TM © 1999 Professional Postgraduate Services ® Diabetic Dyslipidemia

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© 1999 Professional Postgraduate Services®

Diabetic Dyslipidemia

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© 1999 Professional Postgraduate Services®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

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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.

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T M

© 1 9 9 9 P ro fe s s io n a l P o s tg ra d u a te S e rv ic e s ®

0

5

10

15

20

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T M

© 1 9 9 9 P ro fe s s io n a l P o s tg ra d u a te S e rv ic e s ®

T h e S tro n g H e a rt S tu d y : D iffe re n c e s in C V D R is kF a c to rs b y D ia b e tic S ta tu s in M e n a n d W o m e n *

*A d ju s te d fo r a g e a n d c e n te r.

A d a p te d fro m H o w a rd B V e t a l. D ia b e te s C a re . 1 9 9 8 ;2 1 :1 2 5 8 -1 2 6 5 .

-4.4

-3.7

-7.5

-5.3

-8

-7

-6

-5

-4

-3

-2

-1

0

Men

Women

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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

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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

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Accelerated atherosclerosis

Clinical diabetes

Hyperinsulinemia Impairedglucose

tolerance

HypertriglyceridemiaDecreased HDL-C

Essentialhypertension

Insulin resistance

Insulin Resistance and Atherosclerosis: Posited Relationships

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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

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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

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Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502.Lamarche B et al. Circulation. 1997;95:69-75.

Significance of Small, Dense LDL• Low cholesterol content of LDL particles

particle number for given LDL-C level• Associated with levels of TG and LDL-C, and

levels of HDL2

• Marker for common genetic trait associated with risk of coronary disease (LDL subclass pattern B)

• Possible mechanisms of atherogenicity– greater arterial uptake uptake by macrophages oxidation susceptibility

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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

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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.

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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.

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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.

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


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

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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)


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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.

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© 1999 Professional Postgraduate Services®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

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Drug TG HDL-C LDL-C

Fibric acid derivatives 35-50 10-25 10-15

Bile acid sequestrants * 15-30

Nicotinic acid 25-30 10-30 10-25* May increase in patients with pre-existing hypertriglyceridemia.

Range of lipid effects (%)

Hypolipidemic Drug Therapy

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Lovastatin 20 mg 19 27 6 9

Pravastatin 20 mg 24 32 2 11

Simvastatin 20 mg 25 33 11 9

Atorvastatin 10 mg 29 39 6 19

Cerivastatin 0.3 mg 19 28 10 13

* Values reported in Package Inserts.

Lipid effects (%)*

Hypolipidemic Drug Therapy:HMG-CoA Reductase Inhibitors

Drug at starting dose TC LDL-C HDL-C TG

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-27

8

-24

-30

-18

8

-30*

-42*-45-40-35-30-25-20-15-10-505

10

Atorvastatin 10 mg

Simvastatin 10 mg

Mean % from baseline

at 4 wk(N=17)

*P<0.01

Best JD. Atherosclerosis. 1994;109:312. Abstract.Data on file. Parke-Davis, Morris Plains, NJ.

TC LDL-C TG

HDL-C

Effects of Lipid-Lowering Therapy in Patients With Type 2 Diabetes

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* 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

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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

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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

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TM © 1999 Professional Postgraduate Services ® Diabetic Dyslipidemia