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Triglycerides Cholesterol HDL-C or N NIDDM N or or N IDDM
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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
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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
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IDL + HDL-C VLDL Triglycerides TRIGLYCERIDES FA + Glycerol Ketone
Lipoprotein Lipase TRIGLYCERIDES FA + Glycerol Ketone bodies TRIGLYCERIDES Intracellular Lipase FFA Glycerol
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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
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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
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Marked hypertriglyceridaemia
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Marked hypertriglyceridaemia
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Eruptive xanthomata
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Foam cell in bone marrow
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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)
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Increased Triglyceride circulating synthesis free fatty acid VLDL IDL
Cholesteryl ester HDL Triglyceride HDL cholesterol decreased Cholesteryl ester IDL Triglyceride LDL Small LDL
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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
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Nutritional change over three centuries
12 Sugar 10 Fat 8 Potato Energy foods MJ/d/person 6 4 Cereal 2 1770 1810 1860 1910 1970 Year After Revd Hugh Trowell
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Statin Trials - Secondary Prevention
TC 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
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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
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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
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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
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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:
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Statin Trials - Primary Prevention
TC 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%
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Rancho Bernardo Study Non-diabetic 4 Diabetic 3
Relative risk of CHD death 2 1 Women Men
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10 20 30 40 Non-diabetic IDDM without proteinuria with Relative cardiovascular mortality
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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%)
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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
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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:
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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:
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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
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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)
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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
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Non-alcoholic hepatic steatosis
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