Diabetic Dyslipidemia and Atherosclerosis Henry Ginsberg, MD.

Diabetic Dyslipidemia and Diabetic Dyslipidemia and

AtherosclerosisAtherosclerosis

Henry Ginsberg, MDHenry Ginsberg, MD

Interrelation Between Atherosclerosis Interrelation Between Atherosclerosis and Insulin Resistanceand Insulin Resistance

HypertensionHypertension

ObesityObesity

HyperinsulinemiaHyperinsulinemia

DiabetesDiabetes

HypertriglyceridemiaHypertriglyceridemia

Small, dense LDLSmall, dense LDL

Low HDLLow HDL

HypercoagulabilityHypercoagulability

InsulinInsulinResistanceResistance

InsulinInsulinResistanceResistance AtherosclerosisAtherosclerosisAtherosclerosisAtherosclerosis

Abdominal obesity

TG + HDL-C

Glucose intolerance

Hypertension

Atherosclerosis

Ethnicity

Insulin Resistance and Hyperinsulinemia: Insulin Resistance and Hyperinsulinemia: Clinical CluesClinical Clues

Elevated total TG

Reduced HDL-C

Small, dense LDL-C

Dyslipidemia in the Insulin Resistance Dyslipidemia in the Insulin Resistance SyndromeSyndrome

Dyslipidemias in Adults with DiabetesDyslipidemias in Adults with DiabetesFramingham Heart StudyFramingham Heart Study

Increased cholesterol

Increased LDL

Decreased HDL

Increased triglycerides

NormalNormal DMDM NormalNormal DMDM

14%

11%

12%

9%

13%

9%

21%

19%

MENMEN WOMENWOMEN

21%

16%

10%

8%

24%

15%

25%

17%

Garg A et al. Diabetes Care 1990;13:153-169.

Mean Plasma Lipids at Diagnosis of Mean Plasma Lipids at Diagnosis of Type 2 Diabetes - Type 2 Diabetes - UKPDSUKPDS

Number of Pts

TC (mg/dl)

LDL-C (mg/dl)

HDL-C (mg/dl)

TG (mg/dl)

Type 2Type 2 ControlControlMENMEN

UKPDS Group. Diabetes Care 1997;20:1683-1687.

* P<0.001, ** P<0.02 comparing type 2 vs. controll

2139

213

139

39**

159*

52

205

132

43

103

Type 2Type 2 ControlControlWOMENWOMEN

1574

224

151*

43*

159*

143

217

135

55

95

Relation Between Insulin Resistance and Relation Between Insulin Resistance and HypertriglyceridemiaHypertriglyceridemia

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

* Total area under 3-hour response curve (mean of 2 tests).

625

500

400

300

200

100

100 200 300 400 500 600Insulin Response to Oral Glucose*

Pla

sma T

G (

mg

/dL)

r = 0.73P < 0.0001

Association Between Hyperinsulinemia Association Between Hyperinsulinemia and Low HDL-Cand Low HDL-C

20

30

40

50

60

HD

L-C

(m

g/d

L)

Reaven GM. In: LeRoith D et al., eds. Diabetes Mellitus. Philadelphia: Lippincott-Raven,1996:509-519.

Nonobese

Hyperinsulinemic

Normoinsulinemic

Obese

P<0.005

P<0.005

Mechanisms Relating Insulin Resistance Mechanisms Relating Insulin Resistance and Dyslipidemiaand Dyslipidemia

Fat CellsFat Cells LiverLiver

InsulinInsulin

IRIR XX

FFAFFA



InsulinInsulin

IRIR XX

TGTG Apo BApo B VLDLVLDL

VLDLVLDL

FFAFFA

(hepatic(hepaticlipase)lipase)



KidneyKidneyInsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


VLDLVLDL HDLHDL

TGTGApo A-1Apo A-1

FFAFFA

(hepatic(hepaticlipase)lipase)



KidneyKidneyInsulinInsulin

IRIR XX

(CETP)(CETP)

CECE


(CETP)(CETP)

VLDLVLDL HDLHDL

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

SDSDLDLLDL

LDLLDL

TGTGApo A-1Apo A-1

TGTGCECE

FFAFFA

IncreasedIncreased

Dyslipidemia in DiabetesDyslipidemia in Diabetes

DecreasedDecreased

Triglycerides

VLDL

LDL and small dense LDL

Apo B

HDL

Apo A-I

LDL Subclass Phenotypes in LDL Subclass Phenotypes in Diabetes MellitusDiabetes Mellitus

Men*Men* Diabetic Nondiabetic

Women**Women** Diabetic Nondiabetic

** Selby JV et al. Circulation 1993; 88:381-387.

IntInt BB

* Feingold KR et al. Arterioscler Thromb 1992; 12:1496-1502.

2987

54543

2847

3485

2129

309

5124

366

LDL SubclassLDL Subclass

nn AA

PercentPercent

Increased susceptibility to oxidation

Increased vascular permeability

Conformational change in apo B

Decreased affinity for LDL receptor

Association with insulin resistance syndrome

Association with high TG and low HDL

Small Dense LDL and CHD: Small Dense LDL and CHD: Potential Atherogenic MechanismsPotential Atherogenic Mechanisms

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

Accumulation of chylomicron remnants

Accumulation of VLDL remnants

Generation of small, dense LDL-C

Association with low HDL-C

Increased coagulability

- plasminogen activator inhibitor (PAI-1)

- factor VIIc

- Activation of prothrombin to thrombin

Hypertriglyceridemia and CHD Risk: Hypertriglyceridemia and CHD Risk: Associated AbnormalitiesAssociated Abnormalities

TG Metabolism in CHD: TG Metabolism in CHD: Studies in theStudies in the Postprandial StatePostprandial State

400

300

200

100

0

TG

(m

g/d

L)

UncorrectedUncorrectedCorrected for Fasting Corrected for Fasting

TG Level*TG Level*

Hours after Test Meal

300

200

100

0

Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345.

0 2 4 6 8 0 2 4 6 8

CHD Cases

Controls

Controls

Error bars = SEM

CHD Cases

Increased plasma fibrinogen

Increased plasminogen activator inhibitor 1

Increased platelet aggregability

Factors Promoting Thromboembolic Factors Promoting Thromboembolic Disease in DiabetesDisease in Diabetes

Thompson SG et al. N Engl J Med 1995;332:635-641.

Predisposition to thrombosisPredisposition to thrombosis

- Platelet hyperaggregability

- Elevated concentrations of procoagulants

- Decreased concentration and activity of antithrombotic factors

Predisposition to attenuation of fibrinolysisPredisposition to attenuation of fibrinolysis

- Decreased t-PA activity

- Increased PAI-1

- Decreased concentrations of 2-antiplasmin

Adverse Effects on Balance Between Adverse Effects on Balance Between Thrombosis and Fibrinolysis in Subjects Thrombosis and Fibrinolysis in Subjects with Diabeteswith Diabetes

Sobel BE. Circulation 1996;93:1613-1615.

PAI-1 Activity in Blood in Patients with PAI-1 Activity in Blood in Patients with Type 2 DiabetesType 2 Diabetes

0

5

10

15

20

PA

I-1 A

ctiv

ity (

AU

/mL)

McGill JB et al. Diabetes. 1994;43:104-109.

Lean

No Diabetes

Diabetes

Obese

PAI-1 = plasminogen activator inhibitor type 1

Elevation of PAI-1 Induced by Elevation of PAI-1 Induced by Hyperinsulinemia, Hyperglycemia, and Hyperinsulinemia, Hyperglycemia, and Increased FFA in Blood of Normal SubjectsIncreased FFA in Blood of Normal Subjects

Calles-Escandon J et al. Diabetes. 1998;47:290-293.*P<0.05 vs saline infusions in same subjects

Values are mean + SD

0

3

6

9

12

15

18

21

PA

I-I (m

g/m

L)

0 2 4 6 8 12Time (h)

10

*Infusion of glucose Infusion of glucose

and intralipidand intralipid

First-line agentsFirst-line agents

HMG CoA reductase inhibitorHMG CoA reductase inhibitor

Fibric acid derivativeFibric acid derivative

Second-line agentsSecond-line agents

Bile acid binding resinsBile acid binding resins

Nicotinic acidNicotinic acid

Pharmacologic Agents for Treatment of Pharmacologic Agents for Treatment of DyslipidemiaDyslipidemia

American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

In diabetic patients, nicotinic acid should be restricted to <2g/day. Short-acting nicotinic acid is preferred.

Effect on lipoprotein

LDL HDL Triglyceride

LDL cholesterol lowering*LDL cholesterol lowering*

- First choice: HMG CoA reductase inhibitor (statin)

- Second choice: Bile acid binding resin or fenofibrate

HDL cholesterol raisingHDL cholesterol raising

- Behavior interventions such as weight loss, increased physical activity and smoking cessation

- Glycemic control

- Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates

Triglyceride loweringTriglyceride lowering

- Glycemic control first priority

- Fibric acid derivative (gemfibrozil, fenofibrate)

- Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol

* Decision for treatment of high LDL before elevated triglyceride is based on clinical trial data indicating safety as well as efficacy of the available agents.

Order of Priorities for Treatment of Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults*Diabetic Dyslipidemia in Adults*

Adapted from American Diabetes Association. Diabetes Care 2000;23(suppl 1):S57-S60.

Diabetic Dyslipidemia and Atherosclerosis Henry Ginsberg, MD.

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