1. Triglycerides
Cholesterol
HDL-C
or N
NIDDM
N or
or N
IDDM

2. Serum cholesterol (mmol/L)
MRFIT
150
Diabetic
100
CVD deaths per 10,000 man years 50
Non-diabetic
<4.5
4.5-
4.9
5.0-
5.4
5.5-
5.9
6.0-
6.4
6.5-
6.9
>7.0
Serum cholesterol (mmol/L)
Stamler et al, Diabetes Care 1993;16:434-44

3. Cholesterol Levels and CHD Mortality Mean serum cholesterol mmol l-1
600
Finland
Ireland
500
England
New Zealand
Australia
Hungary
400
Denmark
Canada
Sweden
W. Germany
CHD mortality 10-5
Israel
300
Poland
Belgium
Italy
200
Switzerland
Yugoslavia
France
100
Japan
5.2
5.8
6.5
7.1
Mean serum cholesterol mmol l-1
Adapted from: Leon Simon, Am J Card 1986;May 30:Vol 57

4. IDL + HDL-C VLDL Triglycerides TRIGLYCERIDES FA + Glycerol Ketone
Lipoprotein
Lipase
TRIGLYCERIDES
FA + Glycerol
Ketone
bodies
TRIGLYCERIDES
Intracellular
Lipase
FFA
Glycerol

5. VLDL Triglyceride Secretion
2.5
2.0
µg/h/mg cell protein
1.5
1.0
100
200
300
400
500
Insulin (µU/ml)
Durrington et al, J Clin Invest 1982;70:63-73

6. Lipoprotein Physiology
Chylomicrons
Gut TG TG
Lipoprotein
Lipase TG TG TG TG
VLDL
Liver TG
Lipoprotein
Lipase TG TG
LDL
LDL receptor
Intracellular cholesterol
synthesis inhibited

7. Marked hypertriglyceridaemia

8. Marked hypertriglyceridaemia

9. Eruptive xanthomata

10. Foam cell in bone marrow

11. CHD Risk in Four Men with NIDDM
62 years; smokers; no family history/personal history of CHD; SBP 160 mmHg
A B C D
Serum cholesterol (mmol/L)
LDL cholesterol (mmol/L)
HDL cholesterol (mmol/L)
Serum triglycerides (mmol/L) CHD incidence (% / 6 years)

12. Increased Triglyceride circulating synthesis free fatty acid VLDL IDL
Cholesteryl ester
HDL
Triglyceride
HDL
cholesterol
decreased
Cholesteryl ester
IDL
Triglyceride
LDL
Small LDL

13. Age-adjusted Results at Initial Examination of Mexican Americans
Diabetic Non-diabetic
after 8 years after 8 years
Men Women Men Women p-value
BMI kg/m <0.001
Triglycerides mmol/L <0.001
Cholesterol mmol/L
LDL-C mmol/L
HDL-C mmol/L <0.001
SBP mmHg <0.001
DBP mmHg
Fasting glucose mol/L <0.001
Fasting insulin pmol/L <0.001
Haffner et al, JAMA 1990;263:2893

14. Nutritional change over three centuries12
Sugar 10
Fat 8
Potato
Energy foods MJ/d/person 6 4
Cereal 2
1770
1810
1860
1910
1970
Year
After Revd Hugh Trowell

16. Statin Trials - Secondary PreventionTC
LDL-C
HDL-C TG
CHD
incidence
Coronary
intervention
procedures % 8% 10 4S
(TC=6.7
mmol/L)
-10
-10%
-20
-30
-29%
-40
-35%
-33%
-37% 10 5%
CARE
(TC=5.4
mmol/L)
-10
-20
-14%
-20%
-30
-24%
-28%
-27%
-40 10 6%
LIPID
(TC=5.6
mmol/L)
-10
-20
-12%
-18%
-20%
-30
-25%
-23%
-40

17. 4S All-cause CHD Coronary mortality events revascularisation n
Effect of Treatment
All-cause CHD Coronary
mortality events revascularisation n
Diabetes* % % % ns p= p=0.005
IFG** % % % p= p= p=0.001
Non-diabetic % % % non IFG p= p< p<0.001
* fasting glucose 126 mg/dL (7.0 mmol/L)
** fasting glucose mg/dL ( mmol/L)
Haffner et al, Arch Intern Med 1999;159:2661-7

18. 4S Non-diabetic, IFG* Diabetes** non IFG
Placebo Simva Placebo Simva Placebo Simva
New CHD % % % % % % events
% actively % % % treated patients avoiding new CHD events
* FBG mmol/L
** FBG 7.0 mmol/L
Haffner et al, Arch Intern Med 1999;159:2661-7

19. CARE CHD mortality n & morbidity p-value Diabetes 586 -25% <0.05
IFG** % ns
Non-diabetic % <0.001 Non-IFG
* Expanded end-point
** Impaired fasting glucose mg/dL
Goldberg et al, Circulation 1998;98:2513-9

20. Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial
Rate of new Relative risk CHD events in reduction by n placebo group* pravastatin p-value
Overall % % <0.001
Non-diabetic % % <0.001
Diabetic % % ns
* over 6.1 years
N Engl J Med 1998;339:

21. Statin Trials - Primary PreventionTC
LDL-C
HDL-C TG
CHD
incidence
Coronary
intervention
procedures % 10 5%
WOSCOPS
(TC=7.0
mmol/L)
-10
-20
-12%
-20%
-30
-26%
-40
-31%
-37% 10 5%
AFCAPS
/TexCAPS
(TC=5.7
mmol/L)
-10
-20
-13%
-19%
-30
-27%
-40
-33%
-40%

22. Results of Clinical Trials of Lipid-lowering Drugs: Principal Endpoint - New Coronary Heart Disease
Drugs which principally Type Duration  in  in  in new lower cholesterol (years) serum new CHD CHD cholesterol incidents incidents for 1%  in cholesterol
LRC (Lipid Research Clinics) 1oRCT/ % % % resin
4S 2oRCT/ % % % statin
WOSCOPS 1oRCT/ % % % statin
CARE 2oRCT/ % % % statin
LIPID 2oRCT/ % % % statin
AFCAPS/TexCAPS 1oRCT/ % % % statin

23. Results of Clinical Trials of Lipid-lowering Drugs: Principal Endpoint - New Coronary Heart Disease (2)
Drugs which principally Type Duration  in  in  in new lower triglycerides (years) serum new CHD CHD cholesterol incidents incidents for 1%  in cholesterol
WHO 1oRCT/ % 20% 2.2% fibrate
Helsinki 1oRCT/ % 34% 3.4% fibrate
Stockholm 2oRCT/ % 41% 3.2% fibrate niacin
VA-HIT 2oRCT/ % 22% 5.5% fibrate
BIP 2oRCT/ % 7% 1.5% fibrate

24. VA High-density Lipoprotein Cholesterol Intervention Trial (VA-HIT)
2531 men aged <74 years with CHD (MI 61%, CABG or PTC 57%; or coronary stenosis >50%)
HDL cholesterol <1.0 mmol/L (mean 0.83)
Triglyceride <3.4 mmol/L (mean 1.8)
LDL cholesterol <3.6 mmol/L (mean 2.9) (mean serum cholesterol 4.5)
Randomised to placebo or gemfibrozil 600 mg bd*
Duration 5.1 years
* gemfibrozil SR 1200 mg od initially
Bloomfield et al, N Eng J Med 1999;341:410-8

25. VA-HIT Cholesterol = 4.5 mmol/L HDL-C +8% CHD morbidity + mortality
LDL-C TG 0%
-4%
-22%
-31%
Bloomfield et al, N Eng J Med 1999;341:410-8

26. VA-HIT CHD & n stroke incidence p-value Diabetes 627 -24% 0.05
Non-diabetic %
Bloomfield et al, N Engl J Med 1999;341:410-8

27. Bezafibrate Infarction Prevention (BIP) Study
3090 patients (91% men) aged years, previous myocardial infarction / stable angina
Cholesterol mmol/L (mean 5.4 mmol/L)
HDL-C <1.15 mmol/L (mean 0.9 mmol/L)
Triglycerides 3.4 mmol/L (mean 1.6 mmol/L)
Bezafibrate retard 400 mg daily or placebo
Duration 6.2 years
Circulation 2000;102:21-7

28. Baseline cholesterol 5.4, HDL 0.9, triglyceride 1.6 mmol/L
BIP Study
HDL-C
New CHD events
+14%
Triglycerides
Triglyceride
Cholesterol
LDL-C
All
<1.7
>1.7
>2.0
>2.3
-5%
-5%
-4.6%
-7.9%
-9.4%
-21.6%
-25%
Baseline cholesterol 5.4, HDL 0.9, triglyceride 1.6 mmol/L
-39.5%
Circulation 2000;102:21-7
Circulation 2000;102:21-7

29. Helsinki Heart Study 30 Gemfibrozil 20
CHD incidence (no per 1000 man years)
Placebo 10
<2.3
>2.3
<2.3
>2.3
TG mmol/L
<5.0
<5.0
>5.0
>5.0
LDL:HDL-C
Manninen et al, Circulation 1992;85:37-45

30. Diabetes in Helsinki Heart Study
n Effect of treatment p-value
Diabetes % (n=10 events) ns
Whole study % (n=140 events) p<0.02
Koskinen et al, Diabetes Care 1992;15:820-5

32. Joint British Societies Recommendations (BCS/BHA/BHS/BDA) recommendations on lipid levels
Secondary prevention
All patients should have TC <5.0 mmol/L, LDL-C <3.0 mmol/L
Primary prevention
All patients with absolute 10-year CHD risk >15% and TC >5.0 mmol/L on repeat measurements should have their cholesterol lowered to the above levels using a statin

33. Rancho Bernardo Study Non-diabetic 4 Diabetic 3
Relative risk of CHD death 2 1
Women
Men

34. 10 20 30 40
Non-diabetic
IDDM
without
proteinuria
with
Relative cardiovascular mortality

35. Indications for Statin Treatment in Diabetes Mellitus (no distinction between men and women)
Cholesterol >5 mmol/L + established CHD or other clinically significant atherosclerosis
Cholesterol >5 mmol/L + proteinuria
Cholesterol >5 mmol/L + CHD risk >15%* over next 10 years (=cardiovascular risk >20%)
* where resources permit (minimum standard of care >30%)

36. Indications for Statin Treatment in Diabetes Mellitus
Unresolved issues
How is risk assessed, especially in IDDM?
At what age to begin treatment in IDDM?
What is the objection to giving statin to all diabetic patients with cholesterol >5 mmol/L

37. Finnish Social Insurance Institution Diabetes Register
Type 2 diabetes aged years
Non-diabetic controls from population register
100 80 60
% not dying from CHD 40
Nondiabetic subjects without prior MI n = 1304
Diabetic subjects without prior MI n = 890 20
Nondiabetic subjects with prior MI n = 69
Diabetic subjects with prior MI n = 169 1 2 3 4 5 6 7 8
Years
Haffner et al N. Engl. J. Med. 1998; 339:

38. Organisation to Assess Strategies for Ischaemia
(OASIS) Registry
8013 Men and Women presenting with unstable angina on non-Q wave MI
1718 Diabetic Hospitals ( Australia, N & S America, Europe) 30 +
Diabetes / CVD
RR = 2.07 ( ) - +
No Diabetes / CVD - 25
RR = 1.58( ) 20
RR = 1.42 (1.42( )
New cardiovascular events /100 15
RR = 1.00 10 5 3 6 9 12 15 18 21 24
Months
CVD + = previous MI, stroke, CCF, PTCA or CABG
Malmberg et al Circulation 2000, 102:

39. Clinical Trials of Lipid-lowering Drugs in Progress in Diabetes (November 2000)
HPS (Heart protection study)
1o (n=3985) 2o (n=1978)
Simvastatin / Antioxidants
FIELD (Fenofibrate Intervention
and Event Lowering in Diabetes 1o
Fenofibrate
CARDS (Collaborative AtoRvaStatin) 1o
Atorvastatin
ASPEN (981-71)
1o + 2o
Atorvastatin
LDS (Lipids in Diabetes Study) 1o
Cerivastatin / Fenofibrate

40. Heart Protection Study (HPS) :Main Conclusions
• 5 years of statin treatment typically prevents these
“major vascular events” in about:
100 of every 1000 with previous MI
other CHD
diabetes (age 40+)
previous stroke
other PVD
Irrespective of cholesterol level (or age, sex, or
other treatments)

41. Glucose tolerance (Himsworth)
200
180
160
Dietary calories
Carbohydrate:Fat
Blood sugar mg/dL
140
7% : 80%
19% : 69%
120
52% : 35%
100
75% : 13% 1 2 3
Hours

42. Non-alcoholic hepatic steatosis