Dr. R. V. S. N. Sarma., M.D., M.Sc.

, (Canada)
Consultant Physician and Chest Specialist

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 What types of lesions cause MI ?
Coronary stenosis severity prior to MI
100 100
14%

80 80
Coronary stenosis (%)

18%

60 60 68%

40 40

20 20

0 0
Ambrose Little Nobuyoshi Giroud All four
1988 1988 1991 1992 studies
<50% 50%-70% >70%
Falk E, et al. Circulation. 1995;92:657-671.
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 What types of lesions cause MI ?
Coronary stenosis severity prior to MI
100 100
14%

80 80
Coronary stenosis (%)

18%

60 60 68%

40 40

20 20

0 0
Ambrose Little Nobuyoshi Giroud All four
1988 1988 1991 1992 studies
<50% 50%-70% >70%
Falk E, et al. Circulation. 1995;92:657-671.
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 CV Risk Factors in Diabetes
12
10.0
10

8
6.5
6
3.2
4
2.3
2

0
Microalbuminuria Smoking Diastolic BP Cholesterol

Eastman RC, Keen H. Lancet 1997;350 Suppl 1:29-32.

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 Causes of death in Diabetes

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 Why is it so ?

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 DM – Strongest RF for CVD

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 Duration of T2DM and CVD
48%

29%
24%
21%
15%

≤2 3-5 6-9 10-14 15+

Years after DM Diagnosis

Harris, S et al.; Type 2 Diabetes and Associated Complications in Primary Care in
Canada: The Impact of Duration of Disease on Morbidity Load. CDA 2003.

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 Duration of DM - CV Mortality
4 p for trend <0.001
3.5
Relative Risk

3
2.5
2
1.5
1
0.5
0
<5 6 to 10 11 to 15 16 to 25 26 +

Duration of Diabetes (years)

Cho, et al. J Am Coll Card 2002:40:954.
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 Life Expectancy with Diabetes

Years
DM
90 No DM 1600
80 1400
70 1200
60 Diabetes
1000 No Diabetes
50
800
40
600
30
400
20
10 200
0 0
Men Women Mortality rate/100,000

Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.

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 Cardiovascular Disease and T2DM
20%
Prevalence of CV Disease

Diabetes
15%
No Diabetes

10%

5%

0%
Hypertension Heart Disease
Hux JE, et al. Diabetes in Ontario, an ICES Practice Atlas 2003.

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 Clinical Outcome for Diabetes
4-year Follow-up
14
12
10
8
%
6
4
2
0
CV Death MI Stroke Dialysis

HOPE / MICRO-HOPE. Lancet 2000;355:253.

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 ACS and Diabetes – Up to 1 Year
25
P<0.0001
No Diabetes
20 21.3
N = 3429
% of patients

Diabetes P<0.0001
15 N = 1149
14.4 14.1
P=0.035
10
8.9 7.9
P<0.0001 7.
5 1
3.9
1.8
0
In-Hospital Non-fatal MI 1-y All-Cause 1-y
Mortality Mortality Mortality/MI

Yan R, et al. Can J Cardiol 2003;19(suppl A):260A.

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 OASIS Study: Total Mortality
0.25
Diabetes/CVD +, (n = 1148)
RR = 2.88 (2.37-3.49)
Diabetes/CVD -, (n = 569)
0.20 No Diabetes/CVD +, (n = 3503)
No Diabetes/CVD -, (n = 2796)
Event rate

0.15 RR=1.99 (1.52-2.60)

0.10 RR=1.71 (1.44-2.04)

0.05
RR=1.00

0.0

Months  3 6 9 12 15 18 21 24
Malmberg K, et al. Circulation 2000;102:1014–1019.
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 Predictors of CV Risk in DM
Age; But Gender looses its power

MAU (Microalbuminuria)

W/H Ratio (Abdominal Obesity)

LP(a) (Lipoprotein small ‘a’)

LDL Cholesterol

Not the Glycemic levels !!

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 DM = CAD - Because
• CVD is responsible for 60 - 75% of mortality in T2DM
• CVD is 4 times more prevalent in diabetes; CADI is more
• CVD prevalence increases with age, so is T2DM
• CVD in DM is often severe, silent, poor prognosis and fatal
• Diabetes ↑ mortality, 50% pre adm / recurrent MI and ACS
• Diabetes erases the protection conferred to women
• At diagnosis of T2DM, most patients have evidence of CVD
• Abnormal Glucose tolerance is a strong CV Risk factor

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 How to interpret ?

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 Lipoproteins
HDL LDL

C C
T TG
G
A I, A II B 100

VLDL CM

TG TG
C
B 100 + E +C B 48+E+C

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 Atherogenic Particles
Non-HDL-C
Measurements Apolipoprotein B

VLDL VLDLR IDL LDL SDL

TG rich particles Cholesterol rich

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 The Good, Bad, Ugly and Deadly
• Total Cholesterol < 200
• ‘Good’ Cholesterols (HDL)
– HDL 1, HDL 2, HDL 3 > 50
• ‘Bad’ Cholesterols (Non HDL) < 150
– LDL, IDL < 100
– VLDL, VLDL-R < 30
– Lp(a), Small LDL < 20

HDL 1 and HDL 2 are protective

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 Today’s Safer Values
 Total Cholesterol < 200
 Triglycerides < 150
 LDL Cholesterol < 100 preferably < 70
 HDL Cholesterol > 50 (for women 55)
 Bad Cholesterols the lower the better
 Good Cholesterols the higher the better
 Non HDL Cholesterol < 130
 Lp(a) values < 20

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 What are the Mechanisms ?

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 Atherosclerosis and Insulin
Resistance
Hypertension
Obesity
Hyperinsulinemia

Insulin Diabetes
Atherosclerosis
Resistance Hyper triglyceridemia
Small, dense LDL
Low HDL
Hyper coagulability

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 Insulin Resistance - Clinical Clues
• Abdominal obesity
• ↑ TG + ↓ HDL-C
• Glucose intolerance
• Hypertension
• Atherosclerosis
• Ethnicity (Indians, Negroid races)

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 Dyslipidemia in DM and IRS
• Elevated total TG
• Reduced HDL
• Small, dense LDL
• ↑ HDL 3 and ↓ HDL1 and HDL 2
• LDL is not usually high
• Postprandial Hyper lipemia

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 Dyslipidemia in DM and IRS
Increased Decreased
• Triglycerides • HDL

• VLDL • Apo A-I

• LDL, sLDL

• Apo B

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 Dyslipidemia based on TG and LDL

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 Dyslipidemia based on TG and Apo B

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 Mechanisms of DM Dyslipidemia
Fat Cells Liver
FFA

IR X

Insulin

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 Mechanisms of DM Dyslipidemia
Fat Cells Liver
FFA

 TG VLDL
 Apo B
IR X  VLDL

Insulin

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 Mechanisms of DM Dyslipidemia
Fat Cells Liver
FFA CE

 TG VLDL (CETP) HDL

(hepatic
 Apo B lipase)
IR X  VLDL TG
Apo A-1

Kidney
Insulin

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 Mechanisms of DM Dyslipidemia
Fat Cells Liver
FFA CE

 TG VLDL (CETP) HDL

(hepatic
 Apo B lipase)
IR X  VLDL TG
Apo A-1
CE (CETP) TG
Kidney
Insulin
SD
LDL
LDL
(lipoprotein or hepatic lipase)
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 IR and TG Increase
625
r = 0.73
500 P < 0.0001
Plasma TG (mg/dL)

400

300

200

100

100 200 300 400 500 600

Insulin Response to Oral Glucose
Olefsky JM et al. Am J Med. 1974;57:551-560.

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 DM, IRS and HDL
Hyperinsulinemic
P < 0.005
Normoinsulinemic
HDL-C (mg/dL)

P < 0.005

Non-obese Obese
Reaven GM. In: Le Roith D et al., eds. Diabetes Mellitus.1996:509-519.

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 Effects of  TG on CV Risk
• Accumulation of chylomicron remnants
• Accumulation of VLDL remnants
• Generation of small, dense LDL
• Association with low HDL
• Increased coagulability
•  PAI-1, and  factor VIIc
• Activation of prothrombin to thrombin

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 Small Dense LDL and CHD
Potential Atherogenic Mechanisms
• Increased susceptibility to oxidation
• Increased vascular permeability
• Conformational change in Apo B
• ↓ Affinity for LDL receptor (↓ clearance)
• Association with insulin resistance syndrome
• Association with high TG and low HDL

Austin MA et al. Curr Opin Lipidol 1996;7:167-171.

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 What the studies say ?

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 Clear Excess mortality in DM

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 A New Paradigm !!!

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 is hopelessly inadequate !!

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 A A1c (Hb A1c)
B Blood pressure (goal)
C Cholesterol (all
lipids)
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 Ticking Clock of T2DM
1. Micro-vascular (DR, DKD, DPN, DAN)
 At the onset of hyperglycemia
 Control of hyperglycemia essential
 The A1c target of less than 7 must (A)
2. Macro-vascular (CAD, CVD, PVD)
 At the onset of insulin resistance
 Blood pressure goal of 130/80 (B)
 Control of lipid abnormalities (C)
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 Goals inT2DM for VP
Risk Factor Goal or Target
Glycemia Hb A1c < 6.5%
Blood Pressure < 130/80 mm Hg
LDL target < 100 mg%; better < 70
HDL target > 40 men, > 50 women
TG target < 150 mg%
BMI < 25 kg/m2
Physical activity At least 5 days - 2 km/day

ADA, CDA, IDF, WWD

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 From Blood Sugar to Blood Vessel
ACEi (Ramipril) Vasoprotective, anti HT, ↓ ED
ASA (75 to 150 mg%) Anti inflamm., Anti Platelet

Statin (Powerful, full) ↓ LDL, TG, Corrects ED, Inflam

BP Goal Vascular damage, LVH, CVA

Glycemic control ↓ Micro vascular ? Macrovascular

Physical activity ED, ↓ Inflammation, ↑ HDL

Diet and TLC ↓ TG, LDL, Glycemia, Weight

Smoking cessation ↓ ED and Inflammation

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 ACEi in T2DM - VP
• Antihypertensive, vasoprotective, antithrombotic, and
anti-inflammatory properties – Inevitable in DM

• Reduce CV events, Reduce atherosclerosis

• Reduce renal disease which is a strong CV risk factor

• Metabolically ‘friendly’ drugs that prevent rises in glucose

& prevent diabetes

• Well-tolerated with few side effects

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 Recommendations

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 MNT and Dyslipidemia
• Total CHO to be reduced < 50% of calories

• Saturated fat must reduced to< 7% of calories

• MUFA and PUFA up to 15% of calories

• Protein in take to be increased – 25% of cal.

• Dietary fiber > 20 g/day -Soy protein, Fenugreek

• Vegetables, Nuts and fruits must every day

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 Priorities for Treatment
 If all lipid values are normal
1. Lifestyle interventions (TLC)
MNT, Physical Activity, Weight and Waist reduction

2. Statin in a minimum dose of 10 mg o.d

3. Follow up every one year by full lipid profile
4. All Indians must be tested for LP(a) and
If > 30 mg% - Niacin SR 350 to 500 mg started

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 Priorities for Treatment
 LDL cholesterol lowering – First priority
1. Lifestyle interventions (TLC)
2. Drugs - First choice – Statin with or without
3. Cholesterol absorption inhibitors (EZ)
4. Second choice – Niacin and Fibrate
5. Add on – BAR (Bile acid binding resins)

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 Priorities for Treatment
 HDL cholesterol raising – Second priority
1. Lifestyle interventions
2. First choice - Niacin ( doses <2 g/day)
3. Preferably short acting Niacin
4. Fibrates are second choice

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 Priorities for Treatment
 Triglyceride lowering – Third priority
1. First choice: Lifestyle interventions
2. Glycemic control is the best Rx for ↓TG
3. Fibrates
4. Niacin
5. High dose statins (if LDL is also high )

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 Priorities for Treatment
 Triglyceride Lowering (continued)
• In case of severe hyper triglyceridemia (> 1000
mg), severe fat restriction (< 10 % of calories ) in
addition to pharmacological therapy is necessary to
reduce the risk of pancreatitis and lipemia effects

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 Priorities for Treatment
 Combined Dyslipidemia
1. First choice: Glycemic control + Statin
2. Glycemic control+ Statin + Fibrate
3. Glycemic control+ Statin + Niacin

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 Drug Rx. – Effect on Lipoproteins
Pharmacological Agents LDL HDL TG

Statins (HMG CoA Reductase In)     

Fibrates (PPAR- γ Activators)   

BAR (Bile Acid Sequestering
Resins)
  

Niacin (Plain or SR)   

ADA. Diabetes Care 2003;26 (suppl 1):S 83-S 86

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 Drugs for Dyslipidemia
Statins Fibric Acid Niacin
• Rosuvastati • Fenofibrate • Neasyn SR
n • Gemfibrozil • Neasyn
• Atorvastati • Benzafibrat • Nialip
n e • Neaspan
• Simvastatin • Clofibrate
• Lovastatin • Ciprofibrat
• Pravastatin e
• Cervistatin • Clofibride

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 Treatment of  LDL
High LDL

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice: Statin

Add on drug - EZ , Niacin, BAR

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 Treatment of  HDL
Low HDL

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Niacin

Add on drug - Finofibrate

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 Treatment of  TG
High TG

Therapeutic Lifestyle Change

Drug Therapy

Therapy of Choice : Fibrate

Add on drug – Statin, Niacin

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 Anti Diabetic Drugs and Lipids
LDL
Anti Diabetic Agents LDL HDL TG Size

Metformin (Mildly favourable)    

Pioglitazone (Very favourable)    
Rosiglitazone (less favourable)    
Sulfonylureas (Unfavourable)    
Insulin (Not Atherogenic at all)    

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 Anti HT Drugs and Lipids

Anti hypertensive agents On Lipids

ACEi and ARBS (Excellent) 
CCBs (Neutral on lipids) 
Diuretics (Unfavourable) 
 Blockers (Very unfavourable) 
 Blockers (Mildly unfavourable) 

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 To Reiterate
 Glycemic goal alone is not adequate at all

 CAD must be prevented at all costs

 The A, B, C of Diabetes must be addressed

 Statins in full dose  Fibrate or Niacin

 All T2DM must receive drugs/advise on

 ACEi/ARB, ASA, Statin, TLC, PA, ↓ Weight

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