Diabetic Dyslipidemia

Hypertension Obesity Hyper-insulinemia

Diabetes Hypertri-glyceridemia

Small,dense LDL

Low HDL Hypercoagu-lability

Atherosclerosis

Insulin Resistance

Interrelation Between Atherosclerosis and Insulin Resistance

SHEEP: Risk Factors for Nonfatal MI in Men and Women

SHEEP=Stockholm Heart Epidemiology Program.

Reuterwall C et al. J Intern Med. 1999;246:161-174.

Risk Factor

Diabetes

High TC (6.5 mmol/L)

High TG (6.3 mmol/L)

HTN (170/95 mm Hg)

Overweight (BMI 30 kg/m²)

WHR (0.85)

Physical inactivity

Smoking

Job strain

Men

Women 0 1 2 3 4 5 6 7 8

Odds RatioOdds Ratio

National Diabetes Data Group. Diabetes in America. 2nd ed. NIH;1995.

Atherosclerosis in Diabetes• ~80% of all diabetic mortality

– 75% from coronary atherosclerosis

– 25% from cerebral or peripheral vascular disease

• >75% of all hospitalizations for diabetic complications

• >50% of patients with newly diagnosed type 2 diabetes have CHD

Haffner SM et al. N Engl J Med. 1998;339:229-234.

0 1 2 3 4 5 6 7 8

0

20

40

60

80

100

Nondiabetic subjects without prior MI (n=1,304)Diabetic subjects without prior MI (n=890)Nondiabetic subjects with prior MI (n=69)Diabetic subjects with prior MI (n=169)

Survival(%)

Year

Risk Similar in Patients With Type 2 Diabetes and No Prior MI vs Nondiabetic Subjects With Prior MI

Kannel WB. Am Heart J. 1985;110:1100-1107.Abbott RD et al. JAMA. 1988;260:3456-3460.

Women, Diabetes, and CHD

• Diabetic women are at high risk for CHD

• Diabetes eliminates relative cardioprotective effect of being premenopausal

– risk of recurrent MI in diabetic women is three times that of nondiabetic women

• Age-adjusted mean time to recurrent MI or fatal CHD event is 5.1 yr for diabetic women vs 8.1 yr for nondiabetic women

Framingham Heart Study 30-Year Follow-Up:CVD Events in Patients With Diabetes (Ages 35-64)

109

20

11

9 63819

3*

30

0

2

4

6

8

10

Age-adjusted annual rate/1,000

Men Women

Total CVD CHD Cardiac failure

Intermittent claudication

Stroke

Riskratio

P<0.001 for all values except *P<0.05.

Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease.Ruderman N et al, eds. Oxford; 1992.

SMC=smooth muscle cell.

Adapted from Bierman EL. Arterioscler Thromb. 1992;12:647-656.

Potential Mechanisms of Atherogenesis in Diabetes• Abnormalities in apoprotein and lipoprotein particle

distribution

• Glycosylation and advanced glycation of proteins in plasma and arterial wall

• “Glycoxidation” and oxidation

• Procoagulant state

• Insulin resistance and hyperinsulinemia

• Hormone-, growth-factor–, and cytokine-enhanced SMC proliferation and foam cell formation

149

26

11 12139

21*

34*

19*

0

10

20

30

40

50 Men without diabetes

Men with diabetes

TC260

TG235

VLDL-C40

LDL-C190

HDL-C31

Prevalence(%)

*P<0.05.LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).

Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169.

Abnormal Lipid Levels in Men With Type 2 Diabetes

21

8

31

16

10

24

38

15

25*

17*

0

10

20

30

40

50 Women without diabetes

Women with diabetes

TC275

TG200

VLDL-C35

LDL-C190

HDL-C41

Prevalence(%)

*P<0.05.LRC approximate 90th percentile age- and sex-matched values, except for HDL-C (10th percentile).

Adapted from Garg A, Grundy SM. Diabetes Care. 1990;13:153-169.

Abnormal Lipid Levels in Women With Type 2 Diabetes

The Strong Heart Study: Differences in CVD RiskFactors by Diabetic Status in Men and Women*

*Adjusted for age and center.

Adapted from Howard BV et al. Diabetes Care. 1998;21:1258-1265.

-4.4

-3.7

-7.5

-5.3

-8

-7

-6

-5

-4

-3

-2

-1

0

Men

Women

HDL-C(mg/dL)

LDL Size(Å)

Differencebetweensubjectswith andwithoutdiabetes

A BIntermediatepattern

0

2

4

6

8

10

12

Glucose(mmol/L)

Adapted from Reaven GM et al. J Clin Invest. 1993;92:141-146.

Steady-state plasma glucose

n=19

n=17

n=19

Association of Small, Dense LDL With Insulin Resistance

0

1

2

3

CHD mortality

(per 1,000)

Fontbonne AM et al. Diabetes Care. 1991;14:461-469.

29 30-50 51-72 73-114 115

Quintiles (pmol) of fasting plasma insulin

P<0.01

CHD Mortality and Hyperinsulinemia:Paris Prospective Study (n=943)

0102030405060

1 2 3 4 5

% M

acro

vasc

ula

rd

isea

se

P<0.001

01020304050607080

1 2 3 4 5

% M

acro

vasc

ula

rd

isea

se

P<0.05

0102030405060

1 2 3 4 5

% C

HD

P<0.002

01020304050607080

1 2 3 4 5

% C

HD

Nondiabetic controls(n=178)

Noninsulin-treatedtype 2 diabetics (n=154)

Fasting C-peptide quintiles (1-5)

Janka HU. Horm Metab Res. 1985;15(suppl):15-19.

Prevalence of Macrovascular Disease and CHD According to Quintiles of Fasting C-Peptide

Glucose(mmol/L)

Time (min) Time (min)

Reaven GM et al. J Clin Invest. 1993;92:141-146.

Insulin(pmol/L)

0

2

4

6

8

10

30 60 120 180

Plasma glucose

LDL diameter averagePattern A: 268±4 (n=52)Intermediate: 261±3 (n=29)Pattern B: 250±4(n=19)

0

200

400

600

800

1000

30 60 120 180

Insulin

Responses to a 75-g Oral Glucose Challenge in Relation to LDL Particle Diameter

7.4

3.3

10.5

3.4

0

5

10

15Type 2 (n=135)

Others (n=3,946)

Type 2 on placebo (n=76)

Type 2 on gemfibrozil (n=59)

5-Yr incidenceof CHD (%)

*Myocardial infarction or cardiac death.NS=not significant.

Koskinen P et al. Diabetes Care. 1992;15:820-825.

P<0.02

P=NS

Primary CHD* Prevention in Patients With Type 2 Diabetes: The Helsinki Heart Study

UKPDS: Intensive Blood-Glucose vs ConventionalTreatment in Patients With Type 2 Diabetes

RR=relative risk.PVD=peripheral vascular disease.

UKPDS Group. Lancet. 1998;352:837-853.

Any diabetes-related end point 0.88 (0.79–0.99) 0.029

Diabetes-related deaths 0.90 (0.73–1.11) 0.34

All-cause mortality 0.94 (0.80–1.10) 0.44

MI 0.84 (0.71–1.00) 0.052

Stroke 1.11 (0.81–1.51) 0.52

Amputation or death from PVD 0.65 (0.36–1.18) 0.15

Microvascular disease 0.75 (0.60–0.93) 0.0099

Favors Favors Log-rank RR (95% CI) intensive conventional P value

Clinical End Point0.1 1 10

Any diabetes-related end point 0.76 (0.62–0.92) 0.0046

Diabetes-related deaths 0.68 (0.49–0.94) 0.019

All-cause mortality 0.82 (0.63–1.08) 0.17

MI 0.79 (0.59–1.07) 0.13

Stroke 0.56 (0.35–0.89) 0.013

Peripheral vascular disease 0.51 (0.19–1.37) 0.17

Microvascular disease 0.63 (0.44–0.89) 0.0092

UKPDS: Tight Blood Pressure Control vs LessTight Control in Patients With Type 2 Diabetes

RR=relative risk.

UKPDS Group. BMJ. 1998;317:703-713.

RR for Favors Favors tight control tight less tight P

(95% CI) control control value

Clinical End Point10.1 10

Secondary Prevention: CHD Risk Reduction in the 4S Subgroup of Patients With Diabetes

Pyörälä K et al. Diabetes Care. 1997;20:614-620.

Total mortality 232167

2415

CHD mortality 172991712

Major CHD event 578407

4424

Any CHD event 871667

5641

CABG or PTCA 363238

2015

Cerebrovascular event 907012

5

Any atherosclerotic event 961750

6146

NondiabeticDiabetic

P S

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4

RR with 95% CIs

No. patients Simvastatin Placebowith events better better

0.60

0.70

0.80

0.90

1.00

4S: Total Mortality Reduction in a Subgroup of Patients With Diabetes

Pyörälä K et al. Diabetes Care. 1997;20:614-620.

Proportion alive

Yr since randomization

- P=0.08

- P=0.001

Diabetic, simvastatin

Diabetic, placebo

Nondiabetic, simvastatin

Nondiabetic, placebo

29%

43%

4S: Major CHD Event Reduction in a Subgroup of Patients With Diabetes

Pyörälä K et al. Diabetes Care. 1997;20:614-620.

0.50

0.60

0.70

0.80

0.90

1.00

Proportionwithout

major CHD event

Yr since randomization

- P=0.002

- P=0.0001

Diabetic, simvastatin

Diabetic, placebo

Nondiabetic, simvastatin

Nondiabetic, placebo

32%

55%

4S: Treatment Benefit in Subgroup With Impaired Fasting Glucose (FG 110-125 mg/dL)

Haffner SM et al. Diabetes. 1998;(suppl 1):A54. Abstract.

-46

-56

-40-43

-60

-50

-40

-30

-20

-10

0

Totalmortality

Coronarymortality

Majorcoronary

events

Revas-culari-zations

inevents

(%)

P=0.005

P=0.001P=0.010

CARE: Reduction of Coronary Events in Patients With Diabetes

N=4,159 males and females; 976 diabetics.

Goldberg R et al. Circulation. 1996;94:I-540. Abstract.

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5

% withevent

Yr

27%

22%

- P=0.001Diabetic, pravastatin

Diabetic, placebo

Nondiabetic, pravastatin

Nondiabetic, placebo- P=0.012

6

Post-CABG: Effect of Aggressive Lipid Lowering on a Subgroup of Patients With Diabetes

Substantial progressionPer patient % of grafts 27.0 43.3 0.49 27.8 39.0 0.60

(0.20-1.19) (0.46-0.79) Number of grafts 122 104 1,238 1,214

OcclusionPer patient % of grafts 11.5 19.2 0.54 10.4 16.0 0.61

(0.15-2.02) (0.41-0.92) Number of grafts 122 104 1,238 1,214

Therapy Therapy

Diabetes No Diabetes

Hoogwerf BJ et al. Diabetes. 1999;48:1289-1294.

RR RRAggressive Moderate (99% CI) Aggressive Moderate (99%

CI)

DAIS: Impact of Aggressive Therapy on Atherosclerosis in Patients With Type 2 DiabetesStudy population• N=418 (305 men, 113 women)• Type 2 diabetes 1 minimal lesion on angiography• Mild elevations of LDL-C or TG + TC:HDL-C 4Treatment• 8 weeks on Step I diet• Randomized, blinded to micronized fenofibrate (200 mg/d)

and placeboPrimary end point• Progression or regression of CAD on quantitative angiography

DAIS=Diabetes Atherosclerosis Intervention Study.

Steiner G et al. Am J Cardiol. 1999;84:1004-1010.

mg/dL

* Significant difference between genders.

Steiner G et al. Am J Cardiol. 1999;84:1004-1010.

DAIS: Mean Baseline Lipoprotein Levels

215

40

133

214212

38

131

215223

44

137

212

0

50

100

150

200

250

TC HDL-C LDL-C TG

All Men Women

P=0.0005*

P=0.0001*

P=NS

P=NS

Mean%

*P=0.0001.

Steiner G. Diabetes. 1999;48(suppl 1):A2. Abstract 0005.

DAIS: Interim Lipid Results in Patients With Type 2 Diabetes

0.8 0.6 1.6 2.1

-9.0

6.7

-5.7

-27.2-30

-20

-10

0

10

20

30

TC* HDL-C* LDL-C* TG*

Placebo Fenofibrate

*Researchers report that results suggest benefit to patients.

Steiner G. XIIth International Symposium on Atherosclerosis; June 27, 2000; Stockholm, Sweden.

DAIS: Final Results in Patients With Type 2 DiabetesCAD• Treatment with fenofibrate resulted in 40% reduction in rate

of progression of localized CAD versus placebo• 23% reduction in combined coronary events following fenofibrate

treatment (P=NS*)Lipids• Average reductions with fenofibrate: TC, 10%; LDL-C, 6%;

TG, 29%; average increase in HDL-C, 6%Safety• Very few serious adverse events; no significant differences in

tolerability between fenofibrate and placebo treatments; 95% compliance

ADA-Suggested Standards for Biochemical Indices of Metabolic ControlBiochemical index Acceptable Borderline* High

Fasting plasma glucose (mg/dL) <115 126>200

Postprandial (2 hr)plasma glucose (mg/dL) <140 200

>235

Hemoglobin A1c (%)† (Goal: <7%) <6 >7>10

Fasting plasma TC (mg/dL) <200 200-239240

Fasting plasma TG (mg/dL) <200 200-399400

Fasting plasma LDL-C (mg/dL) <100 100-129130

(100 if CAD)

Fasting plasma HDL-C (mg/dL) >45 35-45<35

* Current ADA recommendations call for therapeutic action for values above “borderline.”† Adjust for normal lab values.Adapted from Garber AJ et al. Diabetes Care. 1992;15:1068-1074; ADA. Diabetes Care. 1993;16:828-834; and ADA. Diabetes Care. 1998;21(suppl 1):S36-S39.

Glycemic Control for People With Diabetes

Diabetic ActionBiochemical index Nondiabetic goal suggested

Preprandial glucose (mg/dL) <115 80-120 <80>126

Bedtime glucose (mg/dL) <120 100-140 <100>160

Hemoglobin A1c (%) <6 <7 >8These values are for nonpregnant individuals. “Action suggested” depends on individual patient circumstances. Hemoglobin A1c is referenced to a nondiabetic range of 4.0-6.0% (mean 5.0%, standard deviation 0.5%).

ADA. Diabetes Care. 1996;19(suppl 1):S8-S15.

1999 ADA Risk Stratification Based on Lipoprotein Levels in Adults With Diabetes*

ADA. Diabetes Care. 1999;22:S56-S59.

Risk LDL-C HDL-C TG

High 130 <35 400

Borderline 100-129 35-45 200-399

Low <100 >45 <200

*Values represent mg/dL. For women, HDL-C should be increased by 10 mg/dL.

1999 ADA Recommendations Based on LDL-C Levels in Adults With Diabetes*

ADA. Diabetes Care. 1999;22:S56-S59.

Initiation LDL-C Initiation LDL-CStatus level goal levelgoal

With CHD, PVDor CVD >100 100 >100100

Without CHD,PVD, and CVD >100 100 130†

100

*Values represent mg/dL.†Some authorities recommend drug initiation between 100 and 130 mg/dL.

Medical nutrition txMedical nutrition tx Drug txDrug tx

Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults• LDL-C lowering

– first choice: HMG-CoA reductase inhibitors (statins)– second choice: bile acid binding resin or fenofibrate

• HDL-C raising– behavioral interventions (weight loss, physical activity, smoking

cessation)– glycemic control– difficult (except with niacin, which is relatively contraindicated, or fibrates)

• TG lowering– glycemic control first priority– fibric acid derivative (gemfibrozil, fenofibrate)– statins (moderately effective at high dose in patients with TG and

LDL-C)

ADA. Diabetes Care. 1999;22:S56-S59.

Order of Priorities for Treatment of Diabetic Dyslipidemia in Adults• Combined hyperlipidemia

– first choice: improved glycemic control plus high-dose statin

– second choice: improved glycemic control plus statin plus fibric acid derivative (gemfibrozil or fenofibrate)

– third choice: improved glycemic control plus resin plus fibric

acid derivative

or

improved glycemic control plus statin plus niacin (glycemic control must be monitored carefully)ADA. Diabetes Care. 1999;22:S56-S59.

* Without vascular disease.† With vascular disease.

Approach to Patients With Diabetes and Hyperlipidemia

AcceptableLDL-C <100

TG <200

Monitor annually

Improvement

Hypercholesterolemia Goal

LDL-C <130*LDL-C <100†

HMG-CoAResin

HypertriglyceridemiaGoal

TG <400* TG <200†

Fibrate HMG-CoA if LDL

Mixed DyslipidemiaGoal

TG <400 LDL-C <130*TG <200 LDL-C <100†

HDL-C >35

HMG-CoAFibrate + resin

HyperchylomicronemiaTG 1000

Fibrate and fat restriction

(<10% of calories)

Measure (fasting): TC, TG, HDL-C,LDL-C (calculated), glucose, HbA1c

Higher risk: LDL-C 130, TG 400, HDL-C <35Lower risk: LDL-C <100, TG <200, HDL-C >45

Regulate diabetes: weight loss, exercise,restrict dietary saturated fat and cholesterol

No improvement

Continuum of Patients at Risk for a CHD Event

Post MI/Angina

Other Atherosclerotic Manifestations

Subclinical Atherosclerosis

Multiple Risk Factors

Low Risk

SecondaryPrevention

PrimaryPrevention

Courtesy of CD Furberg.

CV Health

Discontinued Tx

Intolerance to Tx

Inappropriate Tx No Tx

Under-recognition

Aggressive Tx

Drug Tx

NCEP ATP-II

Diet/Exercise

Awareness

Dead End

Progre

ss R

oad

Co

mp

lacency W

ay

The Solution? It’s Our Choice

CHD

#1 Killer