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

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

• 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/dl
• Secondary preventionCARE NEJM 1996 586 -28
  3,5 mmol/l -25 (p0.05) 137
  mg/dl4S Diabetes 202 -36 4,8 mmol/l -55
  (p0.002) Care 1997 186 mg/dl

Haffner Diabetes Care 1 1998
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Risk Reduction by Simvastatin
Estimated CHD reduction after treating 100 CHD
patients for 6 years
49
24
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Pyörälä K et al. Diabetes Care 20(4) 614 - 620,
1997
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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

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AtherosclerosisThe Overall Picture
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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
332481-487, 1995 Anderson et al. N Engl J Med
332488-493,1995 ODriscoll et al. Circulation
951128-1131, 1997
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Myocardial ischemia
Placebo (N20)
Lovastatin (N20)
Andrews et al. Circulation 1997
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Study Design

• 43 non-diabetic patients
• Normal CAG
• Positive exercise test
• 43 61 yrs
• Serum total cholesterol gt 7.75 mmol/l ( gt 300
  mg/dl)
• Step 1 diet 12 weeks
• Randomized for diet (n20) or statins (n23) 16
  weeks
• Statins withdrawn
• Lipid profile
• Exercise test
• Repeat after 20 weeks
• Lipid profile
• Exercise test

A.P. Mansur, et al. Heart 199982689
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Results

• At week 28
• Statin group significant reductions in plasma
  lipids Positive exercise test 23 gt 3
• Diet group no significant changes in plasma
  lipids Positive exercise test 20 gt 15
• At week 48
• Statin group plasma lipids returned to base
  line levels 17 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 199982689
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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

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Atherogenic Lipoproteins
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Post-CABG StudyAggressive vs Moderate Treatment
Mean achieved.
Post-CABG Trial Investigators. N Engl J Med.
1997336153-162.
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Is Lower Better? Aggressive Lipid Lowering is
Associated with More Favorable Outcomes



Grafts with occlusion or death
Grafts with new lesions
Grafts with progression or death
P?0.001 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 1997336153162.
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On-Treatment LDL Levels and Correlation with
Major Coronary Events in 4S
Circulation 199796I-717
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Study Hypothesis Lower Is Better
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Is Lower Better? TNT/ IDEAL Study Hypotheses
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Normal Plasma Cholesterol
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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

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National Institute of Health, USAAdult Treatment
Panel II

• Patient category LDL-initiation Level LDL goal
• Dietary therapy
• CHD risk factors lt 2 gt 150 mg/dl lt 150 mg/dl
• CHD risk factors gt 2 gt 125 mg/dl lt 125 mg/dl
• With CHD gt 100 mg/dl lt 100 mg/dl
• Drug treatment
• CHD risk factors lt 2 gt 200 mg/dl lt 150 mg/dl
• CHD risk factors gt 2 gt 150 mg/dl lt 125 mg/dl
• With CHD gt 100 mg/dl lt 100 mg/dl

Circulation 1994891329
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Current consensus (U.S.)NCEP LDL-C Goals

• Risk Profile LDL-C-goal
• Diagnosed CHD lt 100 mg/dl (2.6 mmol/l)
• gt 2 risk factors lt130 mg/dl (3.4 mmol/l)
• lt 2 risk factors lt160 mg/dl (4.2 mmol/l)

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European Atherosclerosis Guidelinesmanagement
of hypercholesterolemia

• Therapeutic group Conservative Drugs (based on
• measures (weight LDL-cholesterol)
• loss, lipid-lowering,
• diet
• Cholesterol 200250 mg/dl effective in
  majority Only in CHD or very
• LDL cholesterol 135175 mg/dl high risk and un-
• responsive to diet
• Cholesterol 250300 mg/dl Need close dietary CHD
  or high risk if LDL
• LDL cholesterol 175200 mg/dl compliance gt 125
  mg/dl and
• Most respond unresponsive to diet
• adequately
• Cholesterol gt 300 mg/dl Need close dietary
  Justified even in ab-
• LDL-cholesterol gt 200 mmol/l compliance sense of
  other risk
• Three month trial factors in genetic
• dyslipidemias

Nutrition Metabolism and Cardiovascular Disease
19982113
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Current consensus (Europe)ESC/EAS LDL-C Goals

• Risk Profile LDL-C-goals
• Diagnosed CHD 115 - 135 mg/dl (3.0 - 3.5 mmol/l)
• Moderate risk 135 - 155 mg/dl (3.5 - 4.0 mmol/l)
• No heart disease 55 - 175 mg/dl (4.0 - 4.5 mmol/l)

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Second Joint Task Force Guidelines
Lipoprotein marker Goal of therapy LDL-C goal
lt3.0 mmol/L (115 mg/dL) Total-C goal lt5.0 mmol/L
(190 mg/dL)
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Statin Treatment at Four CHD Risk Levels
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
Pickin et al. Heart 1999 82325
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Archie Cochranes PleaAll effective
treatments be made availableAppears
unsustainable at current level of funding and
health level service resources
Pickin et al. Heart 1999 82325
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PracticalGuidelines
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Guidelinestreatment goals?

• Total cholesterol lt 5.0 mmol/l (200 mg/dl)
• LDL-cholesterol lt 3.0 mmol/l (115 mg/dl)
• triglycerides lt 2.0 mmol/l (80 mg/dl)
• HDL-cholesterol gt 1.0 mmol/l (40 mg/dl)
• 5,3,2,1 rule

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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)

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GuidelinesDrugs

• Step 1 LDL-reduction
• Step 2 HDL-cholesterol increase and triglyceride
  decrease
• Start statins when
• LDL-cholesterol gt 3.0 mmol/l
• HDL-cholesterol lt 0.9 mmol/l en TG lt 2.0 mmol/l
• TG lt 4.5 mmol/l

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Priorities for Lipid lowering

• Secondary prevention
• Patients with diabetes mellitus type 2
• Patients with genetic dyslipidemia's
• Patients with multiple risk factors

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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

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