Vascular Protection in DM

Dr. R. V. S. N. Sarma., Dr. R. V. S. N. Sarma., M.D., M.Sc., M.D., M.Sc., (Canada)(Canada)

Consultant Physician and Chest Consultant Physician and Chest SpecialistSpecialist

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What types of lesions cause MI ?

Falk E, et al. Circulation. 1995;92:657-671.

100100

8080

6060

4040

2020

00

14%14%

18%18%

68%68%

All fourAll fourstudiesstudies

50%-70%<50% >70%

100100

6060

4040

2020

00AmbroseAmbrose

19881988LittleLittle19881988

NobuyoshiNobuyoshi19911991

GiroudGiroud19921992

Cor

onar

y st

enos

is (

%)

Cor

onar

y st

enos

is (

%)

Coronary stenosis severity prior to MICoronary stenosis severity prior to MI

8080

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What types of lesions cause MI ?

Falk E, et al. Circulation. 1995;92:657-671.

100100

8080

6060

4040

2020

00

14%14%

18%18%

68%68%

All fourAll fourstudiesstudies

50%-70%<50% >70%

100100

6060

4040

2020

00AmbroseAmbrose

19881988LittleLittle19881988

NobuyoshiNobuyoshi19911991

GiroudGiroud19921992

Cor

onar

y st

enos

is (

%)

Cor

onar

y st

enos

is (

%)

Coronary stenosis severity prior to MICoronary stenosis severity prior to MI

8080

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

CV Risk Factors in Diabetes

3.2

2.3

6.5

10.0

0

2

4

6

8

10

12

Microalbuminuria Smoking Diastolic BP Cholesterol

Od d

s R

a tio

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Causes of death in Diabetes

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Why is it so ?Why is it so ?

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DM – Strongest RF for CVD

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Years after DM Diagnosis

≤ 2 3-5 6-9 10-14 15+

15%

21%24%

29%

48%

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.

Duration of T2DM and CVD

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Duration of DM - CV Mortality

0

0.5

1

1.5

2

2.5

3

3.5

4

< 5 6 to 10 11 to 15 16 to 25 26 +

Duration of Diabetes (years)

p for trend <0.001

Cho, et al. J Am Coll Card 2002:40:954.

Rel

ativ

e R

isk

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Life Expectancy with Diabetes

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

0102030405060708090

Men Women

YearsDMNo DM

0200400600800

1000120014001600

Mortality rate/100,000

DiabetesNo Diabetes

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Cardiovascular Disease and T2DM

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

0%

5%

10%

15%

20%

Hypertension Heart Disease

Pre

vale

nce

of C

V D

isea

se

Diabetes

No Diabetes

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Clinical Outcome for Diabetes

4-year Follow-up

0

2

4

6

8

10

12

14

CV Death MI Stroke Dialysis

%

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

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ACS and Diabetes – Up to 1 Year

% o

f pa

tient

s

1.83.9

7.1

8.9 7.9

14.4 14.1

21.3

P<0.0001

P=0.035

P<0.0001

P<0.0001

0

5

10

15

20

25

In-Hospital

Mortality

Non-fatal MI 1-y All-Cause

Mortality

1-y

Mortality/MI

N = 3429

N = 1149

No Diabetes

Diabetes

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

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OASIS Study: Total Mortality

3 6 9 12 15 18 21 24

0.25

0.20

0.15

0.10

0.05

0.0

Months

Eve

nt

rate

RR = 2.88 (2.37-3.49)

RR=1.99 (1.52-2.60)

RR=1.71 (1.44-2.04)

RR=1.00

Malmberg K, et al. Circulation 2000;102:1014–1019.

Diabetes/CVD +, (n = 1148)

No Diabetes/CVD +, (n = 3503)

Diabetes/CVD -, (n = 569)

No Diabetes/CVD -, (n = 2796)

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Predictors of CV Risk in DM

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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 ?How to interpret ?

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Lipoproteins

CTG

B 100 + E +C

CTG

B 100

CTG

A I, A II

HDL LDL

VLDL

TG

B 48+E+C

CM

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Apolipoprotein BApolipoprotein BNon-HDL-CNon-HDL-C

MeasurementsMeasurements

TG rich particlesTG rich particles

VLDLVLDL VLDLRVLDLR IDLIDL LDLLDL SDLSDL

Atherogenic Particles

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Cholesterol richCholesterol rich

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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Various Sub Types

• LDL Sub types – (Seven subtypes as of now)– LDL 1– LDL 2a, 2b– LDL 3a, 3b– LDL 4a, 4b

• HDL Sub Types(Six sub types as of now)– HDL 1– HDL 2a, 2b– HDL 3a, 3b, 3c

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Today’s Safer ValuesTotal 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 What are the Mechanisms ?Mechanisms ?

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Atherosclerosis and Insulin Resistance

HypertensionHypertension

ObesityObesity

HyperinsulinemiaHyperinsulinemia

DiabetesDiabetes

Hyper triglyceridemiaHyper triglyceridemia

Small, dense LDLSmall, dense LDL

Low HDLLow HDL

Hyper coagulabilityHyper coagulability

InsulinInsulinResistanceResistance

InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis

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• Abdominal obesity

• ↑ TG + ↓ HDL-C

• Glucose intolerance

• Hypertension

• Atherosclerosis

• Ethnicity (Indians, Negroid races)

Insulin Resistance - Clinical Clues

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• Elevated total TG

• Reduced HDL

• Small, dense LDL

• ↑ HDL 3 and ↓ HDL1 and HDL

2

• LDL is not usually high

• Postprandial Hyper lipemia

• Lipemia Retinalis

Dyslipidemia in DM and IRS

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Increased

Decreased• Triglyceride

s

• VLDL

• LDL, sLDL

• Apo B

• HDL

• Apo A-I

Dyslipidemia in DM and IRS

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Dyslipidemia based on TG and LDL

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Dyslipidemia based on TG and Apo B

Mechanisms of DM Dyslipidemia

Fat CellsFat Cells LiverLiver

InsulinInsulin

IRIR XX

FFAFFA

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InsulinInsulin

IRIR XX

TGTG Apo BApo B VLDLVLDL

VLDLVLDL

FFAFFA


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(hepatic(hepaticlipase)lipase)


KidneyKidneyInsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


HDLHDL

TGTGApo A-Apo A-

11

FFAFFA

VLDLVLDL


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(hepatic(hepaticlipase)lipase)


KidneyKidneyInsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


(CETP)(CETP)

HDLHDL

(lipoprotein or hepatic lipase)(lipoprotein or hepatic lipase)

sLDLsLDLLDLLDL

TGTGApo A-1Apo A-1

TGTGCECE

FFAFFA

VLDLVLDL


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InsulinInsulin

IRIR XX


FFAFFA

VLDLVLDL


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VLDL -RVLDL -R AtherogeAtherogenicnic

↓ ↓ VLDL VLDL ClearancClearanc

ee

↓ ↓ LPLLPL Apo CApo C+

IR and TG Increase

Olefsky JM et al. Am J Med. 1974;57:551-560.

Insulin Response to Oral Glucose

625

500

400

300

200

100

100 200 300 400 500 600

Pla

sma T

G (

mg/d

L)

r = 0.73P < 0.0001

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DM, IRS and HDLH

DL-

C (

mg/d

L)

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

Non-obese

Hyperinsulinemic

Normoinsulinemic

Obese

P < 0.005

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P < 0.005

• 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

Effects of TG on CV Risk

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• Increased susceptibility to oxidation

• Increased vascular permeability

• Increased binding to arterial wall proteoglycons

• Conformational change in Apo B

• ↓ Affinity for LDL receptor (↓ clearance)

• Association with insulin resistance syndrome

• Association with high TG and low HDL

Small Dense LDL and CHD Potential Atherogenic Mechanisms

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

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What the studies What the studies say ?say ?

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Clear Excess mortality in DM

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A New Paradigm !!!A New Paradigm !!!

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Vascular Protection in Diabetes Mellitus

Vascular Protection in Diabetes Mellitus

2004

This material has been reviewed and is supported by the Canadian Diabetes Association for its medical and scientific accuracy.

is hopelessly is hopelessly inadequate !!inadequate !!

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AA A1c (Hb A1c)A1c (Hb A1c)

BB Blood pressure Blood pressure (goal)(goal)

CC Cholesterol (all Cholesterol (all lipids)lipids) 51www.drsarma.in

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1. ACE inhibitors or ARBs2. ASA (Acetyl Salicylic Acid)3. Atorvastatin (Lipid management)4. A1c control (Glycemic control)5. Blood pressure goal (<130/80)6. Control of Nephropathy, Proteinuria

(MAU)7. Cigarette smoking cessation8. Weight and waist management9. Physical Activity – at least 2 km/d x

5 d

Ticking Clock of T2DM

1. Micro-vascular (DR, CKD, 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) VP 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 FactorRisk Factor Goal or TargetGoal 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 Inflammation56www.drsarma.in

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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RecommendationsRecommendations

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• 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

• Fish oils – Omega-3 fatty acids

MNT and Dyslipidemia

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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

Priorities for Treatment

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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)

Priorities for Treatment

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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.Concern about Dysglycemia

5.Fibrates are second choice

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Priorities for Treatment Triglyceride lowering – Third

priority

1.First choice: Lifestyle interventions - CHO

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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This is no longer tenable LDLc Statin

Triglyceride Fibrate

HDL Niacin

• Statins should be given to all DM –• Except for T1DM and T2 DM < 30 yrs

• If TG > 400 – Fibrate must be combined

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Myopathy with Statins

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Drug Rx. – Effect on Lipoproteins

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

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Drugs for Dyslipidemia

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Anti Diabetic Drugs and Lipids

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Anti HT Drugs and Lipids

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Glycemic goal alone is not adequate at

all

CAD must be prevented at all costs

Vascular Protection in DM is the only key

Statins in full dose Fibrate or Niacin

All T2DM must receive drugs/advise on

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

To Reiterate

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Vascular Protection in DM

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