Transcript DM Rx. Dr.Sarma

1
MANAGEMENT
OF TYPE 2 DM
A Rational Approach
Dr. R.V.S.N. Sarma., M.D., M.Sc.,
www.drsarma.in
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Diabetes Mellitus
1. Type 2 DM (No more called NIDDM)
2. Not merely ‘SUGAR DISORDER’
3. Multi system disease – A syndrome
4. Metabolic – Endocrine – Vascular – Neural
5. Cardiac – Cerebral – Renal – Ophthalmi
From Bl. sugar control to blood vessel protection
We should aim for total Metabolic Control
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Global Rankings for DM
Estimated figures in millions
Rank
1
2
3
4
5
6
7
8
9
Country
India
China
USA
Indonesia
Japan
Pakistan
Russia
Brazil
Italy
2003
35.5
23.8
17.7
8.4
6.8
5.2
5.1
4.6
4.3
WHO report, Diabetes Care 27:1047–1053, 2004
2030
79.4
42.3
30.3
21.3
8.9
13.9
5.5
11.3
5.2
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Better we all realize !!
1. India is the Diabetic Capitol of the World
2. DM is the leading cause of blindness in < 60 yr
3. Over 60% of ESRD is due to Diabetes
4. 70 % Diabetics die of – CHD, CVD
5. Leading cause of non traumatic LL amputation
6. MAU is the strongest predictor of CHD
7. So, screen all for DM and for risk factors
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T1DM and T2DM
Defects & Differences
Type 1 Diabetes

Insulinopenia
ID
Total  cell failure
-cell failure
Type 2 Diabetes
IR - Insulin
Resistance
IR
ID
ID - Insulin
Deficiency
‘More Heterogenous’
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Normal
Type 2 DM
Type 1 DM
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DM Deaths – World wide
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DM Prevalence
Developed Countries
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DM Prevalence
Developing Countries
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Natural History of T2DM
Water level
Water level
in the well
Well
 cells
Duration of use
 cell
reserve
Duration of www.drsarma.in
DM
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FPG in T2DM
(untreated DM)
FPG in mg %
500
400
300
200
100
0
7
20
Duration of Diabetes in years
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Insulin Defects in T2DM
Normal  Cell
1. Absence or delay in 1st Phasea primary defect of T2DM
2. Blunting of 2nd Phasesecondary to high blood sugar
Insulin output
1. ‘Selective Unresponsiveness’
2. ‘Secretory Rigidity’ - Defective
glucose recognition
3. ‘Gluco-toxicity’ to  cells
1st phase
2nd
Phase
Basal Steady State
Time
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 Cell
defect
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Mandatory Examinations
1. Family H/o DM
1. Fasting and PP BG
2.
H/o Angina, IHD, IC
2.
HbA1c on Dx. & 3-6 months
3.
H/o Smoking
3.
Lipid profile, Lp(a), hs-CRP
4.
H/o Hypoglycemia
4.
CHD Risk factors
5.
Exam for all pulses
5.
MAU - ACR
6.
B.P recording
6.
ECG for LVH, IHD
7.
Foot exam - Trophic
7.
Echo for LVD, LVH
8.
PNP and ANP
8.
Stress test in equivocal cases
9.
Fungal, Infect, Pruritus
9.
Fundus exam for DR
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Type 2 DM
Diagnosis
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Diagnosis – O-GTT
DM
DM
126 mg%
200 mg%
IGT
140 mg%
IFG
100 mg%
Normal
Normal
FPG
PPG
75g of oral glucose – 2 hrs. after
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Diagnosis – Criteria







FBG > 126 & PPBG > 200 - same day
RBG > 200 mg % on 2 occasions or
Never make a diagnosis on single test
Never diagnose based on glycosuria
Glucometer is not ideal for diagnosis
For Diagnosis Plasma Glucose only
For Screening or Monitoring BGM
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Diagnosis - Practical Points
1. Do not label one a diabetic by glycosuria alone
For, one may have renal glycosuria
2. Benedict’s less accurate; shows any reducing substance.
Glucose oxidase test strips confirm glucosuria
3. Urine test is useful – Albumin, MAU, Ketones
4. Never make a Dx. based on a single blood sugar test
5. O-GTT (2 sample) is the gold standard for Dx. of DM
6. HbA1c – Not for Dx. Follow up once in 3 to 6 months
7. Majority of diabetics are not symptomatic – so screen
One may present first time with complications – too late
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Fasting Hyperglycemia
 Due to↑ Hepatic Glucose Output - HGO
 Glycogenolysis – breakdown of glycogen
 Lipolysis – breakdown of fats
 Gluconeogenesis – breakdown of proteins
 Because of ↓in basal insulin secretion
 More important than postprandial spikes
 Develops after some time in T2DM
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Post Prandial Hyperglycemia
Blood sugar can rise above normal if
1. ↓ Decreased peripheral utilization
2. ↓ In insulin secretion after meal
3. Delay in insulin secretion – No 1st phase
4. ↓ In insulin sensitivity (resistance)
5. Excessive CHO consumption
6. A combination of any of the above
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Acarbose, Miglitol
Metformin
Pio glit, Rosi.
SU, Repag.
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Type 2 DM
Monitoring
A Paradigm Shift from
Blood Glucose to HbA1C
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Different Hemoglobins




Fetal Hemoglobin – Hb F
Adult Hemoglobin – Hb A
Sickle cell disease – Hb S
Hemoglobinopathies – Hb C, Hb E
Glucose in the blood reacts with the
Hemoglobin A to form Glycated Hb.
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Glycated Hb - GHb

Different types of Glycation products are
formed from the HbA depending on the
carbohydrate moiety – namely
 HbA1a1 - Fr 1,6 diphos –N-term. valine
 HbA1a2 - Gl 6 phos –N-terminal valine
 HbA1b - Other CHO – N-term. valine
 HbA1c - Glucose – N-terminal valine
 Normally less than 6% of Hb is HbA1c
(Previously called glycosylated Hb.)
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Estimation of HbA1c
 There are many methods of estimation
 HPLC (High Performance Liquid
Chromatography) – Gold standard.
 Immuno-turbimetric meth. – HbA1cAb
 Affinity chromatography
 Electrophoretic methods
 Method based on chemical reactions.
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Advantages of HbA1c
•
•
•
•
Index of long-term control over 120 days
It is not a snap shot like FBG/PPBG
Can be done at any time of day
Not influenced by diet, exercise,
emotional disturbances on test day
• The index of control for clinical practice
• Useful if missed drugs / default on diet
• Useful in DD of stress hyperglycemia
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Limitations of HbA1c
• Should not be used for Dx. of Diabetes
• Cannot be an emergency room test to
titrate Insulin or ODA dosage
• Can not register hypoglycaemia
• Not sensitive enough for use in GDM
•  Anaemia, Uraemia, Pregnancy
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HbA1c is ‘weighted’
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Correlation of MPG - HbA1c
HbA1C %
MPG mg%
5
100
6
135
7
8
9
10
11
12
13
170
205
240
275
310
345
380
Mean Plasma Glucose =
(35.6 x HbA1c %) – 77.3
HbA1c =
(MPG mg% + 77.3) / 35.6
Diabetes Care
Vol.26 (S), P33, 2003
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Which is the best measure
of monitor control of DM
 Fasting Blood Glucose (FBG) ?
 2 hour Postprandial Glucose (PPBG) ?
Answer is
Mean Amplitude of Glucose Excursions
(MAGE) –
This is best reflected by HbA1c
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Any Diabetes Related Endpoint
p<0.0001
Hazard ratio
5
1
21% decrease per 1% decrement in HbA1c
0.5
0 5
6
7
8
9
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
10
11
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Diabetes Related Deaths
Hazard ratio
5
p<0.0001
1
21% decrease per 1% decrement in HbA1c
0.5
0 5
6
7
8
9
10
11
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
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Microvascular Endpoints
15
Hazard ratio
10
p<0.0001
1
37% decrease per 1% decrement in HbA1c
0.5
0 5
6
7
8
9
10
11
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
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Amputation or Death from PVD
20
Hazard ratio
10
p<0.0001
1
43% decrease per 1% decrement in HbA1c
0.1
0 5
6
7
8
9
10
11
Updated mean HbA1c
UKPDS 35. BMJ 2000; 321: 405-12
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Blood Sample – Practical Points








The whole blood glucose is 15% higher
We need to estimate plasma glucose
Na F is to be used as the anti-coagulant
Centrifuge and separate plasma within 1 hour
For HbA1c – we need EDTA added blood –
HbA1c measurement – No fasting is required
C-Peptide or Serum Insulin – Only on fasting
Shouldn’t add any anti-coagulant for C peptide
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Indian Diabetic Risk Score (IDRS)
Parameter
Age
Classification
1. < 35 yrs
2. 35 – 49 yrs
3.  50 yrs
Abdominal
1. < 90 cm for ♂; < 80 cm for ♀
Obesity
2. 90-99 cm for ♂; 80-89 cm for ♀
3.  100 cm for ♂; > 90 cm for ♀
Physical
1. Regular Exercise + Strenuous work
Inactivity
2. Regular Exercise or Strenuous work
3. No Exercise and Sedentary work
Family H/o
1. No family history of DM
Diabetes
2. Either parent / sibling DM
3. Both parents / sibling DM
Interpretation
< 20 Least risk; 20 to 50 Moderate risk;
50 to 70 High risk; > 70 Very high risk.
Points
0
20
30
0
10
20
0
20
30
0
10
20
Range
0 to 100
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Prevention of Type 2
Diabetes
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Percent developing
Incidence
of diabetes
Diabetes
All
Placebo (n=1082)
Metformin (n=1073, p<0.001 vs. Placebo)
Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
Lifestyle
p<0.001vs.vs.
Metformin ,
Metformin(n=1079,
(n=1073, p<0.001
Plac)
Placebo (n=1082) p<0.001 vs. Placebo)
Cumulative incidence (%)
40
30
participants
Risk reduction
31% by metformin
58% by lifestyle
20
10
0
0
1
2
Years from randomization
The DPP Research Group, NEJM 346:393-403, 2002
3
4
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Exercise
 Question is not what ? – We need exercise
 Do 45 minutes of aerobic exercise
at least 5 times a week.
• Swimming
• Brisk walking
• Dancing
• Running
• Biking
• Jogging
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Management
Strategies
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T2DM Treatment
3
Diet
Insulin
Exercise
Monitoring
Oral Agents
Education
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Life Style
Modifications
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WHO recommendation -Diet
CARBOHYDRATES : 50-60%
- mainly from complex carbohydrates
FATS : 25%
- saturated 7%
- poly-unsaturated 9%
- mono-unsaturated 9%
- cholesterol < 300 mg/day
PROTEINS : 12-20%
SODIUM : < 6 g/day
- hypertensive diabetic, < 3 g/day
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Managing Diabetes
Follow a Healthy Meal Plan
Eat Least
Eat Moderately
Sugar, Fat, Alcohol, Salt
Protein Foods
Eat More
Carbohydrate Foods
Eat Most
Vegetables
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The New Food Pyramid
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EXERCISE
Benefits
•
•
•
•
•
Reduces weight
Improves cardiovascular function
Increases fitness
Increases physical working capacity
Improves sense of well-being /quality of life
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Management of T2DM
3
Old
Paradigm
Insulin
2
1. Glycemic targets
not met
2. Monotherapy
Oral is not durable
drugs
3. 1Fails to address dual defect
4. Perpetuates failure of Rx.
Diet
5.+Glucotoxicity ↓ response
Exercise
‘Step-Care’
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Stages of T2DM
Insulin Resistance
IR
Stage 1
1. Insulin Resistance
2. Hyper Insulinemia
3. Normal Glucose Tolerance
IR + ID
Insulin Deficiency
Stage 2
1. Insulin Resistance
2. Declining Insulin levels
3. Abnormal Glucose Tolerance
ID
Stage 3
1. Insulin Resistance
2. Very low Insulin levels
3. Hyperglycemia round www.drsarma.in
the clock
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T2DM – Cardiometabolic Basis
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Stage Management
3
Today’s
Paradigm
Frank ID
1. Metformin 2is the sheet anchor
2. Early insulin therapy, Basal Insulin
IR + ID
3. 1
HbA1c target of < 7, OAD Combina.
4. OAD choice based on patient type
IR Alone
5. ABC control; not glycemia alone
6. Prevention of complications - a must
Metabolic Basis
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What is new in Rx. of T2DM
•
•
•
•
•
•
•
•
•
•
The step-care therapy is not advocated now.
Choice of OAD/Insulin to be individualized
Glycemic targets must be achieved quickly
Multiple therapies may be needed
A1c is the target now - within 6 months
Diet alone is not the option now - difficulties
Even prediabetes needs Rx. Aggressively
Total ABC control – not glycemia alone
Combination of OAD + Insulin, early insulin
Avoid hypoglycemia by proper drug choice
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Stage Based Management
Stage 1
Stage 2
Stage 3
Pre Diabetic State
N FBG, ↑ PPBG
↑ FBG, ↑ PPBG
Weight Reduction
Diet and Exercise
Diet and Exercise
Physical Activity
Metformin, -GI !!
Metformin
May be Metformin
SU, GLT
TZD, SU (↓ effect)
No drug app. FDA
TZD, RA insulin
Basal In, AM PM In.
7% per yr - DM
Amylinomimetics
Exenatide, Pramlin.
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Today’s Treatment Goals
Keeping HbA1c and FBG, PPBG with in limits
1. Exercise – Diet – Weight reduction
2. OHAs and Insulin
Correction of all metabolic abnormalities
1. Normalizing lipids, BP Goal < 130/80
2. Reducing Obesity and Waist Circumference
Prevention and Rx. of complications
1. Macrovascular, 2. Microvascular, 3. Metabolic
Special emphasis on Prevention of CHD
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Complications of T2DM
1.
Metabolic Complications
1. IR; Obesity, Lipids – ↑TG, ↓HDL, ↑ sLDL
2. Thrombogenic ( ↑PAI-1, ↑ fibrinogen) profile
2.
Micro-vascular Complications
1. Diabetic Retinopathy (DR)
2. Diabetic Kidney Disease (DKD) – Nephropathy
3. Diabetic Neuropathy – DPN, DAN
3.
Macro-vascular Complication
1. Coronary Artery Disease (CAD)
2. Stroke, CVD, TIA, HT
3. Peripheral Vascular Disease (PVD)
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Ticking Clock of T2DM
1. Micro-vascular Complications
 At the onset of hyperglycemia
 Control of hyperglycemia essential
 The A1c target of less than 7 must (A)
2. Macro-vascular Complication
 At the onset of insulin resistance
 Blood pressure goal of 130/80 (B)
 Control of lipid abnormalities (C)
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How to Identify IR ??
Features
Insulin Resistance
Hyperglycemia
↑ PPBG, Usually FBG is N
Obesity, ↑ WC, ACN
BMI > 23, WC > 90, ACN+
↑ TG, ↓ HDL, ↑ sLDL
Dyslipidemia Present
Cluster of metabolic factors Metabolic Syndrome
Hypertension (>130/80)
Usually is a feature
Recent weight change
Increase
Fasting C peptide / Insulin
Increased (HOMA)
Treatment
OAD – Met, TZD, Exercise
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Insulin – C peptide
 Insulin is a dimer of
two peptides. Each
peptide consists of A
and B chains
 A has 21 amino acids;
B has 30 amino acids;
The two chains are
linked by pair of S – S
bonds
 C peptide has 35 amino
acids and is cleaved
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Measures of Insulin Resistance
 Can we measure insulin resistance ? Yes !
 It is useful in special situations as follows:
 It will be of use to confirm IR (Stage 1)
 C Peptide is useful detect SU failure
 What are the measures ? – F-C-Peptide, FBG
 CISI – Composite Insulin Sensitivity Index
 QUICKI – Quantitative Insulin Sensitivity Index
 HOMA IR – Homeostasis Model Assessment
• HOMA calculator is available
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How to treat Insulin Resistance ?
Diet, Exercise, TLC
Weight reduction, Waist reduction
ID
IR
Metformin – unmasks Insulin receptors
Insulin sensitizers – TZDs - PPARγ
Abolition of Glucotoxicity
Control of hypertension
Control of Metabolic abnormalities
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ABC - The Target Values





Hb A1c – Target less than 7% better 6.0%
Blood Pressure - < 130/ 80
Blood Glucose must not go below 60 mg%
BMI < 23, WC < 36” (32”)
Cholesterol - LDL < 100 mg
HDL > 40 (50)
TG < 150 mg
Lp(a) < 25 mg
hs-CRP < 3
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Major Classes of Medications
1. Drugs that sensitize
the body to insulin
and/or control HGO
TZD – Glitazones
And Metformin
2. Drugs that stimulate
the pancreas to make
more insulin
Sulfonylureas and
Meglitinides
3. Drugs that slow the
absorption of starches
-GI – Acarbose,
Miglitol,Voglibose
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Site & Mode of Action of OADs
Site of action
MOA
 Insulin
secretion
 HGO
Agents
Sulfonylureas
Repaglinide
Nateglinide
production
Biguanides
Glitazones
Slow CHO
Digestion
- glucosidase
inhibitors
 Peripheral
insulin sensitivity
Glitazones
Biguanides
Adapted from DeFronzo R. Ann Intern Med 1999;131:281
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Timeline for Utilization of Therapies
Metformin, TZD, (-GI add on)
SU
Meglitinide
Lifestyle
Glucose
350
300
250
200
150
100
50
Insulin
Post Meal Glucose
Fasting Glucose
250
Relative
Function
200
Insulin Resistance
150
100
50
Insulin Level
At risk
for Diabetes
Beta cell failure
0
-10
-5
0
5
10
15
20
25
30
Years of Diabetes
© International Diabetes Center. From Kendall D, Bergenstal R.
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Metformin
Efficacy
1.
2.
3.
4.
5.
Decreases HGO – Reduces FBG mainly.
↑ insulin-mediated peripheral glucose uptake
Improves Insulin sensitivity, No hypoglycemia
Decreases micro-vascular complications (UKPDS)
Take 2 to 3 weeks for the effect to be seen
Side Effects
1.
2.
3.
4.
Diarrhea & Abdominal Pain; Lactic acidosis ?
Causes small decrease in LDL and TG
No effect on Blood Pressure; Modest weight loss
Don’t use if > 80 yrs; or Impaired renal function
(Serum Cr > 1.4 mg/dL for ♀ or 1.5 mg/dL ♂)
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Sulfonylureas (SU)
Glimepiride, Gliclazide, Glipizide, Glybenclamide
Efficacy
1.
2.
3.
Stimulate pancreatic Insulin Secretion
Reduces FBG mainly – less effect on PPBG
Effects are seen almost from day one
Side Effects
1.
2.
3.
4.
5.
Hypoglycemia - more with Glybenclamide
Weight gain may be a problem (may ↑ IR)
Skin rashes and urticaria – Sulfa like allergy
Lipid neutral; No effect on Blood Pressure
Least expensive class of medication
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Which SU to choose ??
1. Glybenclamide (Daonil) is a long acting SU
2. Incidence of hypoglycemia is high with Daonil
3. The continuously stimulate the -cell – ↑ apoptosis
4. Glipizide and Gliclazide need to be used twice a day
5. Glimepiride is the best among the SU – OD
6. Its action on -cell is short lived –less hypoglycemia
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Which Sulfonylurea to choose ?
Sulfonylurea
Effectiveness
Dosage
Hypogly Metabolite
Glimepiride (III) *
Potent - OD
1 to 8 mg
Least.
Inactive
Gliclazide (II)
Potent - BID
40 to 80 mg
Less
Inactive
Glipizide (II)
Most potent -BID 5 to 15 mg
Less
Active
Glibenclamide (II)
Long acting OD
2.5 to 15 mg More
Active
Chlorpropamide (I) Long acting
Not in use
Most
Active
Tolbutamide (I)
Not in use
More
Active
Intermediate
* No action on KATP of Heart
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Thiazolidinediones (TZD)
Pioglitazone & Rosiglitazone (PPARγ modulators)
1. Target insulin resistance – the core defect
2. Muscle and adipose cells made sensitive to insulin
3. Suppress HGO also, No hypoglycemia
4. Preserve  cells and improve CV outcomes
5. Take 6 weeks for the maximum effect
Side Effects
1.
Weight gain, edema, some ↓ in B.P
2. Hypoglycemia (if taken with insulin or SU, GLT)
3.
Contraindicated in - abnormal liver function or CHF
4.
Improves HDL cholesterol and plasma TG
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Which Glitazone to choose ?
Effects
Pioglitazone
Rosiglitazone
LDL
Neutral
Increases
TG
Decreases
Neutral
HDL
Increases more
Increases
Dosage
15 - 30 mg OD
2 - 4 mg BID
HbA1c reduction 0.8 – 1.5 %
0.5 – 1.2 %
Cost per day
Rs. 8 to 16
Rs. 2 to 4
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Glinides (GLT)
Repaglinide and Netaglinide
Efficacy



Short rapid stimulation of Insulin from pancreas
Decrease the peak of postprandial glucose
No effect on FBG and Insulin Resistance
Other Effects
1.
2.
Hypoglycemia (less than with SU)
No meal – no tablet – effect instantaneous
3.
4.
5.
Weight gain
No effect on plasma lipid levels
Safer at higher levels of serum creatine > SUwww.drsarma.in
Alpha-glucosidase Inhibitors
Acarbose, Miglitol, Voglibose
Efficacy
1.
2.
3.
4.
5.
Inhibit the enzyme -glucosidase in the gut
Prevent conversion of complex CHO to simple CHO
Thus delay the absorption of CHO
Hence, reduced PPBG excursions
Very modest in efficacy, usually take 6-8 weeks
Side Effects
1.
2.
3.
4.
Flatulence or abdominal discomfort common
No effect on lipids or blood pressure
No weight gain or loss
Contraindicated in IBD or Cirrhosis
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Efficacy of Monotherapy - OADs
Drug Class
FBG Reduction
↓ HbA1c
Metformin (BG)
60-70 mg%
1.5 %
Sulfonylureas (SU)
60-70 mg%
1.5 %
Glinides (GLT)
35-40 mg%
1.0 %
Gliazones (TZD)
30-40 mg%
1.0 %
Acarbose (-GI)
20-30 mg%
0.6 %
DeFronzo Annals of Internal Medicine 1999;131:281-303, Nathan N Engl J Med 2002; 347:1342-1349
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Durability of OADs
N Engl J Med 355; 23 December 7, 2006
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Summary of all effects of Rx.
Intervention
Diet
Excercise
Metformin
Sulfonylureas
Glitazones
Insulin
Glycemia
Lipids
B.P.
B.V
Weight
+
+/+
+
+
++
+
+
+
+
+
+
+
+
+
++
++
+
No
No
No
↑
+
+
+
+
+
↑
Diabetes Spectrum Vol. 5, # 3, 103-108
No
↑↑
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Basis of Treatment Decisions
Dx. of T 2 DM (2 readings)
LIFE STYLE
Hb A1c < 9.0 %
No IR Features
RF N / Abn.
Test Hb A1c %
Early Insulin +/- OAD
IR Features +
CHF +/-
N FBG, ↑ PPBG
LFT N /↑
↑FBG, PPBG N
OAD = BG, SU, TZD, RG, AGI,
Acute/ DKA
Hb A1c > 9.0 %
DM 5 yr / 5+ yrs
SU aller.
lipid
HT
↑FBG, ↑ PPBG
OAD + In. + Amy + Ex
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75
Treatment Algorithm
NEJM 355; 2478 23 December 7, 2006
Dx. of T 2 DM (2 readings)
Y
HbA1c < 9%
HbA1c > 9%
TLC + Metformin 3 mon.
HbA1c < 7
I+OAD
No
Add Basal Insulin
Add SU
3M
HbA1c < 7
Y
No
↑ Insulin + OAD
HbA1c < 7
Y
Add TZD
3M
Add TZD
HbA1c < 7%
No
Basal Insulin
No
Y
Add
SU
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76
General Points
1. Metformin is the first line drug
2. Add Pioglitazone / Rosi – if IR
3. Add SU – Glimepiride or Gliclazide if ID
4. Repaglanide or Acarbose add on for high PPBG
5. Sulfa Allergy – Avoid Sulfonyl Ureas
6. Insulin + SU – weight gain, Insulin + TZD ??
7. -GI never alone as single agents (pre DM – ? yes)
8. DM over 10 yrs – OAD alone may not work
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77
Key Contraindications
1. Liver Disease, Ch. Alcoholism – TZD, Met, SU
2. Renal insufficiency – Metformin, SU
3. CHF and fluid overload – TZD, Metformin
4. Advanced age – Metformin, Glybenclamide
5. Sulfa Allergy – Sulfonyl ureas
6. Insulin + SU – Obesity, Insulin + TZD ??
7. -GI in Inflammatory bowel disease, Liver dis.
8. Pregnancy and Acute states – No OHAs
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Insulin in
Type 2 DM
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79
Central Point
Problem
In T2DM, a disordered regulation of
Hepatic Glucose Output (HGO) is the
crucial defect
Solution
Insulin is the primary regulator of
overnight Hepatic Glucose Output
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80
Insulin in T2DM - Certain Myths
1. Type 2 diabetics are non-insulin dependent
Hence it is incorrect to use insulin for them - No
2. Secondary sulfonylurea failure is a misnomer
Remember it is the pancreas & not the drug that
fails – ‘Secondary Secretory failure’
3. Type-2 DM is characterized by Insulin
Resistance – So why use Insulin ?
4. Insulin is atherogenic – isn’t it ? – No
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81
Barriers to Insulin use
Patient Barriers
Solutions
 Fear of injections
 Fear of hypoglycemia
 Fear of weight gain
 Only for ‘Severe DM’
Provider Barriers
 Improved comfort & convenience
 Sever hypoglycemia is rare
 Weight gain seen with most Rxs.
 Glucose normalization is the key
Solutions
 Insulin is atherogenic?  No !!, DIGAMI, UKPDS, DCCT
 Difficulty in convincing  Improved devices, Dr education
 Complex to adjust dose  Simplify regimens and dosing
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82
Benefits of Insulin Therapy
1. Prevention of acute metabolic crises
2. Quick return to ‘health’
3. ↓ ↓ symptoms of glucosuria and hyperglycemia
4. Sense of well-being
5. Anabolic & anti–catabolic effects of insulin
6. Restoration of -cell function
7. -cell protection from apoptosis & preservation
8. Postponement of ‘Secretory Failure’
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83
Insulin – Adverse Effects
1. Hypoglycemia
2. Weight gain – It is rather restoration
of lost weight than true weight gain
3. Atherogenicity hypothesis is disproved.
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84
Insulin Regimens
1. Temporary Insulin Therapy – TIT
2. Basal Interm. Action Insulin Therapy - BIAIT
3. Basal Insulin + Day time SU – BIDS
4. Convention Insulin Therapy – CIT
5. Intensive Insulin Therapy – IIT (Pumps)
6. Insulin + OAD combination
7. Analogs versus conventional
8. Inhaled Insulin, Insulin snuff, Oral HIM
Annals of Internal Medicine Volume 145 • Number 2, July 2006
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85
Insulin Preparations
Rapidity of Action
Ultra- rapid-action
Onset 10’ -20’ Peak 30 min
Insulin preparation
Lispro (Humalog), Glulisin (Apidra)
Aspart (Novolog)
Short Acting
Onset 30’ to 60’, Peak 2 hr
Intermediate Acting (Human)
or Analog 1 -4 h, Peak 4 -10 h
Long Acting 1-3 No Peak 24 h
Mixtures (Human)1 h, P 3-12 h
Regular (Human) Insulin
Humulin R, Novolin R
NPH (Human) Humulin N, Novolin N
Insulin Detemir (analog) - Levemir
Insulin Glargine (Lantus)
70/30 or 50/50 Humulin, 70/30 Novolin
Mixtures (Analog)
Onset 30’-1h, Peak 3-12 h
75/25 or 50/50 Humalog (NPL + Lispro)
70/30 Novolog neutral (Protamin + Aspart
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86
Classification based on FBG
• LADA-Latent Autoimmune Diabetes of Adults
• MODY – Maturity Onset Diabetes of Young
1. Mild – FBG < 140 mg%
• Insulin virtually not needed
2. Moderate – FBG 141 to 250 mg%
• BIAIT – Basal IA Insulin Therapy
3. Severe – FBG > 250 but < 300 mg%
• AM – PM Insulin – Mix. SA & IA, I Pump
4. Very Severe – FBG > 300 mg%
• Treat as though it is Type 1 Diabetes
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Three Types of Profiles
Patient Profile
Choice of Regimen
Choice of Insulin
↑ PPG, N FBG,
RA Insulin Pre Meal
Human Regular or
Lispro or Aspart
↑ FBG, Day time
Euglycemia
Bed time IA Insulin
+/- OAD
Insulin NPH or
Detemir
↑ FBG, ↑ PPG
‘Round the clock
hyperglycemia’
NPH Detemir BID
IA insulin BID or
or 70:30 BID,
LA Insulin HS + OAD or Glargine HS
Annals of Internal Medicine Volume 145 • Number 2, July 2006
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88
Insulin in T2DM
4
3
2
1
mixed & split
insulin regimen
Mixed insulin
regimen
Single mixed
insulin regimen
Single insulin
regimen
AM SA + IA
PM SA + IA
AM IA insulin
PM SA Insulin
SA + IA
Insulin AM
Bed time IA
Insulin + OHA AM
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89
T2DM – New
Therapies
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90
Exubera (Inhaled Insulin)
Insulin Blisters
for Aerosol
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91
Pramlintide
 Amylin -a hormone secreted by the -cells of pancreas
 It is very similar to Insulin in its action – Structure dif.
 Amylin handles 20% of our glucose metabolism
 Pramlintide is an analog of natural hormone - Amylin
 It is available only as s.c inj. like insulin
 It slows gastric empting; It suppresses Glucagon;
It reduces HGO – all like insulin
 It is available as SYMLIN inj. For both forms of DM
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92
Exenatide
 We have two hormones in intestines - Incretins
• GLP-1 (Glucagon Like Peptide-1) and
• GIP (Glucose dependent Insulinotropic Polypetide)
 Normally Incretins are degraded by DPP IV enzyme
 Exenatide is a synthetic analog of GLP-1 – Mimetic
 It is very similar to the GLP-1 in venom of Gila mon.
 This is resistant to degradation by DPP IV enzyme
 Exenatide inj. enhances postprandial insulin secretion
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93
Gila (Hee-la) Monster
Lizard Spit
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94
Exenatide (Byetta)
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95
Liraglutide
 Modified GLP-1
 Binds to albumin
 Injection form only
 Can reduce fasting and PP hyperglycemia
 It is an additional Rx. option
 Can be combined with OADs
 Does not cause hypoglycemia.
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96
Sitag‘Liptin’
 Normally Incretins are degraded by DPP IV enzyme
 Liptins are compounds which inhibit the DDP IV
 Liptins increase the action of natural GLP-1
 These are oral drugs – hence advantageous
 These ↑ postprandial insulin secretion via GLP-1
 Sitag-liptin, Vildag-liptin, Sexag-liptin are useful Rx
 They are 2nd line agents. Combined with OADs
 Do not cause hypoglycemia.
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97
Future Therapies
1. RIMONABANT – CB1- R blocker – ↓ Obesity – thus DM
2. GLITAZARs – Dual PPAR activator – Glycemia, Lipids
•
Muraglitazar, Tesaglitazar, Ragaglitazar
3. VOGLIBOSE – New -GI Inhibitor - ↓ PPBG
4. ACIPIMOX – ↓ FFA and ↓ IR - FBG
5. PIMAGIDINE – ↓ AGPs & prevents DM complications
6. ZENERESTAT – ↓ Sorbitol & Fructose – DM PNP
7. ZOPOLRESTAT – ↓ Aldose Red. – DM PNP
8. Acetyl L-Carnitine – ↑ NCV – DM PNP/ ANP
9. BIMOCLOMOL – ↑ Heat Shock Proteins – DR & DKD
10. EXO- 226 – ↓ Glycation of Proteins – DKD
11. Insu. Like GF, HIM 2 (oral), Englitazone – New TZD
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Future Diagnostic Tests





Glucose sensors – to be applied on to skin
Peel of patch tests – Read the Sugar in sweat
Micro needle inserted continuous monitors
Antibodies to insulin for insulin resistance
HbA1c monitors – like glucose monitors
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99
Glycosylation of hair
•
•
•
•
•
•
•
Hair glycosylation using thiobarbituric acid TBA
Glycosylation of hair is  in diabetes mellitus
Both insulin dependent , non-insulin dependent
Glycosylation of hair is proportionate to HbA1c
Due to the presence of hexosyl lysome in hair
Long hair sample provides a long term record.
May have forensic application & in population
studies.
BMJ, 1996, vol. 288 pp. 669-670
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Prevention of
Complications
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101
How to prevention
Complications of Diabetes ?
1.
2.
3.
4.
5.
6.
7.
8.
9.
Weight reduction, Exercise
Strict control hyperglycemia
Achieving lipid profile targets
Smoking cessation
Rx. of Hypertension with ACEi/ ARB
Low dose aspirin therapy
Statin therapy for all T2DM
ACEi or ARB for all with MAU
Early detection and evaluation
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102
HT Rx. Algorithm in DM
Diabetes Spectrum Vol. 5, # 3, 103-108
BP > 130/80 (2 readings)
>140/90/MAU/TOD
No TOD / AlTLC cont.
ACE/ARB + TLC 1 M
Yes
Goal BP 130/80
Yes
Add Diuretic
1 Month
No
Yes
Add Verapamil
1 Month
No
Yes
Sub Amlodepine
1 Month
No
Yes
Add  blocker
1 Month
No
No
?
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Treatment of Dyslipidemia







Every T2DM must get 10 mg of Atorvastatin
LDL is raised – Statin or Statin+ Ezetemibe
TG is raised – Fenofibrate
HDL is low – Niacin
Combined dyslipidemia – Combinations
Lp(a) is raised – Niacin
hs-CRP is raised – Aspirin & Statin (already)
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Take Home – A B C D E

A

B



C
D
E
A1c – target of < 7%; Better 6%
Aspirin for all DM
ACEi or ARB for all DM
Blood Pressure target of 130/80
Blood Glucose monitoring
Cholesterol LDL <100, Statin for all DM
Diet modifications, Do not smoke
Exercise 45’ every day, Education on DM
Equivalent to having CAD is DM
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Issues
Previous Methods
T2DM Stages No definite staging
Diagnosis
New Practice Guide
105
IR (1)  IR+ID (2)  ID (3)
Half hourly GTT or Just BS 2 sample O-GTT – Gold Standard
Insulin Resis. Not given due emphasis
It takes the center stage
Follow Up
FBG or PPBG
HbA1c 3 monthly, Not FBG, PBG
Rx Paradigm
Diet  OAD  Insulin
[TLC+ Met]  other OAD  Insulin
Rx Decisions Not tailored, Bl Sug. based HbA1c based, All factors taken
1st line OAD
SU – Diabetes  Daonil
Insulin use
Delayed until pt is burnt out Early basal Insulin or intens. Insul
Focus on
Glycemic control alone
Prescriptions
Limited to OAD and Insulin Aspirin, Statin, ACEi + DM Rx.
Prevention
Was not the emphasis
Emphasis
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Not worried for  apoptosis Preserve the  cell at
all costs
Metformin, ↑ TZD, SU limitations
Total Metabolic control  A,B,C
Prevent DM & prevent complicati.
106
Let us together
win the war
against Diabetes
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107
Wish You All
A Happy New Year
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