1. The concept of Diabetes & CV risk: A lifetime risk challenge John Deanfield, MD University College London London, United Kingdom Cardio Diabetes Master Class Asian chapter January 28-30 2011, Shanghai Slide lecture prepared and held by: Presentation topic

2. Heart Protection Study: Impact of Diabetes on CV outcome HPS Collaborative Group. Lancet. 2003;361:2005 0 10 20 30 40 50 Incidence of major vascular events (%) Placebo Simvastatin 40 mg RRR 12% RRR 23% RRR 22% RRR 19% RRR 31% Diabetes + CHD No diabetes + CHD Diabetes + other CVD No diabetes + other CVD Diabetes + no CVD 1009972568357225195511481144914551457

3. CVD Accounts for 71% of Costs of Chronic Complications of Diabetes 11% 8% 5% 71 % Cardiovascular disease Neurological symptoms Renal complications Peripheral vascular disease Endocrine/metabolic Ophthalmic complications Other Total US expenditure in 2002 = US$ 24.6 billion American Diabetes Association. Diabetes Care 2003;26:917-32

4. Cholesterol in China (2000-2001) Jiang H. Circulation, 2004;110:405-411 112,500,000 Borderline HC 42,540,000 HC 90,803,000 Low HDL ≥ 200 mg/dl 25 20 15 10 5 0 Prportion % MenWomen 21.3 14.0 11.3 18.1 11.6 9.5 Aware Treated Controlled 10 8 6 4 2 0 Prportion % MenWomen 8.8 3.5 1.9 7.5 3.4 1.5 ≥ 240 mg/dl

5. Diabetes in China : 1994-2008 Yang NEJM 2010 362 1090-101

6. Potentially Modifiable Risk Factors and MI : INTERHEART Study 15152 Cases 14820 Controls in 262 Centres in 52 Countries Yusuf Lancet September 11 2004 0 1 2 3 Smoking BP Alcohol -20 0 20 40 60 ApoB/ApoA1 DM Stress Obesity Fr/Veg Phys Act. Odds Ratio PAR (%) 9 RFs acounted for 90% of MI in men and 94% in women

7. Cubbon RM et al. Eur Heart J 2007; 28: 540–545 Temporal Mortality Trends in MI in Patients with and without Diabetes (a comparison of 1762 patients in 1995 with 1642 patients in 2003)

8. Atherosclerosis: Risk Reduction Strategy Lifetime Risk  Treat to lower levels  Target global risk  Start earlier

9. CARDS: Cumulative Hazard for MI and CV death Atorvastatin Cumulative Hazard (%) Relative Risk -37% (95% CI: -52, -17) P=0.001 Years Placebo 0 5 10 15 012344.75

10. Time to First Major Cardiovascular Event in Patients With Diabetes TNT Study HR = 0.75 (95% CI 0.58, 0.97) P=0.026 Atorvastatin 10 mg Atorvastatin 80 mg 0123456 Time (years) 0.20 0.10 0.15 0.05 0 Cumulative incidence of major cardiovascular events Relative risk reduction = 25% Atorvastatin 80mg Atorvastatin 10mg

11. Residual Disease Progression in Diabetes Despite Intensive LDL-C Lowering Δ Percent Atheroma Volume No DM LDL<80 DM LDL>80 DM LDL<80 No DM LDL>80 Nicholls J Amer Coll Cardiol 2008;52:255-62 -0.5 0.0 0.5 1.0 1.5

12. Multiple Risk Factors and CVD Death in Diabetic and Non diabetic Men (MRFIT) Stamler J et al Diabetes Care 1993;16:434. Age-adjusted CVD death rate/10,000 person-years 140 120 100 80 60 40 20 0 No Diabetes Diabetes None One onlyTwo onlyAll three Number of risk factors

13. Steno-2 Study in T2 DM: CV Outcome* *Death from CVD, MI, CABG,PCI, stroke, amputation, or surgery for PAD. Gæde P et al N Engl J Med 2003;348:383-393. Primary endpoint (%) 0 36 129660 48 8472 24 0 60 30 40 20 10 50 Intensive therapy Conventional therapy Months of follow-up P=0.007

14. Atherosclerosis: ‘Investing in your Arteries’ Early Intervention for Lifetime Risk management

15. Coronary Heart Disease Mortality in Beijing 1984-1999 Critchley J. Circulation, 2004;110:1236-1244 2500 2000 1000 500 0 -500 -1000 1984 1999 Cholesterol 77% 1822 Extra deaths Attributable to Risk Factor Changes Diabetes 19% BMI4% Smoking1% 642 fewer deaths by treatments AMI treatments 41% Hypertension treatment 24% Secondary prevetion 11% Heart failure 10% Aspirin for Angina 10% Angina: CABG & PTCA 2%

16. Tuzcu Circ 2001 103:2075-10 5.07 mm 2 EEM Area 13.2 mm 2 Atheroma Area 8.13 mm 2 32 Year Old Female 17% 37% 60% 85% 71% 0 20 40 60 80 100 <2020-2930-3940-49≥50 Prevalence of Atherosclerosis (%) Donor Age (years) Prevalence of Atherosclerosis by Donor Age

17. CV Risk Factors in Childhood and Carotid IMT in Adults Raitakari et al JAMA 2003;290;2277-2283 Men Women P<0.001 0.88 0.80 0.72 0.64 0.56 0.48 Mean maximum carotid IMT (mm) Risk factors measured at ages 12-18yrs No. of risk factors 0123 or 4

18. Framingham Heart Study Lifetime Risk Adjusted Cumulative Incidence 50% 39% 27% Attained Age 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 50 60 70 80 90 69% 50% 46% 36% 5% 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 50 60 70 80 90 8% ≥2 Major RFs 1 Major RF ≥ Elevated RF ≥ Not Elevated RF All Optimal RFs Men Women Lloyd-Jones Circ. 2006; 113: 791-798

19. Age and CV Risk in Diabetes Booth Lancet 2006; 368: 29-36 30 25 20 15 10 5 0 20-3031-4041-4546-5051-6056-6061-6566-7071-7576-8081-85 Women Women with diabetes Women without diabetes Age (years) 30 25 20 15 10 5 0 20-3031-4041-4546-5051-6056-6061-6566-7071-7576-8081-85 Men Men with diabetes Men without diabetes Age (years)

20. LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9 142X or PCSK9 679X Allele LDL Cholesterol in Black Subjects (mg/dl ) PCSK9 142X or PCSK9 679X 300 30 20 10 0 0 50 100 150 200250 300 No Nonsense Mutation (n=3278) 50 th Percentile Frequency (%) PCSK9 142X or PCSK9 679X (N=85) 30 20 10 0 0 50 100 150 200 250 Cohen NEJM 2006; 354:1264-72 28% Coronary Heart Disease (%) No Yes P=0.008 12 8 4 0 88%

21. -60% -40%-20%0% Primary Prevention: Influence of Age on Relationship Between Cholesterol and CHD Law MR et al. BMJ 1994;308:367-372. Age 70 Reduction in risk in men with 10% reduction in total cholesterol (10 cohort studies) Age 50 Age 40

22. Vasan et al. N Engl J Med. 2001;345:1291-1297. High-Normal BP and CVD Risk: Framingham Study Women Time (years) 10 8 6 4 2 0 02468101214 P<.001 Men Cumulative Incidence (%) 1412 10 8 6 4 2 0 Time (years) 02468101214 P<.001 High normal 130-139/85-89 mm Hg Normal 120-129/80-84 mm Hg Optimal <120/80 mm Hg Prehypertension

23. Anderson, BMJ 1998; 317: 167 Screening BP (mmHg) Final BP (mmHg) CHD (%) Stroke (%) Cancer (%) All-cause death (%) Treated BP 185 / 114 145 / 89 20.1* 4.5* 8.9 37.4* “Normotensive” 145 / 93 -- 10.3 1.8 10.8 29.2 *p <0.02 Beyond BP?:Outcome in treated BP (n=686) vs. “Normotensive” (n=6810) Men after > 20yrs

24. BP Treatment in Type 2 DM 4733 age 62.2 years intensive vs standard BP treatment over 4.7 years ACCORD Study Group NEJM 2010;362:1575-1585

25. TROPHY Study: ARB in ‘Prehypertension’ 100 80 60 40 20 0 Cumulative Incidence (%) 01234 Placebo Candesartan Study Year Julius NEJM 2006; 354 : 1685-97

26. Lifetime Management of Atherosclerosis Risk Benefits of early intervention from  Less Exposure / burden?  Disease modification?

27. Cardiovascular Continuum: Vascular Biology Targets Tissue injury (MI, stroke, renal insufficiency, peripheral arterial insufficiency) Pathological remodelling Target organ damage End-organ failure (CHF, ESRD) Death Early tissue dysfunction - endothelium Atherothrombosis and progressive CV disease Risk factors Oxidative and mechanical stress Inflammation Dzau V Circ 2006 114; 2850-2870

28. RAS Blockade, Adipocytes and Diabetes Lenz O Kidney International 2008 74: 851-853

29. Intravascular Ultrasound of Coronary Arteries Determining the Atheroma Area EEM Area Lumen Area Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory (EEM Area — Lumen Area) Precise planimetry of EEM and lumen borders allows calculation of atheroma cross-sectional area On multivariate analysis the only parameter On multivariate analysis the only parameter independently associated with slowing of disease independently associated with slowing of disease progression in the Pioglitazone group was progression in the Pioglitazone group was Triglyceride/HDL-C ratio Triglyceride/HDL-C ratio P=0.03 P=0.03 Nicholls et al JACC 57 No 2 2011

30. Benefit of Treating the Metabolic Syndrome Tuomilehto J et al. N Engl J Med 2001;344:1343-1350. InterventionControl After 4 years risk of diabetes reduced by 58% 11% 23% % with Diabetes

32. ….It is essential that the new guidelines incorporate the logical concept that a long term disease requires a long term solution Forrester JACC 2010; 56: 630-636

33. ….Consider statins for younger persons, perhaps starting at 30 in those with risk factors that convey high lifetime risk (as opposed to 10 yr risk) for CHD Pletcher JACC 2010; 56: 637-640 A reasonable next step for ATP IV?

34. CV Risk Management-Long way to go?  Lifetime risk reduction is the target  More active management of high risk subjects such as diabetics  In addition to ‘Lower and Broader’ RF treatment, Early Management key to further reduction in CV events