Diabetic Dyslipidemia

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

www.drsarmwww.drsarma.ina.in

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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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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

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)

SDSDLDLLDL

LDLLDL

TGTGApo A-1Apo A-1

TGTGCECE

FFAFFA

VLDLVLDL


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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

• 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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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) 48www.drsarma.in

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) 49www.drsarma.in

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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 Inflammation52www.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

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.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

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

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Drugs for Dyslipidemia

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Treatment of LDL

High LDLHigh LDL

Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change

Add on drug - EZ , Niacin, BARAdd on drug - EZ , Niacin, BAR

Therapy of Choice: StatinTherapy of Choice: Statin

Drug TherapyDrug Therapy

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Treatment of HDL

Low HDLLow HDL


Add on drug - FinofibrateAdd on drug - Finofibrate

Therapy of Choice : NiacinTherapy of Choice : Niacin


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Treatment of TG

High TGHigh TG


Add on drug – Statin, NiacinAdd on drug – Statin, Niacin

Therapy of Choice : FibrateTherapy of Choice : Fibrate


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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

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

To Reiterate

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Diabetic Dyslipidemia

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