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The concept of Diabetes & CV risk: A lifetime risk challenge

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

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The concept of Diabetes & CV risk: A lifetime risk challenge

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

  2. Heart Protection Study: Impact of Diabetes on CV outcome 50 Placebo Simvastatin 40 mg 40 RRR12% Incidence of major vascular events (%) RRR22% 30 RRR19% RRR23% 20 RRR31% 10 1009 972 5683 5722 519 551 1481 1449 1455 1457 0 Diabetes + CHD No diabetes + CHD Diabetes + other CVD No diabetes + other CVD Diabetes + no CVD HPS Collaborative Group. Lancet. 2003;361:2005

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

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

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

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

  7. Temporal Mortality Trends in MI in Patientswithandwithout Diabetes (a comparisonof 1762 patients in 1995 with 1642 patients in 2003) Cubbon RM et al. Eur Heart J 2007; 28: 540–545

  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 Relative Risk -37% (95% CI: -52, -17) 15 Placebo P=0.001 10 Atorvastatin Cumulative Hazard (%) 5 0 0 1 2 3 4 4.75 Years

  10. Time to First Major Cardiovascular Eventin Patients With Diabetes TNT Study Atorvastatin 10 mg Atorvastatin 80 mg HR = 0.75 (95% CI 0.58, 0.97) P=0.026 0.20 Atorvastatin 10mg 0.15 Atorvastatin 80mg Cumulative incidence of major cardiovascular events 0.10 0.05 Relative risk reduction = 25% 0 0 1 2 3 4 5 6 Time (years)

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

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

  13. 60 50 40 30 20 10 0 Steno-2 Study in T2 DM: CV Outcome* Conventional therapy P=0.007 Primary endpoint (%) Intensive therapy 24 36 48 0 12 60 72 84 96 Months of follow-up *Death from CVD, MI, CABG,PCI, stroke, amputation, or surgery for PAD Gæde P et al N Engl J Med 2003;348:383-393.

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

  15. Coronary Heart Disease Mortalityin Beijing 1984-1999 2500 1822 Extra deaths Attributable to Risk Factor Changes 2000 Cholesterol 77% 1000 Diabetes 19% BMI 4% Smoking 1% 500 0 642 fewer deaths by treatments AMI treatments 41% Hypertension treatment 24% Secondary prevetion 11% Heart failure 10% Aspirin for Angina 10% Angina: CABG & PTCA 2% -500 -1000 1999 1984 Critchley J. Circulation, 2004;110:1236-1244

  16. EEM Area13.2 mm2 5.07mm2 Atheroma Area 8.13 mm2 Prevalence of Atherosclerosis by Donor Age 100 85% 80 71% 60% 60 Prevalence ofAtherosclerosis (%) 37% 40 17% 20 0 <20 20-29 30-39 40-49 ≥50 Donor Age (years) 32 Year Old Female Tuzcu Circ 2001 103:2075-10

  17. CV Risk Factors in Childhood andCarotid IMT in Adults Risk factors measured at ages 12-18yrs No. of risk factors 0 1 2 3 or 4 P<0.001 P<0.001 0.88 0.80 Mean maximum carotid IMT (mm) 0.72 0.64 0.56 0.48 Women Men Raitakari et al JAMA 2003;290;2277-2283

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

  19. Age and CV Risk in Diabetes Men Women 30 30 Women with diabetes Women without diabetes Men with diabetes Men without diabetes 25 25 20 20 15 15 10 10 5 5 0 0 20-30 31-40 41-45 46-50 51-60 56-60 61-65 66-70 71-75 76-80 81-85 20-30 31-40 41-45 46-50 51-60 56-60 61-65 66-70 71-75 76-80 81-85 Age (years) Age (years) Booth Lancet 2006; 368: 29-36

  20. LDL Cholesterol and Coronary Heart Disease among Black Subjects by PCSK9142X or PCSK9679X Allele No Nonsense Mutation (n=3278) 12 50th Percentile 30 P=0.008 20 8 88% 10 Frequency (%) Coronary Heart Disease (%) 0 0 100 200 250 50 150 300 PCSK9142X or PCSK9679X (N=85) 4 28% 30 20 0 No Yes 10 PCSK9142Xor PCSK9679X 0 0 100 200 50 150 300 250 Cohen NEJM 2006; 354:1264-72 LDL Cholesterol in Black Subjects (mg/dl)

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

  22. 14 12 10 8 6 4 2 0 High-Normal BP and CVD Risk: Framingham Study High normal 130-139/85-89 mm Hg Prehypertension Normal 120-129/80-84 mm Hg Optimal<120/80 mm Hg Women Men 10 8 P<.001 P<.001 6 Cumulative Incidence (%) 4 2 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 Time (years) Time (years) Vasan et al. N Engl J Med. 2001;345:1291-1297.

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

  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 Placebo 60 40 Candesartan Cumulative Incidence (%) 20 0 0 1 2 3 4 StudyYear 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 Pathological remodelling Atherothrombosis and progressive CV disease Target organ damage Early tissue dysfunction - endothelium End-organ failure (CHF, ESRD) Oxidative and mechanical stress Inflammation Death Risk factors Dzau V Circ 2006 114; 2850-2870 Tissue injury (MI, stroke, renal insufficiency, peripheral arterial insufficiency)

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

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

  31. ….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

  32. A reasonable next step for ATP IV? ….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

  33. 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

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