1. The Global Challenge Peter Sever The International Centre for Circulatory Health National Heart and Lung Institute Imperial College London

3. Cuna Indians Yanamamo Indians Congo pygmies Kalahari bushmen Kenyan nomads Pacific Atoll Polynesians New Guinean Highlanders

4. 2003 - 17 million deaths from Cardiovascular disease. (30% of all global deaths) 7.2 million due to ischaemic heart disease 5.5 million due to cerebrovascular disease 4.0 million due to hypertensive and other heart conditions 20 million survive an MI or stroke annually The Global Burden of Cardiovascular Disease

5. The UK Burden of Cardiovascular Disease 200,000 deaths per annum from CVD (35% of all deaths) 95,000 deaths from CHD 55,000 deaths from stroke Estimated total cost to the UK economy £30.7 billion per annum of which 47% (£14.4 billion) are direct health care costs

6. * Contribution of Risk Factors to Burden of Disease Mortality* Percentage of Mortality Attributable to Risk Factors *Based on The World Health Report 2003. Yach et al. JAMA. 2004;291:2616-2622. Developing countries Developed countries Blood pressure Tobacco Underweight Alcohol Cholesterol Unsafe sex Overweight Unsafe water, sanitation, hygiene Low fruit and vegetable intake Indoor smoke from solid fuels Physical inactivity

7. The Global rise in Cardiovascular Disease Increase in energy dense, nutrient poor foods high in saturated fat, salt and refined carbohydrates. Decrease in physical activity lead to Increases in BP and cholesterol, obesity and type 2 diabetes Increase in tobacco smoking

10. Changes in risk factors in the UK Reductions in population BP ( by 5-10 mmHg systolic depending on age) Reduction in population levels of cholesterol ( by 0.5 – more than 1 mmol/L) Tobacco consumption reduced ( by approx 50%) but Dramatic increase in obesity and type 2 diabetes ( increase by 74% in past 6 years)

11. 2009 Death rates from CHD for people aged under 65: projections for England Impact of a x4 increase in CHD events in those with diabetes ?

12. Impact of targeted pharmacological intervention: Blood Pressure and Cholesterol Estimated usual BP or Cholesterol Population wide reduction Targeted intervention Frequency

13. Coronary Heart Disease Systolic blood pressure difference between randomised groups (mmHg) Relative risk of CHD 0.25 0.50 0.75 1.00 1.25 1.50 -10-8-6-4-2024

14. Stroke 0.25 0.50 0.75 1.00 1.25 1.50 -10-8-6-4-2024 Systolic blood pressure difference between randomised groups (mmHg) Relative risk of stroke

15. Proportional benefit independent of baseline BP

16. Relative risk reductions in CHD and Stroke events in blood pressure difference trials according to pretreatment systolic blood pressure CHD eventsStroke events Law, Morris and Wald. BMJ 2009:338;1669

17. mm Hg 0 Time (years) Baseline0.511.522.533.544.555.5 Last visit 140 160 180 atenolol  thiazide amlodipine  perindopril 137.7 136.1 Mean difference 2.7 163.9 164.1. Sever P, Poulter N et al. Am J Cardiol. 2005;96 [suppl]:39F-44F 18 15 12 9 6 3 CHD Stroke Event Rate* *per 1000 patient years not randomised to statin ASCOT- BPLA: Time to benefit Systolic Blood Pressure

18. Groups Events (%) TreatmentControl RR & CI (Treatment : Control) Prior disease: Post-MI1681 (11·7)2207 (15·4) Other CHD568 (8·7)744 (11·4) None1088 (4·5)1469 (6·1) Age (years): ≤651671 (6·1)2344 (8·5) >651666 (9·5)2076 (11·9) Gender: Male2686 (7·8)3630 (10·6) Female651 (6·1)790 (7·3) Treated hypertension: Yes2038 (8·2)2596 (10·4) No1299 (6·4)1824 (9·1) History of diabetes: Yes776 (8·3)979 (10·5) No2561 (7·2)3441 (9·6) Diastolic BP: ≤90 mmHg2711 (7·8)3590 (10·3) >90 mmHg618 (6·1)827 (8·2) 0·51·01·5 TreatmentControl better p < 0·00001 Heterogeneity/trend p-value p = 0·2 p = 0·01 p = 0·1 p = 0·2 p = 0·8 CTT Collaboration: Effects on major coronary events per mmol/L LDL cholesterol reduction subdivided by baseline prognostic factors Overall3337 (7·4)4420 (9·8) 0·77 (0·74 – 0·80)

19. 36% reduction ASCOT - LLA Primary End Point: Nonfatal MI and Fatal CHD HR = 0.64 (0.50-0.83) Atorvastatin 10 mgNumber of events100 PlaceboNumber of events 154 p=0.0005 Sever P, Dahlof B,Poulter N, Wedel H et al. Lancet 2003 :361;1149-58

20. ASCOT: Post-hoc Analysis of Benefit Across the whole Cholesterol Range The primary endpoint: TC Range (mmol/L) Hazard Ratio95% CIP Value <5.00.6280.369-1.0950.098 5.0-5.90.6150.421-0.8970.011 ≥6.00.6890.451-1.0540.084 Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58 Thus proportional benefit independent of baseline cholesterol

21. Censoring Time Risk Reduction Event Rate (%)Atorvastatin Placebo 83 2.4 14.2 67 5.5 16.6 48 7.5 14.3 45 6.6 12.0 38 5.9 9.5 36 6.0 9.4 Hazard Ratios (95% CI) Atorvastatin betterPlacebo better 30 days 90 days 180 days 1 Year 2 Years End of Study ASCOT-LLA : CHD events Time to benefit * * Per 1000 patient years

22. Benefits of combined intervention

23. Most Patients Have Overlapping CV Risk Factors Of all Hypertensives 65% have dyslipidemia 16% have type 2 diabetes 45% are overweight/obese Of all Dyslipidemics 48% have hypertension 14% have type 2 diabetes 35% are overweight/obese Of all Type 2 Diabetics 60% have hypertension 60% have dyslipidemia 90% are overweight/obese Hypertension Type 2 Diabetes Dyslipidemia Multiple comorbidities increases risk 400-700% 1 Based on Framingham risk

24. ASCOT benefits from combined blood pressure and lipid-lowering Reduction in risk of non-fatal MI and fatal CHD using Framingham model for baseline estimates ** Framingham risk estimate from baseline data ( n=10,305) Final risk in those assigned amlodipine/perindopril and atorvastatin Relative risk reduction 22.8*4.8*79% * per 1000 patient years ** Variables include SBP, smoking status, total and HDL-cholesterol, presence or absence of LVH, age, gender, presence or absence of diabetes. No correction for on- treatment blood pressure

25. A population based intervention : The rationale Age is the most important risk factor (95% MI and stroke deaths occur in over 55 yrs) Many subjects are at substantial risk with numerical values of risk factors within the so called “normal” range. Multiple risk factor intervention required to deliver maximum effect

26. Treat risk factor or Treat risk ? Subject 1 55 year Asian male Smoker BP 140/85 Total cholesterol 5.8 mmol/l HDL cholesterol 0.8 mmol/L 10 yr risk of CVD 25 35 % Treatment none Subject 2 45 year Caucasian female Non smoker BP 165/95 Total cholesterol 5.0 mmol/L HDL cholesterol 1.5 mmol/L 10 yr risk of CVD < 10% Treatment antihypertensive drugs

27. The most important BMJ for 50 years? Richard Smith 28 th June 2003 A pill to prevent 80% of CVD !

28. Treatments Absolute risk over 5 years  25%   20% Overall  55% Cardiovascular events Major side effects Estimated absolute risks of major clinical events over a 5 year period

29. The “Red Heart Pill” - a cardiovascular polypill Dr Reddy’s Laboratory, India 4 component, multidrug, once daily, CVD prevention pill(s)

30. Patients ≥7.5% 5 year cardiovascular risk & no clear indication or contraindication to aspirin, simvastatin, lisinopril or h’c’thiazide (n=5,000) Polypill: aspirin 75, simvastatin 20, lisinopril 10, h’c’thiazide 12.5 (n=2,500) Placebo (n = 2,500) Active 4 week run-in Follow-up visits 3, 6 & 12 months; then six monthly until end of trial Last follow-up visit 3 years after last patient randomised 4 week post trial assessment Polypill – 1 o prevention trial schema Randomisation ~5000 patients, no CVD history, ≥ 7.5% 5-yr risk 3-5 years follow-up Australia, Brazil, India,China the Netherlands, New Zealand, UK, USA 1 o outcome: Major CV events 90% power to demonstrate a 40% reduction in the 1 outcome 0 Rogers, Thom, Poulter et al 2009

31. Can we prevent diabetes and associated cardiovascular disease ?

32. SOURCE: DIABETES ATLAS THIRD EDITION © INTERNATIONAL DIABETES FEDERATION, 2006 GLOBAL PROJECTIONS FOR THE NUMBER OF PEOPLE WITH DIABETES (20-79 AGE GROUP), 2007 and 2025 (MILLIONS)

33. Type 2 Diabetes Type 2 Diabetes >250 million world wide Increase risk of CVD (x 2-4) Most common cause of blindness in middle age and of renal failure 7.5 million new cases per year Global costs $230 billion 2.3 million cases in UK UK costs £1 million per hour 10% UK NHS budget

34. GLADIATOR Global intervention to prevent diabetes and cardiovascular disease RATIONALE “Whilst lifestyle changes including inappropriate calorie intake and lack of exercise are major contributing factors which warrant the introduction of international programmes for intervention, history and reality dictate that this will only achieve limited success. From experience with other risk factors for vascular disease the only practical solution is pharmacological intervention ”

35. GLADIATOR TRIAL Drug treatment to prevent diabetes needs to recognize that in most cases people are at additional risk because of associated levels of blood pressure and cholesterol and that the consequent vascular disease is a result of the interaction of multiple risk factors

36. GLADIATOR TRIAL There is extensive evidence from large scale studies of effective, safe and well tolerated drugs to lower blood pressure, cholesterol and blood sugar No previous study has attempted to prevent diabetes and CVD in an at risk population We propose a multirisk intervention with a realistic chance of reducing new onset diabetes by 70% and new CVD events by 50% over a 4 year period

37. GLADIATOR TRIAL The prevention of type 2 diabetes and cardiovascular endpoints 12,500 subjects,UK, China, India, Middle East and Africa Poulter, Sever, Alberti, Barakat 2009 Follow up average 4 years. 95% power to detect 50% reduction in CV endpoint 99% power to detect 70% reduction in new onset diabetes

38. Conclusions Cardiovascular Disease is increasing globally mainly in the developing world and the former Eastern Bloc states. In the developed world in many countries there have been dramatic reductions in CHD and stroke events largely explained by reductions in known risk factors The emergence of the epidemic of obesity and type 2 diabetes may reverse this trend Whilst lifestyle measures should form the basis of prevention, pharmacotherapy with effective and safe drugs is likely to have a major impact on the prevention of diabetes and CVD