Atherosclerosis, Dyslipidaemia and Diabetes

Section 1 -Epidemiology and Risk Factors Section 2 - Classification of Dyslipidaemias and Pathogenesis of Atherosclerosis Section 3 - Lipoproteins and Lipid Metabolism Section 4 - Guidelines and Unmet Need Section 5 - Statins and Lipid-modifying Therapies Section 6 - Key Statin Trials Section 7 - Diabetes: a Risk Factor for CHD? Section 8 - The Metabolic Syndrome Section 9 - Outcome Trials in Diabetes Section 1 -Epidemiology and Risk Factors Section 2 - Classification of Dyslipidaemias and Pathogenesis of Atherosclerosis Section 3 - Lipoproteins and Lipid Metabolism Section 4 - Guidelines and Unmet Need Section 5 - Statins and Lipid-modifying Therapies Section 6 - Key Statin Trials Section 7 - Diabetes: a Risk Factor for CHD? Section 8 - The Metabolic Syndrome Section 9 - Outcome Trials in Diabetes Atherosclerosis, Dyslipidaemia and Diabetes Contents

Section 1 Epidemiology and Risk Factors

The Framingham Study: Relationship Between Cholesterol and CHD Risk 0 0 Adapted from Castelli WP. Am J Med 1984;76:4– < – – –294 >295 CHD incidence per 1000 Serum cholesterol (mg/100 mL)

35 Seven Countries Study: Relationship of Serum Cholesterol to Mortality Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136 Serum total cholesterol (mmol/L) Death rate from CHD/1000 men Northern Europe United States Southern Europe, Inland Southern Europe, Mediterranean Japan Serbia

Cholesterol: A Modifiable Risk Factor In the USA, 37% (102 million) have elevated total cholesterol (>200 mg/dL, 5.2 mmol/L) 1 In EUROASPIRE II, 58% of patients with established CHD had elevated cholesterol (5 mmol/L, 190 mg/dL) 2 10% reduction in total cholesterol results in: 15% reduction in CHD mortality (p<0.001) 11% reduction in total mortality (p<0.001) 3 LDL-cholesterol is the primary target to prevent CHD In the USA, 37% (102 million) have elevated total cholesterol (>200 mg/dL, 5.2 mmol/L) 1 In EUROASPIRE II, 58% of patients with established CHD had elevated cholesterol (5 mmol/L, 190 mg/dL) 2 10% reduction in total cholesterol results in: 15% reduction in CHD mortality (p<0.001) 11% reduction in total mortality (p<0.001) 3 LDL-cholesterol is the primary target to prevent CHD Adapted from: 1. American Heart Association. Heart and Stroke Statistical Update; 2002; 2. EUROASPIRE II Study Group. Eur Heart J 2001;22:554–572; 3. Gould AL et al. Circulation 1998;97:946–952

Risk Factors for Cardiovascular Disease Modifiable Smoking Dyslipidaemia Raised LDL-cholesterol Low HDL-cholesterol Raised triglycerides Raised blood pressure Diabetes mellitus Obesity Dietary factors Thrombogenic factors Lack of exercise Excess alcohol consumption Modifiable Smoking Dyslipidaemia Raised LDL-cholesterol Low HDL-cholesterol Raised triglycerides Raised blood pressure Diabetes mellitus Obesity Dietary factors Thrombogenic factors Lack of exercise Excess alcohol consumption Non-modifiable Personal history of CHD Family history of CHD Age Gender Adapted from: Pyörälä K et al. Eur Heart J 1994;15:1300–1331

Levels of Risk Associated with Smoking, Hypertension and Hypercholesterolaemia x1.6 x4 x3 x6 x16 x4.5 x9 Hypertension (SBP 195 mmHg) Hypertension Serum cholesterol level (8.5 mmol/L, 330 mg/dL) Serum cholesterol level (8.5 mmol/L, 330 mg/dL) SmokingSmoking Adapted from Poulter N et al., 1993

Section 2 Classification of Dyslipidaemias and Pathogenesis of Atherosclerosis

Classification of Dyslipidaemias: Fredrickson (WHO) Classification LDL – low-density lipoprotein; IDL – intermediate-density lipoprotein; VLDL – very low-density lipoprotein. (High-density lipoprotein (HDL) cholesterol levels are not considered in the Fredrickson classification.) Phenotype I IIa IIb III IV V Phenotype I IIa IIb III IV V Lipoprotein elevated Chylomicrons LDL LDL and VLDL IDL VLDL VLDL and chylomicrons Lipoprotein elevated Chylomicrons LDL LDL and VLDL IDL VLDL VLDL and chylomicrons Atherogenicity None seen Atherogenicity None seen Prevalence Rare Common Intermediate Common Rare Prevalence Rare Common Intermediate Common Rare Serum cholesterol Serum cholesterol Normal to Serum triglyceride Serum triglyceride Normal Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391

Normal Arterial Wall Tunica adventitia Tunica media Tunica intima Endothelium Subendothelial connective tissue Smooth muscle cell Internal elastic membrane Elastic/collagen fibres External elastic membrane Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18

Pathogenesis of Atherosclerotic Plaques Protective response results in production of cellular adhesion molecules Protective response results in production of cellular adhesion molecules Monocytes and T lymphocytes attach to sticky surface of endothelial cells Monocytes and T lymphocytes attach to sticky surface of endothelial cells Migrate through arterial wall to subendothelial space Lipid-rich foam cells Endothelial damage Macrophages take up oxidised LDL-cholesterol Fatty streak and plaque

CELLULAR ADHESION MOLECULES induces cell proliferation and a prothrombic state activated endothelium attracts monocytes and T lymphocytes which adhere to endothelial cells attracts monocytes and T lymphocytes which adhere to endothelial cells cytokines (e.g. IL-1, TNF-) chemokines (e.g.MCP-1, IL-8) growth factors (e.g. PDGF, FGF) Adapted from Koenig W. Eur Heart J 1999;1(Suppl T);T19–26 The Activated Endothelium

Adapted from Ross R. N Engl J Med 1999;362:115–126 Endothelial Dysfunction in Atherosclerosis Upregulation of endothelial adhesion molecules Upregulation of endothelial adhesion molecules Increased endothelial permeability Increased endothelial permeability Migration of leukocytes into the artery wall Migration of leukocytes into the artery wall Leukocyte adhesion Leukocyte adhesion

Adapted from Ross R. N Engl J Med 1999;362:115–126 Fatty Streak Formation in Atherosclerosis Formation of foam cells Formation of foam cells Activation of T cells Adherence and aggregation of platelets Adherence and aggregation of platelets Adherence and entry of leukocytes Adherence and entry of leukocytes Migration of smooth muscle cells Migration of smooth muscle cells

Adapted from Ross R. N Engl J Med 1999;362:115–126 Formation of the Complicated Atherosclerotic Plaque Formation of the fibrous cap Formation of the fibrous cap Accumulation of macrophages Accumulation of macrophages Formation of necrotic core Formation of necrotic core

Adapted from Ross R. N Engl J Med 1999;362:115–126 The Unstable Atherosclerotic Plaque Rupture of the fibrous cap Rupture of the fibrous cap Thinning of the fibrous cap Thinning of the fibrous cap Haemorrhage from plaque microvessels Haemorrhage from plaque microvessels

Adapted from Weissberg PL. Eur Heart J Supplements 1999:1:T13–18 Atherosclerotic Plaque Rupture and Thrombus Formation Intraluminal thrombus Growth of thrombus Intraplaque thrombus Lipid pool Blood Flow

Adapted from Libby P. Circulation 1995;91:2844–2850 The Synthesis and Breakdown of The Synthesis and Breakdown of Atheromatous Plaques

Adapted from Libby P. Circulation 1995;91:2844–2850 The Vulnerable Atherosclerotic Plaque

Clinical Manifestations of Atherosclerosis Coronary heart disease Angina pectoris, myocardial infarction, sudden cardiac death Cerebrovascular disease Transient ischaemic attacks, stroke Peripheral vascular disease Intermittent claudication, gangrene Coronary heart disease Angina pectoris, myocardial infarction, sudden cardiac death Cerebrovascular disease Transient ischaemic attacks, stroke Peripheral vascular disease Intermittent claudication, gangrene

Section 3 Lipoproteins and Lipid Metabolism

Structure of Lipoproteins Free cholesterol Phospholipid Triglyceride Cholesteryl ester Apolipoprotein

Classification of Lipoproteins Based on density: Chylomicrons Very low-density lipoprotein (VLDL) Intermediate-density lipoprotein (IDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL) Based on density: Chylomicrons Very low-density lipoprotein (VLDL) Intermediate-density lipoprotein (IDL) Low-density lipoprotein (LDL) High-density lipoprotein (HDL)

LDL-CholesterolLDL-Cholesterol Strongly associated with atherosclerosis and CHD events 10% increase results in a 20% increase in CHD risk Risk associated with LDL-C is increased by other risk factors: low HDL-cholesterol smoking hypertension diabetes Strongly associated with atherosclerosis and CHD events 10% increase results in a 20% increase in CHD risk Risk associated with LDL-C is increased by other risk factors: low HDL-cholesterol smoking hypertension diabetes

TriglyceridesTriglycerides Associated with increased risk of CHD events Link with increased CHD risk is complex may be related to: low HDL levels highly atherogenic forms of LDL-cholesterol hyperinsulinaemia/insulin resistance procoagulation state hypertension abdominal obesity May have accompanying dyslipidaemias Normal triglyceride levels <150 mg/dL Very high triglycerides (>1000 mg/dL, 11.3 mmol/L) increase pancreatitis risk Associated with increased risk of CHD events Link with increased CHD risk is complex may be related to: low HDL levels highly atherogenic forms of LDL-cholesterol hyperinsulinaemia/insulin resistance procoagulation state hypertension abdominal obesity May have accompanying dyslipidaemias Normal triglyceride levels <150 mg/dL Very high triglycerides (>1000 mg/dL, 11.3 mmol/L) increase pancreatitis risk

HDL-CholesterolHDL-Cholesterol HDL-cholesterol has a protective effect for risk of atherosclerosis and CHD The lower the HDL-cholesterol level, the higher the risk for atherosclerosis and CHD low level (<40 mg/dL) increases risk HDL-cholesterol tends to be low when triglycerides are high HDL-cholesterol is lowered by smoking, obesity and physical inactivity HDL-cholesterol has a protective effect for risk of atherosclerosis and CHD The lower the HDL-cholesterol level, the higher the risk for atherosclerosis and CHD low level (<40 mg/dL) increases risk HDL-cholesterol tends to be low when triglycerides are high HDL-cholesterol is lowered by smoking, obesity and physical inactivity

ApolipoproteinsApolipoproteins Main protein content of lipoproteins Functions include: Facilitation of lipid transport Activation of three enzymes in lipid metabolism lecithin cholesterol acyltransferase (LCAT) lipoprotein lipase (LPL) hepatic triglyceride lipase (HTGL) Binding to cell surface receptors Main protein content of lipoproteins Functions include: Facilitation of lipid transport Activation of three enzymes in lipid metabolism lecithin cholesterol acyltransferase (LCAT) lipoprotein lipase (LPL) hepatic triglyceride lipase (HTGL) Binding to cell surface receptors

Intestine Skeletal muscle Adipose tissue Adipose tissue Chylomicron remnant Chylomicron remnant Remnant receptor Remnant receptor Liver Dietary triglycerides and cholesterol Dietary triglycerides and cholesterol LP lipase Exogenous Pathway of Lipid Metabolism Exogenous Pathway of Lipid Metabolism to atheroma FFA

Endogenous Pathway of Lipid Metabolism Endogenous Pathway of Lipid Metabolism IDL Large VLDL Large VLDL Small VLDL Small VLDL LDL receptor LDL receptor Liver LPL Lipoprotein lipase HL Hepatic lipase LDL LPL LPL LPL HL HL HL

Reverse cholesterol transport Reverse Cholesterol Transport Peripheral tissues Cell membrane VLDL, IDL, LDL LDL receptor LCAT CETP FC CE CE TG HDL HDL3 TG CE Free cholesterol Triglycerides Cholesterol esters CETP Cholesteryl ester transfer protein LCAT Lecithin cholesterol acyl transferase SRB1 FC ABCA1 Liver

Section 4 Guidelines and Unmet Need

Joint European Guidelines: ESC, EAS, ESH, ISBM, ESGP/FM, EHN Estimate absolute CV risk using chart and initial TC value Absolute CHD risk <20% over 10 years, TC 5 mmol/L Absolute CHD risk 20% over 10 years Absolute CHD risk 20% over 10 years Measure fasting lipids, give lifestyle advice, with repeat lipids after 3 months Measure fasting lipids, give lifestyle advice, with repeat lipids after 3 months Lifestyle advice Aim: TC<5 mmol/L and LDL-C <3.0 mmol/L Follow-up at 5-year intervals Lifestyle advice Aim: TC<5 mmol/L and LDL-C <3.0 mmol/L Follow-up at 5-year intervals TC <5 mmol/L and LDL-C <3.0 mmol/L Maintain lifestyle advice with annual follow-up TC <5 mmol/L and LDL-C <3.0 mmol/L Maintain lifestyle advice with annual follow-up TC 5 mmol/L and/or LDL-C 3 mmol/L Maintain lifestyle advice with drug therapy TC 5 mmol/L and/or LDL-C 3 mmol/L Maintain lifestyle advice with drug therapy Adapted from Wood D et al. Atherosclerosis 1998;140:199–270

NCEP ATP III: Focus on Multiple Risk factors Uses Framingham projections of 10-year absolute CHD risk to identify certain patients with 2 risk factors for more intensive treatment Raises persons with diabetes without CHD to the level of CHD risk equivalent Identifies persons with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified TLC* Uses Framingham projections of 10-year absolute CHD risk to identify certain patients with 2 risk factors for more intensive treatment Raises persons with diabetes without CHD to the level of CHD risk equivalent Identifies persons with multiple metabolic risk factors (metabolic syndrome) as candidates for intensified TLC* National Cholesterol Education Program, Adult Treatment Panel III, JAMA 2001:285;2486–2497 *TLC: therapeutic lifestyle changes

NCEP ATP III: Modifications of Lipid Classification Identifies LDL-cholesterol <100 mg/dL (2.6 mmol/L) as optimal Raises categorical low HDL-cholesterol from <35 to <40 mg/dL (<0.9 to <1 mmol/L) Lowers TG cutpoints to: normal: <150 mg/dL (<1.7 mmol/L) borderline high: 150–199 mg/dL (1.7–2.2 mmol/L) high: 200–499 mg/dL (2.2–5.6 mmol/L) very high: 500 mg/dL (5.6 mmol/L) Identifies LDL-cholesterol <100 mg/dL (2.6 mmol/L) as optimal Raises categorical low HDL-cholesterol from <35 to <40 mg/dL (<0.9 to <1 mmol/L) Lowers TG cutpoints to: normal: <150 mg/dL (<1.7 mmol/L) borderline high: 150–199 mg/dL (1.7–2.2 mmol/L) high: 200–499 mg/dL (2.2–5.6 mmol/L) very high: 500 mg/dL (5.6 mmol/L) National Cholesterol Education Program, Adult Treatment Panel III, JAMA 2001:285;2486–2497

NCEP ATP III Guidelines Patients with Drug therapy considered if LDL -C * TLC: therapeutic lifestyle changes National Cholesterol Education Program, Adult Treatment Panel III. JAMA 2001;285:2486–2497 Initiate TLC* if LDL -C LDL-C treatment goal 0- 1 risk factors 160 mg/dL 160 mg/dL 190 mg/dL (160– 189 mg/dL: drug optional) <160 mg/dL <160 mg/dL 2 risk factors (10- year risk 20%) 130 mg/dL 130 mg/dL - 10 year risk 10 – 20%: 130 mg/dL 10-year risk <10%: 160 mg/dL <130 mg/dL <130 mg/dL CHD and CHD risk equivalents (10- year risk >20%) 100 mg/dL 100 mg/dL <100 mg/dL <100 mg/dL 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L 130 mg/dL drug optional) (100–129 mg/dL:

NCEP ATP III: LDL-Cholesterol Goals National Cholesterol Education Program, Adult Treatment Panel III, JAMA 2001:285;2486–2497 CHD or CHD risk equivalents <2 risk factors 2 risk factors LDL-cholesterol level Target 100 mg/dL Target 130 mg/dL Target 160 mg/dL 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L

NCEP ATP III Guidelines Increase the Number of Patients Eligible for Treatment RiskNCEP ATP II NCEP ATP III % increase in drug-eligible patients HighModerateLowTotal8,61219,5551,26429,43114,71323,6631,26439, Adapted from Davidson MH. Am J Cardiol 2002;89(Suppl 5A):1C–2C

L-TAP: Achieving NCEP ATP II Goal on Lipid-modifying Therapy Percentage of patients 85% of patients received lipid- modifying therapy 85% of patients received lipid- modifying therapy 39% of patients receiving lipid-modifying therapy reached NCEP ATP II LDL-C goal 39% of patients receiving lipid-modifying therapy reached NCEP ATP II LDL-C goal * LDL-C 100 mg/dL (n=4888) (n=4137) <20% of CHD patients who receiving lipid-modifying therapy reached NCEP ATP II LDL-C goal* <20% of CHD patients who receiving lipid-modifying therapy reached NCEP ATP II LDL-C goal* (n=1352) Adapted from Pearson TA et al. Arch Intern Med 2000;160:459–467

EUROASPIRE II: Achieving Joint European TC Goal Percentage of patients 61% of high-risk patients* received lipid-modifying therapy 61% of high-risk patients* received lipid-modifying therapy 51% of patients reached Joint European TC goal** 51% of patients reached Joint European TC goal** *CABG, PTCA, MI or ischaemia, ** TC <5 mmol/L Adapted from EUROASPIRE II. Euro Heart J 2001;22:554–772

Section 5 Statins and Lipid-modifying Therapies

Effect of lipid-modifying therapies on lipids Therapy Bile acid sequestrants Nicotinic acid Fibrates (gemfibrozil) Probucol Statins* Ezetimibe TC–total cholesterol, LDL–low density lipoprotein, HDL–high density lipoprotein, TG–triglyceride. * Daily dose of 40mg of each drug, excluding rosuvastatin. TC Down 20% Down 25% Down 15% Down 25% Down 15–30% LDL Down 15–30% Down 25% Down 5–15% Down 10–15% Down 24–50% Down 15–20% HDL Up 3–5% Up 15–30% Up 20% Down 20–30% Up 6–12% Up 4–9% TG Neutral or up Down 20–50% Down 20–50% Neutral Down 10–29% Patient tolerability Poor Poor to reasonable Good Reasonable Good Adapted from Yeshurun D, Gotto AM. Southern Med J 1995;88(4):379–391, Knopp RH. N Engl J Med 1999;341:498–511, Gupta EK, Ito MK. Heart Dis 2002;4:399–409

Mechanism of Action of Statins: Cholesterol Synthesis Pathway acetyl CoA HMG-CoA mevalonic acid mevalonate pyrophosphate isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate squalene cholesterol dolichols ubiquinones HMG-CoA synthase HMG-CoA reductase Squalene synthase X X Statins

Statin Protein binding (%) Protein binding (%) Metabolised by CYP450 Metabolised by CYP450 Lipophilic Half- life (h) Half- life (h) rosuvastatin atorvastatin simvastatin pravastatin fluvastatin rosuvastatin atorvastatin simvastatin pravastatin fluvastatin ~90% >98% 95–8% ~50% >98% ~90% >98% 95–8% ~50% >98% No Yes No Yes No Yes No Yes No Yes No Yes No ~19 ~15 ~3 ~2 ~3 ~19 ~15 ~3 ~2 ~3 Pharmacokinetics of Statins Adapted from Horsmans Y. Eur Heart J Supplements 1999;1(Suppl T):T7–12, Vaughan CJ et al. J Am Coll Cardiol 2000;35:1–10. Rosuvastatin data from Core Data Sheet

Effects of Statins on Lipids rosuvastatin (10 mg) atorvastatin (10 mg) simvastatin (20 mg) pravastatin (20 mg) fluvastatin (20 mg) rosuvastatin (10 mg) atorvastatin (10 mg) simvastatin (20 mg) pravastatin (20 mg) fluvastatin (20 mg) LDL-C % change LDL-C % change HDL-C % change HDL-C % change TG % change TG % change Adapted from Product Data Sheets.

Pleiotropic Effects of Statins Improving or restoring endothelial function Enhancing the stability of atherosclerotic plaques Decreasing oxidative stress Decreasing vascular inflammation Anti-thrombotic effects Improving or restoring endothelial function Enhancing the stability of atherosclerotic plaques Decreasing oxidative stress Decreasing vascular inflammation Anti-thrombotic effects Adapted from Takemoto M, Liao JK. Arterioscler Thromb Vasc Biol 2001;21:1712–1719

Section 6 Key Statin Trials

Design of Key Statin Trials 4S 1 WOSCOPS 2 CARE 3 LIPID 4 AFCAPS/ TexCAPS 5 HPS 6 ASCOT-LLA 7 4S 1 WOSCOPS 2 CARE 3 LIPID 4 AFCAPS/ TexCAPS 5 HPS 6 ASCOT-LLA 7 Statin Existing CHD Patients Cholesterol Follow-up (years) Follow-up (years) simvastatin 20 mg od pravastatin 40 mg od pravastatin 40 mg od pravastatin 40 mg od lovastatin 40 mg od simvastatin 20 mg od pravastatin 40 mg od pravastatin 40 mg od pravastatin 40 mg od lovastatin 40 mg od Yes No MI, angina (5%) Yes No Yes No MI, angina (5%) Yes No Raised Mean LDL-C 4.87 mmol/L, 188 mg/dL Raised Mean LDL-C 4.97 mmol/L, 192 mg/dL Average Mean LDL-C 3.59 mmol/L, 139 mg/dL Average Mean LDL-C 3.80 mmol/L, 147 mg/dL Average Mean LDL-C 3.89 mmol/L, 150 mg/dL Raised Mean LDL-C 4.87 mmol/L, 188 mg/dL Raised Mean LDL-C 4.97 mmol/L, 192 mg/dL Average Mean LDL-C 3.59 mmol/L, 139 mg/dL Average Mean LDL-C 3.80 mmol/L, 147 mg/dL Average Mean LDL-C 3.89 mmol/L, 150 mg/dL male and female, aged 35– male, aged 45– male and female, aged 21– male and female, aged 31– male and female, aged 45– male and female, aged 35– male, aged 45– male and female, aged 21– male and female, aged 31– male and female, aged 45–73 Study Yes In some patients simvastatin 40 mg od male and female, aged 40–80 Low/average Mean LDL-C 3.4 mmol/L, 130 mg/dL atorvastatin 10 mg od Low/average Mean LDL-C 3.4 mmol/L, 130 mg/dL male and female, aged 40–79

Key Statin Trials and Spectrum of Risk 4S 1 LIPID 2 CARE 4 WOSCOPS 6 AFCAPS/TexCAPS 7 CHD/high cholesterol CHD/average to high cholesterol CHD/average cholesterol No MI/high cholesterol No CHD/average cholesterol HPS 3 CHD*/average to high cholesterol *CHD or CHD risk equivalent, e.g. diabetes Increasing absolute CHD risk ASCOT-LLA 5 Some patients with CHD/ average cholesterol

simvastatin (n=2221) simvastatin (n=2221) 4S Cardiovascular Endpoints Post-MI or Angina Patients with Raised Cholesterol Number of events Outcomes placebo (n=2223) placebo (n=2223) Risk reduction (%) Risk reduction (%) p-value Total mortality* Coronary death Major coronary events PCTA/CABG Total mortality* Coronary death Major coronary events PCTA/CABG <0.001 * primary endpoint The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389

4S: Total Mortality Proportion alive Years since randomisation placeboplacebo simvastatinsimvastatin Log rank p= This improvement in survival is accounted for by the 42% reduction in coronary death. The Scandinavian Simvastatin Survival Study Group. Lancet 1994;344:1383–1389

placebo (n=3293) placebo (n=3293) pravastatin (n=3302) pravastatin (n=3302) Risk reduction (%) Risk reduction (%) p-value Non-fatal MI/CHD death* CHD death Non-fatal MI PCTA/CABG Stroke All cardiovascular deaths Total mortality # Non-fatal MI/CHD death* CHD death Non-fatal MI PCTA/CABG Stroke All cardiovascular deaths Total mortality # <0.001 ns < ns <0.001 ns < ns * primary endpoint # study not powered to detect differences in this endpoint * primary endpoint # study not powered to detect differences in this endpoint WOSCOPS: Cardiovascular Endpoints Subjects with No Previous MI but Raised Cholesterol Outcomes Number of events Shepherd J et al. N Engl J Med 1995;333:1301–1307

WOSCOPS: Non-fatal MI and CHD Death YearsYears Percent with event pravastatin (n=3302) placebo (n=3293) 31% relative risk reduction p< % relative risk reduction p<0.001 Shepherd J et al. N Engl J Med 1995;333:1301–1307

placebo (n=2078) placebo (n=2078) pravastatin (n=2081) pravastatin (n=2081) Risk reduction (%) Risk reduction (%) p-value Non-fatal MI/CHD death* CHD death Non-fatal MI PCTA/CABG Unstable angina Stroke Non-fatal MI/CHD death* CHD death Non-fatal MI PCTA/CABG Unstable angina Stroke ns ns CARE: Cardiovascular Endpoints Post-MI Patients with Average Cholesterol * primary endpoint Outcomes Number of events Sacks FM et al. N Engl J Med 1996;335:1001–1009

CARE: Non-fatal MI or CHD Death Incidence % Years Change in risk, 24% reduction p=0.003 pravastatinpravastatin placeboplacebo Sacks FM et al. N Engl J Med 1996;335:1001–1009

placebo (n=4502) placebo (n=4502) pravastatin (n=4512) pravastatin (n=4512) Risk reduction (%) Risk reduction (%) p-value CHD death* CVD death All-cause mortality CHD death or non- fatal MI Any MI PCTA or CABG Hosp. for unstable angina Stroke CHD death* CVD death All-cause mortality CHD death or non- fatal MI Any MI PCTA or CABG Hosp. for unstable angina Stroke < < * primary endpoint Outcomes LIPID: Cardiovascular Endpoints Post-MI or Unstable Angina Patients with Average/raised Cholesterol Number of events LIPID. N Engl J Med 1998;339:1349–1357

LIPID: Cumulative Risk of Death from CHD Years after randomisation Cumulative risk (%) pravastatinpravastatin placeboplacebo 24% risk reduction p< % risk reduction p< LIPID. N Engl J Med 1998;339:1349–1357

AFCAPS/TexCAPS: Cardiovascular Endpoints Subjects with No History of CHD and Average Cholesterol placebo (n=3301) placebo lovastatin (n=3304) lovastatin Risk reduction (%) Risk p-value Fatal or non-fatal MI + unstable angina + sudden cardiac death* Revascularisations Fatal and non-fatal MI Unstable angina Fatal or non-fatal MI + unstable angina + sudden cardiac death* Revascularisations Fatal and non-fatal MI Unstable angina < < * primary endpoint OutcomesOutcomes Number of events Downs JR et al. J Am Med Assoc 1998;279:1615–1622

AFCAPS/TexCAPS: Fatal/Non-fatal MI, Sudden Cardiac Death, Unstable Angina Cumulative incidence Years of follow-up 0.0 > % risk reduction p<0.001 lovastatinlovastatin placeboplacebo Downs JR et al. J Am Med Assoc 1998;279:1615–1622

Meta-analysis of 38 primary and secondary intervention trials Benefits of Cholesterol Lowering Total mortality (p=0.004) CHD mortality (p=0.012) % in cholesterol reduction Mortality log odds ratio Adapted from Gould AL et al. Circulation. 1998;97:946–952

HPS: Statin Benefits Patients with Low Baseline Cholesterol Levels RR - relative reduction vs. placebo -13% RR P= % RR P= % RR p< % RR p< % RR p< % RR p< Adapted from HPS Collaborative Group, Lancet 2002;360:7–22

ASCOT-LLA: Statin Benefits Hypertensive Patients with Average or Low Baseline Cholesterol Levels Adapted from Sever PS et al. Lancet 2003;361:1149–1158 placebo (n=5137) placebo atorvastatin (n=5168) atorvastatin Hazard ratio p-value * primary endpoint, # includes silent MI, excludes silent MI OutcomesOutcomes Number of events Non-fatal MI # plus fatal CHD* Total CV events and procedures Total coronary events Non-fatal MI plus fatal CHD Fatal and non-fatal stroke Non-fatal MI # plus fatal CHD* Total CV events and procedures Total coronary events Non-fatal MI plus fatal CHD Fatal and non-fatal stroke

Section 7 Diabetes: a Risk Factor for CHD?

Diabetes Mellitus One of the most common non-communicable diseases Fourth or fifth leading cause of death in most developed countries More than 177 million people with diabetes worldwide Incidence of diabetes is increasing – estimated to rise to 300 million by 2025 expected to triple in Africa, the Eastern Mediterranean and Middle East, and South-East Asia to double in the Americas to almost double in Europe One of the most common non-communicable diseases Fourth or fifth leading cause of death in most developed countries More than 177 million people with diabetes worldwide Incidence of diabetes is increasing – estimated to rise to 300 million by 2025 expected to triple in Africa, the Eastern Mediterranean and Middle East, and South-East Asia to double in the Americas to almost double in Europe Adapted from: International Diabetes Federation website

The Chronic Complications of Diabetes Mellitus Macrovascular complications: Heart disease Leading cause of diabetes related deaths (increases mortality and stroke by 2 to 4 times) Microvascular complications: Retinopathy Leading cause of adult blindness Nephropathy Accounts for 43% of new cases of ESRD Neuropathy 60–70% of patients with diabetes have nervous system damage Macrovascular complications: Heart disease Leading cause of diabetes related deaths (increases mortality and stroke by 2 to 4 times) Microvascular complications: Retinopathy Leading cause of adult blindness Nephropathy Accounts for 43% of new cases of ESRD Neuropathy 60–70% of patients with diabetes have nervous system damage Adapted from National Diabetes Statistics US 2000

UKPDS: Typical Lipid Profile in Patients with Diabetes Compared with No Diabetes Adapted from UKPDS. Diabetes Care 1997;20:1683–1687 p<0.001 MenWomen no DM DM no DM Men Women DM no DM DM no DM p<0.001 Men Women Men DM no DM DM Women

PROCAM: Combination of Risk Factors Increases Risk of MI None Hypertension only Diabetes only Hypertens + diabetes Dyslipidaemia Dyslipidaemia + hypertens +/- diabetes Prevalence (%): Adapted from Assman G, Schulte H. Am Heart J 1988;116:1713–1724

Adapted from Malmberg K et al. Circulation 2000;102:1014–1019 OASIS:Patients with Diabetes at Similar Risk to No Diabetes with CVD OASIS: Patients with Diabetes at Similar Risk to No Diabetes with CVD

BARI: Diabetes Results in Less Favourable Outcome After Angioplasty Than No Diabetes No diabetes DiabetesDiabetes 5-year mortality (%) CABG PTCA Adapted from BARI Investigators. N Engl J Med 1996:335:217–225

NHANES: Smaller Changes in CAD Mortality Rates in Patients with Diabetes than No Diabetes Over Time *p<0.001 vs. baseline * Diabetes No diabetes Adapted from Gu K et al. JAMA;281:1291–1297

Section 8 The Metabolic Syndrome

The Metabolic Syndrome and Associated CVD Risk Factors AtherosclerosisAtherosclerosis Endothelial Dysfunction Hypertension Abdominal obesity Hyperinsulinaemia Dyslipidaemia high TGs small dense LDL low HDL-C Diabetes Hypercoagulability Insulin Resistance

NCEP ATP III: The Metabolic Syndrome <40 mg/dL (1.0 mmol/L) <50 mg/dL (1.3 mmol/L) Men Women >102 cm (>40 in) >88 cm (>35 in) Men Women 110 mg/dL (6.0 mmol/L) Fasting glucose 130/85 mm Hg Blood pressure HDL-C 150 mg/dL (1.7 mmol/L) TG Abdominal obesity (Waist circumference) Defining LevelRisk Factor Diagnosis is established when 3 of these risk factors are present National Cholesterol Education Program, Adult Treatment Panel III, JAMA 2001:285;2486–2497

WHO: The Metabolic Syndrome A working definition is glucose intolerance, IGT or diabetes mellitus and/or insulin resistance together with two or more of the following: Impaired glucose regulation or diabetes Insulin resistance Raised arterial pressure 160/90 mmHg Raised plasma triglycerides (1.7 mmol/L, 150 mg/dL) and/or low HDL-C (men <0.9 mmol/L, 35 mg/dl; women <1.0 mmol/L, 39 mg/dL) Central obesity Microalbuminuria (UAER 20 g/min or albumin: creatinine ratio 20 mg/g) Alberti KGMM, Zimmet PZ for the WHO. Diabet Med 1998:15;539–553

AIR: LDL Particle Size is Related to the Metabolic Syndrome p<0.001 Adapted from Hulthe J et al. Arterioscler Thromb Vasc Biol 2000;20:2140–2147

PARIS: CHD Mortality Increases with Increased Impaired Glucose Tolerance G <140 mg/dL IGT G 200 mg/dL Newly diagnosed diabetes G 200 mg/dL Newly diagnosed diabetes Known diabetes p<0.001 n=6055 n=690 n=158 n=135 Adapted from Eschwege E et al. Horm Metab Res 1995;17(Suppl):41–46 G - glucose

Section 9 Outcome Trials in Diabetes

Trials with Fibrates in Patients with Diabetes Frick MH et al. N Engl J Med 1987;317:1237–1245, Koskinen P et al. Diabetes Care 1992;15:820–825, Elkeles RS, Diamond JR, Poulter C et al. Diabetes Care 1998;21(4):641–648, Rubins HB et al. N Engl J Med 1999;341:410–418, DAIS Investigators. Lancet 2001;357:905–910 StudyEffectp-valueComment Helsinki Heart Study (gemfibrozil)75%eventsns Primary prevention; post-hoc subgroup analysis SENDCAP(bezafibrate)65%events0.01 Specifically conducted in Type 2 diabetes; post-hoc analysis for IHD VA-HIT(gemfibrozil)24%events0.05 Secondary intervention; pre-planned subgroup analysis DAIS(fenofibrate)40-42% focal angio changes 0.02 Specifically conducted in Type 2 diabetes; mixed primary and secondary intervention; angio study

Statins Reduce CHD Risk in Patients with Diabetes Study % LDL-C lowering % CHD risk reduction (overall) % CHD risk reduction (diabetes) Primary prevention AFCAPS/TexCAPS 1 (lovastatin; n=239) (p<0.001) 43 Secondary prevention CARE 2 (pravastatin; n=586) 4S 3 (simvastatin; n=202) LIPID 4 (pravastatin; n=782) * 25* 23 (p<0.001) 32 (p<0.001) (p=0.05) 55 (p=0.002) 19 * value for overall group

Adapted from Kreisberg RA. Am J Cardiol 1998;82:67U–73U 4S/CARE: LDL Lowering in Patients with Diabetes

Adapted from Pyörälä K et al. Diabetes Care 1997;20:614–620 4S: CHD Event Reduction in Patients with Diabetes

WOSCOPS: Statin Treatment Protects Against Development of Diabetes Total number of patients Patients developing diabetes % risk reduction p-value Adapted from Freeman DJ et al. Circulation 2001;103:357–362