treatment
Treatment of type 1 DM
 Insulin
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Regimen
Physical activity
Investigational Agents
for type 1
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Metformin
Incretin-Based Therapies
Sodium-Glucose cotransporter 2 inhibitors
Inulin
Type
Example
Rapid
Glulisin, Aspart, Lispro,
Short
Regular
Intermediate
NPH
Long
Glargine, Detemir
Insulin
Lispro
Onset
15-30 min
Peak (hr)
1-2
Duration (hr)
3-5
Aspart
15-30 min
1-2
3-4
Glulisin
Regular
NPH
Detemir
Glargine
15-30 min
0.5-1 hr
2-4 hr
2 hr
1.5 hr
1-2
2-3
4-8
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3-4
4-6
8-12
14-24
22-24
Empiric insulin doses
Type 1:
 Initial: 0.5-0.8 u/kg/d
Type 2:
 With insulin resistance: 0.7-1.5 u/kg/d
Adverse Effects
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Insulin Allergy
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Localized (itching at site)
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Systemic (angioedema, hypotension, anaphylaxis and
death)
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Hypoglycemia
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Lipoatrophy
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Wasting of subcutaneous fat
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Benign, but cosmetically disfiguring
Hypoglycemia
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Blood glucose <40 mg/dL: Patient is generally symptomatic
Blood glucose <20 mg/dL can be associated with seizures and
coma
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Mild hypoglycemia: tremor, palpitations, sweating, and intense hunger.
Diminished cerebral function is not present and patients are capable of
self-treating mild reactions.
Moderate hypoglycemia: neuroglycopenic as well as autonomic
symptoms: headache, mood changes, irritability, decreased attention,
and drowsiness. Patients may require assistance in treating themselves
because of the presence of impaired judgment or weakness. Symptoms
are more severe, usually last longer, and often require a second dose of
a simple carbohydrate.
Severe hypoglycemia: unresponsiveness, unconsciousness, or
convulsions. These reactions require assistance from another individual
for appropriate treatment.
Approximately 10% of patients treated with insulin develop at least
one severe episode of hypoglycemia per year that requires emergency
treatment with parenteral glucagon or IV glucose
Treatment of mild hypoglycemia
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Most hypoglycemic reactions are managed readily with the
equivalent of 10 to 20 g ( 15 g) of glucose
“15-15-15”: 15 g of glucose followed by a second 15 g if the
patient is still symptomatic after 15 minutes
Treatment of moderate to severe hypoglycemia
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Glucagon: SC or IM route into the deltoid or anterior thigh
region.
The dose for < 5 years: 0.25 to 0.5 mg
5 -10 years: 0.5 to 1 mg; and for >10 years:1 mg
Kits with prefilled syringes containing 1 mg glucagon are
available
Patients who are given glucagon should be positioned so that
their face is turned toward the floor
As soon as the patient awakens (10–25 minutes), he or she
should be fed
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IV glucose (~10–25 g administered as 20–50 mL of 50%
dextrose over 1–3 minutes)
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Following the bolus injection of glucose, IV glucose (5–10
g/hour) should be continued until the patient has gained
consciousness and is able to eat
Pramlintide
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amylin analog
Delay gastric empting, blunts glucagon
secretion, enhances satiety
FDA approval for type1 in adults
Induction of weight loss, lower ins dose
Concurrent reduction in prandial ins dose for
decrease in hypoglycemia
Treatment of type 2 DM
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Regimen
Physical activity
Oral agents
Insulin
agents
for type 2 DM
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Biguanides
Sulfonylurea
Non Sulfonylurea secretagogues
Alpha glucosidase inhibitors
Thiazolidinediones
DPP-4 Inhibitors
GLP-1 Analogs
SGLT-2 inhibitors
Metformin
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First line for type 2
Mechanism: Decrease hepatic G, Increase G uptake
↓ HbA1c: 1.5 – 1.7 %
↓ FPG:50-70 mg/dL
If not achieve to goal after 3-6 months addition second agent
Good for dyslipidemia ( ↓5-10% chol, 10-20% TG)
Good for obesity or another factor favoring insulin resistance
ADRs
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Gastrointestinal( diarrhea)
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Lactic Acidosis (↓ lactate to Glu)
Pregnancy
 Hypoglycemia?
Suggested by ADA for reducing risk for developing
DM in patients at high risk
 Contentious use causes a vit B12 deficiency as
many as 30% of patients which can present without
anemia or as a peripheral neuropathy
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Sulfonylurea (SFUs)
Glibenclamide, Gliclazide, Chlorpropamide
Mechanism:
 Stimulate insulin secretion
 May decrease hepatic glucose output
 Enhance peripheral glucose utilization
Sulfonylurea (SFUs)
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FDA approved for monotherapy and
combination with insulin & metformin
Rapid onset: 1 week
Decrease in A1C %1.5-1.7
Decrease in FPG 50-70 mg/dl
Decrease in PPG 92 mg/dl
Sulfonylurea (SFUs)
Common Adverse effects:
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Hypoglycemia
Weight gain
Possible interaction with fluoroquinolones
which also potentiate hypoglycemic action of
glyburide
Non Sulfonylurea secretagogues
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Glinides: Repaglinide,Nataglinide
Mechanism: like SU
Rapid act & short duration compared with SU
so they are given with meals to ↑ postprandial G
utilization
FDA approved monotherapy or combination
with insulin/metformin
Non Sulfonylurea secretagogues
Caution in patients with liver disease
 ADRs:
Mild Hypoglycemia
Weight gain
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Dosing
Repaglinide
If HgA1C < 8 or for first line 0.5 mg with each
meals
In others: 1-2 mg with each meals
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Nateglinide
60-120 mg TDS
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Drug interaction
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Gemfibrozil /Ketokonazole/Itraconazole &
Repaglinide
Thiazolidinediones
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Rosiglitazone
Pioglitazone
Mechanism: Insulin sensitizers
Once daily or twice ,With or without food
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Reduction of HbA1c - 0.5 – 1%
Thiazolidinediones
ADRs
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Mild anemia
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Mild to moderate edema
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Weight gain
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Elevation of serum transaminases
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Osteoprosis
LFT every 1-2 month at baseline , then
periodically
Drug interactions
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Gemfibrozil: ↑ AUC of both (dose reduction of TZD)
Pioglitazone: Induction of CYP3A4
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FDA has restricted use of rosiglitazone owing to data suggesting
an elevated risk of cardiovascular events in type 2 treated with R.
Rosiglitazone
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Lipid profile
+++
Pioglitazone
Alpha glucosidase inhibitors
Acarbose
miglitol
 Mechanism:
Slow absorption of complexcarbohydrate
 FDA approved monotherapy and combination
with SU
Alpha glucosidase inhibitors
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Decrease in A1C %0.5-1
Decrease in FPG 20-30 mg/dl
Decrease in PPG 25-50 mg/dl
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Common Adverse effects: flatulence, diarrhea
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LFTs for acarbose
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Incretin-Based Therapies
Incretins are insulinotropic hormones secreted from specialized
neuroendocrine cells in the small intestinal mucosa in response to
carbohydrate ingestion and absorption.
 2 hormones accounting for most incretin effects:
Glucose dependent insulinotropic polypeptide(GIP)
Glucagon-like peptide-1 (GLP-1)
 Both stimulate pancreatic Β cells in a glucose-dependent manner,
contributing to the early-phase insulin response. GLP-1 also inhibits
pancreatic a cells, thus reducing glucagon secretion.
 Short half life of Incretins via proteolysis cleavage by dipeptidyl
peptidase-4 (DPP-4)
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Dipeptidyl Peptidase-4 Inhibitors
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Sitagliptin
Saxagliptin
Linagliptin
Mechanism: inhibit the degradation of GIP &
GLP-1 on entering the GI vasculature
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Sitagliptin
It does not interfere with CYP nor does it act as
an inhibitor or inducer of CYP system
 It dose not increase risk of pancreatitis
 Adjustment in RF
usual: 100 mg/d
GFR 30-50: 50 mg/d
GFR < 30: 25 mg/d
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GLP 1 like peptide agonists
Exenatide
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SC 5 mcg BD titrated to 10 mcg BD 0-60 min before
morning and evening meals
Degradation by proteolytic enzymes in kidney, adjust in RF
Efficacy: ↓HbA1c is approximately 0.9%
significantly ↓ PPG, a modest effect on FPG
allow some patients to lose weight
ADRs: GI( nausea, Diarrhea), caution in pancreatitis,
hypoglycemia in combination with insulin/SU
Interactions: If rapid absorption is necessary, it is best to
take the medication 1 hour before, or 3 hours after the
injection of exenatide
Liraglutide
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Efficacy: ↓HbA1c is approximately 0.9%
Dosing: 0.6 mg/d for 1 week then 1.2 mg/d
max 1.8 mg/d
ADRs & interactions like Exenatide
↓ PPG and FPG (long half life , suppression of
glucagon overnight)
SGLT2 Inhibitors
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Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor
Dapagliflozin : (Farxiga)5 mg, 10 mg
Initial: 5 mg/d; may increase to 10 mg/d
Administer with or without food
Principle of DM 2 treatment
Metformin, if not contraindicated and if
tolerated, is the preferred initial pharmacological
agent for type 2 diabetes.
 In patients with newly diagnosed DM 2 and
markedly symptomatic and/or elevated BG/
A1C, consider initiating insulin(with/without
additional agents).
 If non insulin monotherapy at maximum
tolerated dose does not Achieve /maintain A1C
target over 3 months, add a second OA/GLP1
agonist/basal insulin.
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A patient-centered approach should be used to
guide choice of pharmacological agents.
Considerations include efficacy, cost, side effects,
weight, comorbidities, hypoglycemia risk, and
patient preferences.
Due to the progressive nature of type 2,
insulin therapy is eventually indicated for
many patients with type 2 diabetes.
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For all patients consider initiating therapy with a
dual combination when A1C is > %9
Consider Insulin therapy when BG is > 300-350
and or A1C > %10-12
Meglitinides may be used instead of SU in
patients with irregular meal schedules /who
develop late postprandial hypoglycemia on a SU
Cardiovascular diseases & risk management
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Hypertension control
Dyslipidemia management
Antiplatelet therapy
Coronary heart disease
Hypertension
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People with diabetes and hypertension should
be treated to a SBP goal of 140 mmHg.
People with diabetes and hypertension should
be treated to a DBP goal of 90 mmHg.
Pharmacological therapy for patients with DM and
HTN should comprise a regimen that includes either an
ACE Inh or an ARBs. If one class is not tolerated, the
other should be substituted.
Consider administering one or more antihypertensive
medications at bedtime
Pregnancy & DM
Target BP goals of SBP 110–129 mmHg and DBP 65–79
mmHg are reasonable, as they contribute to improved
long-term maternal health.
 During pregnancy, treatment with ACE Inh and ARBs
is contraindicated
 Chronic diuretic use during pregnancy has been
associated with restricted maternal plasma volume,
which may reduce uteroplacental perfusion
 Effective and safe in pregnancy: methyldopa, labetalol,
diltiazem, clonidine, and prazosin
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↓HDL cholesterol, often associated with↑ TG are the most
prevalent pattern of dyslipidemia in type 2 DM
In adults, a screening lipid profile is reasonable at the time of
first diagnosis, at the initial medical evaluation, and/or at age 40
and periodically (e.g., every 1–2 years)
Intensify lifestyle therapy and optimize glycemic control for
patients with elevated TG (150 mg/dL and/or low HDL
cholesterol (40 mg/dL men, 50 mg/dL women).
Dyslipidemia management
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Combination therapy (statin/fibrate and
statin/niacin) has not been shown to provide
additional cv benefit above statin alone and is
not generally recommended.
Antiplatelet therapy
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Consider ASA (75–162 mg/d) as a primary prevention strategy
in those with type 1/2 at increased cv risk ; This includes most
men >50 y or women > 60 y who have at least 1 additional major
risk factor (family history of CVD, HTN, smoking, dyslipidemia,
or albuminuria).
ASA should not be recommended for CVD prevention with DM
at low CVD risk such as in men < 50 y and women < 60 y with
no major additional CVD risk factors
In patients between above, clinical judgment is required.
Antiplatelet therapy
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Use ASA (75–162mg/d) as a secondary prevention strategy in
those with DM and a history of CVD
For patients with CVD and documented ASA allergy,clopidogrel
(75 mg/day) should be used
Dual antiplatelet therapy is reasonable for up to a year after an
acute coronary syndrome (ticagrelor, or prasugrel) if PCI was
performed
CORONARY HEART DISEASE
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In patients with known CVD, use ASA and statin therapy (if not
contraindicated) and consider ACE inh to reduce the risk of cv
events.
In patients with a prior MI, b-blockers should be continued for
at least 2 years after the event.
In patients with symptomatic HF, thiazolidinedione should not
be used.
In patients with stable CHF, metformin may be used if renal
function is normal but should be avoided in unstable or
hospitalized patients with CHF.
Microvascular complications
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Nephropathy
Retinopathy
Neuropathy
NEPHROPATHY
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Optimize glucose control to reduce the risk or slow the progression
of diabetic kidney disease.
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Optimize BP control to reduce the risk or slow the progression of
diabetic kidney disease.
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At least once a year, quantitatively assess urinary albumin (e.g., urine
albumin to-creatinine ratio [UACR]) and GFR) in patients with type
1 duration of >5 years and in all patients with type 2
Continued monitoring of UACR in patients with albuminuria is
reasonable to assess progression of diabetic kidney disease.
 Either an ACE inh or ARB is suggested for the treatment of the
non pregnant patient with modestly elevated urinary albumin
excretion (30–299 mg/day) and is recommended for those with
urinary albumin excretion > 300 mg/day.
 An ACE inh or ARB is not recommended for the primary
prevention of diabetic kidney disease in patients with diabetes
who have normal blood pressure and normal UACR (<30 mg/g).
 When ACE inh, ARBs, or diuretics are used, monitor Sr cr and
potassium levels for the development of increased creatinine or
changes in potassium
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Diabetic neuropathy
All patients should be screened for diabetic peripheral neuropathy
(DPN) starting at diagnosis of type 2 and 5 years after the
diagnosis of type 1 and at least annually thereafter
 Screening for signs and symptoms (e.g., orthostasis, resting
tachycardia) of cardiovascular autonomic neuropathy (CAN)
should be considered with more advanced disease
 Tight glycemic control is the only strategy convincingly shown to
prevent or delay the development of DPN and CAN in patients
with type 1 and to slow the progression of neuropathy in some
patients with type 2
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THE END