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

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

Mean serum cholesterol mmol l-1 Cholesterol Levels and CHD Mortality 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

4S All-cause CHD Coronary mortality events revascularisation n Effect of Treatment All-cause CHD Coronary mortality events revascularisation n Diabetes* 483 -21% -42% -48% ns p=0.001 p=0.005 IFG** 678 -43% -38% -43% p=0.02 p=0.003 p=0.001 Non-diabetic 3237 -28% -32% -33% non IFG p=0.005 p<0.001 p<0.001 * fasting glucose 126 mg/dL (7.0 mmol/L) ** fasting glucose 110-125 mg/dL (6.0-6.9 mmol/L) Haffner et al, Arch Intern Med 1999;159:2661-7

4S Non-diabetic, IFG* Diabetes** non IFG Placebo Simva Placebo Simva Placebo Simva New CHD 26.2% 18.6% 30.4% 19.5% 37.5% 23.5% events % actively - 7.6% - 10.9% - 14.0% treated patients avoiding new CHD events * FBG 6.0-6.9 mmol/L ** FBG 7.0 mmol/L Haffner et al, Arch Intern Med 1999;159:2661-7

CARE CHD mortality n & morbidity p-value Diabetes 586 -25% <0.05 IFG** 342 -20% ns Non-diabetic 3104 -25% <0.001 Non-IFG * Expanded end-point ** Impaired fasting glucose 110-125 mg/dL Goldberg et al, Circulation 1998;98:2513-9

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

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

VA-HIT CHD & n stroke incidence p-value Diabetes 627 -24% 0.05 Non-diabetic 1904 -24% 0.009 Bloomfield et al, N Engl J Med 1999;341:410-8

* where resources permit (minimum standard of care >30%) 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%)

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

CARDS Study Design: Collaborative AtoRvastatin Diabetes Study Patient Population Type 2 diabetics No prior MI or CAD Other risk factors + Lipid profile: LDL-C <159 mg/dL (4.14 mmol/L) TG <600 mg/dL (6.78 mmol/L) Collaboration in the UK with DUK and NHS d/b PBO 2,838 Patients atorvastatin 10 mg Min 4 years The CARDS Study (Collaborative Atorvastatin Diabetes Study) is a second study in the clinical program looking at 2050 type II diabetics in the United Kingdom in association with the British Diabetes Association and the National Health Service. These primary prevention patients, with no prior history of Myocardial Infarction or Coronary Artery Disease, but with additional risk factors, will be randomised to either atorvastatin 10mg or placebo. They will be followed for 4 years of treatment and the primary endpoint will be the assessment of time to a major cardiovascular event. Primary Endpoint Time to major CV event (CHD death, non-fatal MI, recanalization, CABG, Stroke) P00000.CLIENT.DRUG.Xxxxxxxxxxx.XX 9/11/2018 6:36 PM 34

CARDS - 132 active sites This map illustrates the broad distribution of CARDS sites . The study has expanded considerably over the past 2 years and grown to a total of 134 sites across the UK and Ireland. P00000.CLIENT.DRUG.Xxxxxxxxxxx.XX 9/11/2018 6:36 PM

CARDS sites - distribution chart illustrate varied mix of CARDS sites involved across the UK and Ireland today. Although we have introduced many primary care sites in recent years, HOSPITALS still make up the majority of the sites. Together with the commercial sites also involved (Synexus and Chiltern), right mix of sites to ensure not only timely recruitment, also quality data ongoing patient care. P00000.CLIENT.DRUG.Xxxxxxxxxxx.XX 9/11/2018 6:36 PM

CARDS Study – Current status 2838 Randomised patients 2298 ongoing in treatment 436 withdrawn from treatment 106 Deaths Current withdrawal rate = 15.3 %