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Cuna Indians

The Global Challenge Peter Sever The International Centre for Circulatory Health National Heart and Lung Institute Imperial College London. Pacific Atoll Polynesians. Cuna Indians. Kenyan nomads. Yanamamo Indians. Congo pygmies. New Guinean Highlanders. Kalahari bushmen.

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Cuna Indians

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  1. The Global ChallengePeter SeverThe International Centre for Circulatory HealthNational Heart and Lung InstituteImperial College London

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

  3. The Global Burden of Cardiovascular Disease 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

  4. 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

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

  6. 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

  7. 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)

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

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

  10. Coronary Heart Disease 1.50 1.25 Relative risk of CHD 1.00 0.75 0.50 0.25 -10 -8 -6 -4 -2 0 2 4 Systolic blood pressure difference between randomised groups (mmHg)

  11. Stroke 1.50 1.25 Relative risk of stroke 1.00 0.75 0.50 0.25 -10 -8 -6 -4 -2 0 2 4 Systolic blood pressure difference between randomised groups (mmHg)

  12. Proportional benefit independent of baseline BP

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

  14. 180 160 140 ASCOT- BPLA: Time to benefitSystolic Blood Pressure atenolol  thiazide amlodipine  perindopril 164.1 mm Hg 163.9 Mean difference 2.7 137.7 136.1 18 CHD 15 Stroke 12 9 • Event Rate* • *per 1000 patient years • not randomised to statin 6 3 0 Last visit Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Time (years) . Sever P, Poulter N et al. Am J Cardiol. 2005;96 [suppl]:39F-44F

  15. CTT Collaboration: Effects on major coronary events per mmol/L LDL cholesterol reduction subdivided by baseline prognostic factors Heterogeneity/trend p-value Events (%) RR & CI Groups Treatment Control (Treatment : Control) Prior disease: Post-MI 1681 (11·7) 2207 (15·4) p = 0·2 Other CHD 568 (8·7) 744 (11·4) None 1088 (4·5) 1469 (6·1) Age (years): ≤65 1671 (6·1) 2344 (8·5) p = 0·01 >65 1666 (9·5) 2076 (11·9) Gender: Male 2686 (7·8) 3630 (10·6) p = 0·1 Female 651 (6·1) 790 (7·3) Treated hypertension: Yes 2038 (8·2) 2596 (10·4) p = 0·2 No 1299 (6·4) 1824 (9·1) History of diabetes: Yes 776 (8·3) 979 (10·5) p = 0·8 No 2561 (7·2) 3441 (9·6) Diastolic BP: ≤90 mmHg 2711 (7·8) 3590 (10·3) p = 0·8 >90 mmHg 618 (6·1) 827 (8·2) 0·77 (0·74 – 0·80) Overall 3337 (7·4) 4420 (9·8) p < 0·00001 0·5 1·0 1·5 Treatment Control better better

  16. ASCOT - LLAPrimary End Point: Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 36% reduction HR = 0.64 (0.50-0.83) p=0.0005 Sever P, Dahlof B ,Poulter N, Wedel H et al. Lancet 2003 :361;1149-58

  17. ASCOT: Post-hoc Analysis of Benefit Across the whole Cholesterol Range The primary endpoint: Thus proportional benefit independent of baseline cholesterol Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

  18. ASCOT-LLA : CHD events Time to benefit * • Risk Reduction Event Rate • (%)AtorvastatinPlacebo • 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 Censoring Time Hazard Ratios (95% CI) 30 days 90 days 180 days 1 Year 2 Years End of Study * Per 1000 patient years Atorvastatin better Placebo better

  19. Benefits of combined intervention

  20. Most Patients Have Overlapping CV Risk Factors Multiple comorbidities increases risk 400-700% 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 • 1 Based on Framingham risk

  21. ASCOT benefits from combined blood pressure and lipid-loweringReductionin risk of non-fatal MI and fatal CHD using Framingham model for baseline estimates ** *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

  22. 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

  23. Treat risk factor or Treat risk ? Subject 1 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 • 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

  24. 28th June 2003 A pill to prevent 80% of CVD ! The most important BMJ for 50 years? Richard Smith

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

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

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

  28. Can we prevent diabetes and associated cardiovascular disease ?

  29. GLOBAL PROJECTIONS FOR THE NUMBER OF PEOPLE WITH DIABETES (20-79 AGE GROUP), 2007 and 2025 (MILLIONS)

  30. 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

  31. GLADIATORGlobal intervention to prevent diabetes and cardiovascular diseaseRATIONALE “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”

  32. 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

  33. 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

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

  35. 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

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