Clinical Trials of Lipid Therapy in Diabetic Subjects (subgroup analysis)

Haffner Diabetes Care; 1: 1998

Study journal N LDL-C Baseline CHD lowering LDL-C reduction

Primary preventionHelsinki HS Diabetes 135 -6 % 4,9 mmol/l -60 % (ns) Care 1992 191 mg/dlAFCAPS/TEXCAPS JAMA 1998 264 -25% 3.9 mmol/l -43 % (ns)

150 mg/dlSecondary preventionCARE NEJM 1996 586 -28 % 3,5 mmol/l -25 % (p=0.05)

137 mg/dl4S Diabetes 202 -36 % 4,8 mmol/l -55 % (p=0.002) Care 1997 186 mg/dl

Risk Reduction by Simvastatin

Estimated CHD reduction after treating 100 CHD patients for 6 years

Expected fatal and non fatal Ml’s

Number of prevenedFatal and non fatal MI’s

patients with diabetes

patients without diabetes

49

29

24

9

Pyörälä K et al. Diabetes Care 20(4): 614 - 620, 1997

Overview Presentation

• Who are at risk– Secondary prevention– Primary prevention - Diabetes Mellitus type 2

• Lowering Cholesterol– Secondary prevention– Primary prevention

• Beyond cholesterol lowering• How low should we go• Guidelines

Atherosclerosis“The Overall Picture”

Relationship Between Endothelial Function and HMG-CoA reductase Inhibitors

Restoration of endothelium-dependent vasomotion is on of the earliest recognizable benefits after treatment with HMG-CoA reductase

inhibitors.

Treasure et al. N Engl J Med 332:481-487, 1995Anderson et al. N Engl J Med 332:488-493,1995O’Driscoll et al. Circulation 95:1128-1131, 1997

Myocardial ischemia

0

5

15

20

10

Baseline 6 months

Andrews et al.; Circulation 1997

Placebo(N=20)

Ep

iso

des

of

isch

emia

0

5

15

20

10

Baseline 6 months

Lovastatin(N=20)

Study Design • 43 non-diabetic patients

– Normal CAG– Positive exercise test– 43 –61 yrs– Serum total cholesterol > 7.75 mmol/l ( > 300 mg/dl)

• Step 1 diet – 12 weeks• Randomized for diet (n=20) or statins (n=23) – 16 weeks• Statins withdrawn

– Lipid profile – Exercise test

• Repeat after 20 weeks– Lipid profile– Exercise test

A.P. Mansur, et al. Heart 1999;82:689

ResultsAt week 28:

Statin group: significant reductions in plasma lipidsPositive exercise test 23 > 3

Diet group: no significant changes in plasma lipidsPositive exercise test 20 > 15

At week 48:

Statin group: plasma lipids returned to base line levels17 patients on statins; positive exercise test in

15

Diet group: Positive exercise test in 14 out of 15 patients

A.P. Mansur, et al. Heart 1999;82:689

Overview Presentation

Who are at riskSecondary prevention

Primary prevention - Diabetes Mellitus type 2

Lowering CholesterolSecondary prevention

Primary prevention

Beyond cholesterol lowering

How low should we go?

Guidelines

Atherogenic Lipoproteins

Aggressive Tx (93-96)*

Moderate Tx (134-136)*

Post-CABG Study:Aggressive vs Moderate Treatment

Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

* Mean achieved.

Follow-up (mo)12 24 36 486

80

90

100

110

120

130

140

150

160

0

LDL-C(mg/dL)

Is Lower Better? Aggressive Lipid Lowering is Associated with More Favorable Outcomes

05

101520

2530354045

Mea

n %

of

gra

fts

per

pat

ien

t

Aggressive Moderate

*P0.001 vs moderate therapy group.Mean lovastatin dose 76 mg in aggressive group and 4 mg in moderate group. After 1 year, mean LDL-C level was 93 mg/dL (2.4 mmol/L) in the aggressive group and 136 mg/dL (3.5 mmol/L) in the moderate group.The Post CABG Trial Investigators. N Engl J Med 1997;336:153–162.

Grafts with occlusion or death

Grafts withnew lesions

Grafts with progression or death

*

* *

On-Treatment LDL Levels and Correlation with Major Coronary Events in 4S

Circulation 1997;96:I-717

10.813.3

18.9

0

4

8

12

16

20

24

58-104 105-126 127-266

LDL Levels (mg/dL)

Maj

or C

oron

ary

Eve

nt

Rat

e

Absolute difference in event rate:

2.3%5.6%

Study Hypothesis: Lower Is Better

With CHDevent(%)

50

0

5

10

15

20

25

70 90 110 130 150 170 190 210

LDL-C (mg/dL)

Secondary preventionPrimary prevention

LIPID-Rx

CARE-PBOCARE-Rx

4S-RxLIPID-PBO

4S-PBO

AFCAPS-Rx

WOS-RxWOS-PBO

AFCAPS-PBO?

Is Lower Better? TNT/ IDEAL Study Hypotheses

With CHDevent(%)

0

5

10

15

20

25

50 70 90 110 130 150 170 190 210

LDL-C mg/dL

Secondary preventionPrimary prevention

TNT 80 mgTNT 10 mg

TNT Entry

IDEAL-sim

IDEAL-Entry

IDEAL-ator

“Normal” Plasma Cholesterol“Normal” Plasma Cholesterol700

(18.0)

300(7.7)

200(5.2)

150(3.9)

100(2.6)

50(1.3)

0Pla

sma

ch

ole

ster

ol

leve

l m

g/d

l (m

mo

l/l)

Physiologic level for plasma LDL-Cholesterol

as predicted from receptor studies

25 mg/dl (0.65mmol/l)

FH Homozygotes

FH Heterozygotes

Normal Adults

Newborns

Guinea pig Cow Rabbit

Rat Sheep CamelPig

Overview PresentationWho are at risk

Secondary prevention

Primary prevention - Diabetes Mellitus type 2

Lowering CholesterolSecondary prevention

Primary prevention

Beyond cholesterol lowering

How low should we go• Guidelines

National Institute of Health, USAAdult Treatment Panel II

Patient category LDL-initiation Level LDL goal

Dietary therapyCHD risk factors < 2 > 150 mg/dl < 150 mg/dlCHD risk factors > 2 > 125 mg/dl < 125 mg/dlWith CHD > 100 mg/dl < 100 mg/dl

Drug treatmentCHD risk factors < 2 > 200 mg/dl < 150 mg/dlCHD risk factors > 2 > 150 mg/dl < 125 mg/dlWith CHD > 100 mg/dl < 100 mg/dl

Circulation 1994:89:1329

Current consensus (U.S.):NCEP LDL-C Goals

Risk Profile LDL-C-goal

Diagnosed CHD < 100 mg/dl (2.6 mmol/l)

> 2 risk factors <130 mg/dl (3.4 mmol/l)

< 2 risk factors <160 mg/dl (4.2 mmol/l)

Therapeutic group Conservative Drugs (based onmeasures (weight LDL-cholesterol)loss, lipid-lowering,diet

Cholesterol 200–250 mg/dl effective in majority Only in CHD or very LDL cholesterol 135–175 mg/dl high risk and un-

responsive to diet

Cholesterol 250–300 mg/dl Need close dietary CHD or high risk if LDL

LDL cholesterol 175–200 mg/dl compliance > 125 mg/dl andMost respond unresponsive to diet

adequately

Cholesterol > 300 mg/dl Need close dietary Justified even in ab-LDL-cholesterol > 200 mmol/l compliance sense of other risk

Three month trial factors in genetic dyslipidemias

European Atherosclerosis Guidelines:management of hypercholesterolemia

Nutrition Metabolism and Cardiovascular Disease 1998:2:113

Second Joint Task Force Guidelines

Lipoprotein marker Goal of therapy

LDL-C goal <3.0 mmol/L (115 mg/dL)

Total-C goal <5.0 mmol/L (190 mg/dL)

CHD events per year

4.5% 3.0% 2.0% 1.5%

NNT for 5 years* 13 20 30 40

Cost per life year gained# £ 5100 £ 8200 £ 10 700 £ 12 500

Cumulative proportion of 5.1% 8.2% 15.8%24.7%proportion of adults in UKabove CHD risk treshold

Annual cost of treatment £ 549 m £ 885 m £ 1 712 m £ 2 673 mif implemented fully in UK

*Number needed to treat for 5 years to prevent one major coronary event# For Simvastatin treatment at 27.4 mg daily

Statin Treatment at Four CHD Risk LevelsStatin Treatment at Four CHD Risk Levels

Pickin et al. Heart 1999; 82:325

Archie Cochrane’s Plea:

“All effective treatments be made available”

Appears unsustainable at current level of

funding and health level service resources

Pickin et al. Heart 1999; 82:325

PracticalGuidelines

Guidelinestreatment goals?

• Total cholesterol < 5.0 mmol/l (200 mg/dl)

• LDL-cholesterol < 3.0 mmol/l (115 mg/dl)

• triglycerides < 2.0 mmol/l (80 mg/dl)

• HDL-cholesterol > 1.0 mmol/l (40 mg/dl)

5,3,2,1 rule

Guidelineslifestyle

• Stop smoking

• Prevent obesity

• exercise : 3 - 5 x week 30 min

• Diet:– Fruit, vegetables, whole grain cereals

– low fat dairy products

– 2 x per week fish and 1 x per week vegetarian

– avoid snacks and sweets

– fish - pasta - olive oil - red wine (Mediterranean-diet)

GuidelinesDrugs

• Step 1: LDL-reduction

• Step 2: HDL-cholesterol increase and triglyceride

decrease

• Start statins when

– LDL-cholesterol > 3.0 mmol/l

– HDL-cholesterol < 0.9 mmol/l en TG < 2.0 mmol/l

– TG < 4.5 mmol/l

Priorities for Lipid loweringPriorities for Lipid lowering

• Secondary prevention

• Patients with diabetes mellitus type 2

• Patients with genetic dyslipidemia's

• Patients with multiple risk factors

Summary

• Who are at risk–Secondary prevention–Primary prevention - Diabetes Mellitus type 2

• Lowering Cholesterol–Secondary prevention–Primary prevention

• Beyond cholesterol lowering

• How low should we go

• Guidelines