1. Why should cardiologist be concerned about cardio metabolic risk? Prof. D John Betteridge U niversity College London Slide lecture prepared and held by: Master Class: Advanced CV Risk management in cardiology June 17-18, 2011, London Presentation topic

2. Intra-Abdominal (Visceral) Fat Visceral Subcutaneous

3. Abdominal obesity: a major underlying cause of acute myocardial infarction (MI) Yusuf et al, 2004 PAR (%) a a Proportion of MI in the total population attributable to a specific risk factor Abdominal obesity predicts the risk of CVD beyond BMI Cardiometabolic risk factors in the INTERHEART Study 0 20 40 60 18 Hypertension 10 Diabetes 20 Abdominal Obesity 49 Abnormal Lipids

4. High waist circumference is associated with multiple cardio vascular risk factors 30 20 10 0 Low HDL-C a High TG b High FPG c High BP d >2 risk factors e Prevalence of high waist circumference associated with (%) US population age >20 years NHANES 1999–2000 cohort

6. The Metabolic Syndrome: Prevalence in the USA Prevalence of Metabolic Syndrome ATP III NCEP clinical definition 22% Ford et al. Prevalence of the Metabolic Syndrome among US adults: Findings from the 3 rd National Health and Nutrition Survey. JAMA 2002; 287:356-359.

7. Increased CAD Events in Metabolic Syndrome, a Meta-Analysis Incident CAD Events in Patients Without Prevalent CVD GAMI AS et al. J Am Coll Cardiol 49:403, 2007 Study RR 1.40 1.28 1.52 1.62 1.48 3.92 1.41 1.48 4.90 1.74 1.49 Girman (b) GodslandHolvöetMcNeillPyöräläRidkerSattarSchillaciTenkanenSummary Excluding outliers summary Decreased risk Increased risk 0.1 0.2 0.5 1 2 5 10

8. Adipose Tissue: A Major Secretory Organ Adipose tissue IL-6 IL-6 Adiponectin Leptin Leptin TNFα TNFα Adipsin (Complement D) Adipsin (Complement D) Plasminogen activator inhibitor-1 (PAI-1) Plasminogen activator inhibitor-1 (PAI-1) Resistin Free fatty Acids Angiotensinogen Angiotensinogen Lipoprotein lipase Lipoprotein lipase Lyon 2003; Trayhurn et al 2004; Eckel et al 2005 IL-1β MCP 1 Vascular Endothelial Growth Factor

9. Dyslipidaemia in Type 2 Diabetes and Metabolic Syndrome Dyslipidaemia in Type 2 Diabetes and Metabolic Syndrome Triglycerides Small, dense LDL Insulin resistance Remnants HDL 2

10. Characteristics of LDL Subclasses Hurt-Camejo E et al Curr Opin Lipidol 2000;11:465 Large, buoyant LDL Small, dense LDL GAG-binding segments (3147–3157) (3359–3367) apo B-100 Free cholesterol Phospholipids Polar lipids: 63.3%Polar lipids: 63.3% Accessible apo B-100: 36.7Accessible apo B-100: 36.7 Low GAG affinityLow GAG affinity Polar lipids: 35.6%Polar lipids: 35.6% Accessible apo B-100: 64.4Accessible apo B-100: 64.4 High GAG affinityHigh GAG affinity

11. Large, buoyant particles Small, dense particles Apo BMore apo B The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL? The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL? At the same LDL-C level, the number of LDL particles is increased, if small and dense Each LDL particle contains one molecule of apo B Apo B concentration increases in direct relation to number of LDL particles Sniderman AD et al Ann Intern Med 2001

12. LDL Subfractions “Control” vs Patient with Insulin Resistance Increasing density Decreasing size I II III DJB-TG 0.9 mmol/l DM-TG 2.95 mmol/l

13. UKPDS: Risk Factors for MI. LDL cholesterolLDL cholesterol HDL cholesterolHDL cholesterol HbA 1cHbA 1c Systolic blood pressureSystolic blood pressure SmokingSmoking Baseline Epidemiology Data Turner et al BMJ 1998

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

15. CHD Prevention Trials with Statins in Diabetic Patients Subgroup Analyses. CAREPravastatin 586 2325 (p=0.05) CAREPravastatin 586 2325 (p=0.05) 4SSimvastatin 202 3255 (p=0.002) 4SSimvastatin 202 3255 (p=0.002) LIPIDPravastatin 782 2419 (NS) LIPIDPravastatin 782 2419 (NS) 4S reanalysisSimvastatin 483 3242 (p=0.001) 4S reanalysisSimvastatin 483 3242 (p=0.001) HPSSimvastatin 3050 2418.4 (p<0.0001) HPSSimvastatin 3050 2418.4 (p<0.0001) CHD % Risk Reduction Overall Diabetes Secondary prevention GREACE Atorvastatin 313 313 51 51 58 (p<0.0001)

16. Time to First Major Cardiovascular Event Patients With Diabetes TNT Study HR = 0.75 (95% CI 0.58, 0.97) P=0.026 P=0.026 Atorvastatin 10 mg Atorvastatin 80 mg 0123456 Time (years) 0.2 0 0.1 0 0.1 5 0.0 5 0 Cumulative incidence of major cardiovascular events* Relative risk reduction = 25% Atorvastatin 80mg Atorvastatin 10mg Shepherd et al Diabetes Care 2006 HR = 0.75 (95% CI 0.58, 0.97) P=0.026 P=0.026 Relative risk reduction = 25%

17. Acute Coronary Syndromes and Diabetes. Is Intensive Lipid Lowering Therapy Beneficial? Results of the PROVE IT-TIMI 22 Trial Population: 978 ACS patients with DM LDL 101mg/dl. 734 clinical history; 219 fasting glucose >126mg/dl (7mmol/l) 25 HbA1c>7%. 3184 without diabetes LDL 108mg/dl Diabetic patients older, more often female, more CVD morbidity, hypertension, PVD but smoked less often Design: RCT of standard (pravastatin 40mg; LDL 81mg/dl; 18%  ) vs intensive statin (atorvastatin 80mg; LDL 57mg/dl; 44%  ) therapy in patients treated early after ACS Secondary endpoint: Death, MI, unstable angina; Non Diabetes Event Rate Rate Diabetes n=978 n=978 No Diabetes n=3184 n=3184 HR 0.75 p= 0.03 HR 0.76 p= 0.002 Ahmed et al European Heart Journal Sept 5 th 2006

18. Implications of Recent Trials Adult Treatment Panel III Guidelines Diabetes Diabetes plus CVD: Diabetes plus CVD: Initiate statin therapy regardless of Initiate statin therapy regardless of baseline LDL-C; baseline LDL-C; LDL goal <70mg/dl (1.8mmol/L) LDL goal <70mg/dl (1.8mmol/L) Circulation 2004;110 227

19. TNT Study Prevalence of Metabolic Syndrome TNT Study Prevalence of Metabolic Syndrome With metabolic syndromeWithout metabolic syndrome 2005 NCEP-based criteria (Circulation 2005 112: 2735) BMI  28 BMI  28 Triglycerides  150 mg/dL (  1.7 mmol/L) Triglycerides  150 mg/dL (  1.7 mmol/L) HDL-C: Men <40 mg/dL (<1.0 mmol/L); Women <50 mg/dL (<1.3 mmol/L) HDL-C: Men <40 mg/dL (<1.0 mmol/L); Women <50 mg/dL (<1.3 mmol/L) Blood pressure  130/  85 mm Hg Blood pressure  130/  85 mm Hg Fasting glucose  100 mg/dL (  5.6 mmol/L) Fasting glucose  100 mg/dL (  5.6 mmol/L) 4417 (44%) 5584 (56%) 22% with DM Deedwania et al Lancet In Press

20. TNT Time to First Major Cardiovascular Event Patients With Metabolic Syndrome TNT Time to First Major Cardiovascular Event Patients With Metabolic Syndrome 0123456 Time (years) 0.0 5 0 Proportion of patients experiencing major cardiovascular event* Relative risk reduction 29% Atorvastatin 10 mg Atorvastatin 80 mg 0.2 0 0.1 0 0.1 5 HR = 0.71 (95% CI 0.61, 0.84) P < 0.0001 HR 0.71 (95%CI 0.61,0.84) p<0.0001 p<0.0001 Atovastatin 80mg/day Atovastatin 10mg/day Deedwania et al 2006 Lancet In Press

21. 304 events Expected completion 2005 Atorvastatin 10 mg 2,838 Patients d/b PBO CARDS: Collaborative AtoRvastatin Diabetes Study Patient Population Type 2 diabetes (40-75y) Type 2 diabetes (40-75y) No prior MI or CVD No prior MI or CVD Other risk factors + Other risk factors + Lipid profile: Lipid profile:  LDL-C <159 mg/dL (4.14 mmol/L)  TG <600 mg/dL (6.78 mmol/L) Collaboration in the UK Collaboration in the UK with Diabetes UK, NHS R&D and Pfizer with Diabetes UK, NHS R&D and Pfizer Primary Endpoint Time to first major CVD event Time to first major CVD event Colhoun et al. Diabetic Med 2002; 32: 259-264. Actual termination June 2003 after Actual termination June 2003 after 2 nd interim analysis 210 events 2 nd interim analysis 210 events

22. Median Lipid Levels by Treatment Median Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L) 023414.5 2341 Years of Study 0 0 1 2 3 4 0 2 4 6 PlaceboAtorvastatin Average difference 26% 1.40 mmol/L (54mg/dL) p<0.0001 Average difference 40% 1.20 mmol/L (46mg/dL) p<0.0001

23. Median Lipid Levels by Treatment Median Lipid Levels by Treatment HDL cholesterol (mmol/L) Triglycerides (mmol/L) 023414.5 2341 Years of Study 0 0 1 21.4 0.2.4.6.8 1 1.2 PlaceboAtorvastatin Average difference 1% 0.02 mmol/L,0.8mg/dL p=0.0002 Average difference 19% 0.39 mmol/L, 35mg/dL p<0.0001

24. CARDS Primary Prevention of CVD in Type 2 Diabetes with Atorvastatin 10mg Cumulative Hazard for Primary Endpoint Relative Risk -37% (95% CI: -52, -17) P=0.001 Atorva Placebo Years 328 305 694 651 1074 1022 1361 1306 1392 1351 1428 1410 Placebo 127 events Atorvastatin 83 events Cumulative Hazard (%) 0 5 10 15 01 2344.75 Number at risk

25. Treatment Effect on Primary Endpoint in CARDS 18 38 55 71 86 97 106 117 124 17 26 34 40 45 52 63 68 74 Atorva Placebo Number of first events HR* 0.63 HR* 0.63 (95% CI: 0.45, 0.91) Colhoun et al Diabetologia 2005

26. Cumulative Hazard for Stroke Placebo 39 events Atorvastatin 21 events Number at risk Atorva Placebo 012344.75 Years 1410 1370 1342 1061 677 321 1428 1402 1378 1093 716 344 0 0.01 0.02 0.03 0.04 Cumulative Hazard (%) Relative Risk -48% (95% CI: -69, -11)

27. 0 5 10 15 40231 Cumulative hazard (%) Years Placebo Atorvastatin 10 mg <65 years Relative Risk-37% (95% CI-57,-7) P=0.019 65 events 42 events ≥65 years Relative Risk -38% (95% CI -58, -8) P=0.017 41 events 62 events Cumulative Hazard for Primary Endpoint in Older People

28. Objective: Does atorvastatin 10mg/day affect kidney status in the CARDS study and does the effect of atorvastatin on CVD events vary by kidney status? Population: 2838 patients with type 2 diabetes and no prior CVD. Outcomes: Estimated glomerular fitration rate (eGFR), albuminuria and CVD events. Measurements: Baseline and follow-up GFR estimated using the Modification of Diet in Renal Disease study equation. Urinary albumin measured on spot urines Results: Atorvastatin therapy led to a small but significant improvement in annual change in eGFR, 0.18mL/min/1.73m 2 /year (95% CI 0.04-0.32, p=0.01) No effect on albuminuria incidence or regression to normoalbuminuria In 970 patients with eGFR 30-60mL/min/1.73m 2 atorvastatin reduced major CVD events by 42% with 61% reduction in stroke

29. Mean within person change in est GFR from baseline Yearly mean within person change in estimated GFR (MDRD) by treatment group and baseline albuminuria Net effect 0.38ml/min/1.73m 2 /year p=0.03 MDRD: Modification of Diet in Renal Disease

30. Joint British Societies’ Guidelines on Prevention of Cardiovascular Disease in Clinical Practice Indications for Statin Therapy in Diabetes Aged >40yrs type 2 or type 1 Aged 18-39yrs type 2 or type 1 and Significant retinopathy Nephropathy Poor glycaemic control (HbA1c> 9%) Hypertension Cholesterol >6mmol/l Features of metabolic syndrome: Trig >1.7mm0l/l; HDL < 1.0 in men, < 1.2mmol/l in women Family history of premature CVD in first degree relative Heart, 2005; 91 Suppl V Targets Targets Total chol <4mmol/l LDL-chol <2mmol/l

31. Objective: To explore the relationship between drug adherence and mortality in survivors of acute myocardial infarction Design: Population-based, observational, longitudinal study of 31,455 elderly MI survivors 1999-2003 in Ontario, Canada. Patient adherence: 80%, 40-79% and <40% days covered. Main Outcome Measure: Long-term mortality, mean follow-up 2.4years assessed by multivariate survival models

32. CARDS: Safety Overview Atorvastatin n=1428 (%) Patients with ≥ one AE All cause 1390 (97.3) Treatment associated 328 (23.0) Discontinuations due to AEs All cause 122 (8.5) Treatment associated 41 (2.9) Dose interruptions due to AEs All cause 201 (14.1) Treatment associated 34 (2.4) Patients with serious AEs All cause 421 (29.5) Treatment associated 15 (1.1) Newman et al Diabetes Vasc Dis Res 2008; 5: 177-183

33. CARDS: Safety Overview Atorvastatin Placebo n=1428 (%) n=1410 (%) Patients with ≥ one AE All cause 1390 (97.3) 1376 (97.6) Treatment associated 328 (23.0) 358 (25.4) Discontinuations due to AEs All cause 122 (8.5) 145 (10.3) Treatment associated 41 (2.9) 48 (3.4) Dose interruptions due to AEs All cause 201 (14.1) 172 (12.2) Treatment associated 34 (2.4) 23 (1.6) Patients with serious AEs All cause 421 (29.5) 431 (30.6) Treatment associated 15 (1.1) 16 (1.1) Newman et al Diabetes Vasc Dis Res 2008; 5: 177-183

34. CARDS: Safety Overview Muscle-related Adverse Events Atorvastatin n=1428 (%) Myalgia All cause 57 (4) Treatment associated 14 (1) Leg Cramps All cause 70 (4.9) Treatment associated 11 (0.8) Myopathy All cause 1 (0.1) Treatment associated 1 (0.1) Newman et al Diabetes Vasc Dis Res 2008; 5: 177-183

35. CARDS: Safety Overview Muscle-related Adverse Events Atorvastatin Placebo n=1428 (%) n=1410 (%) Myalgia All cause 57 (4) 67 (4.8) Treatment associated 14 (1) 17 (1.2) Leg Cramps All cause 70 (4.9) 61 (4.3) Treatment associated 11 (0.8) 10 (0.7) Myopathy All cause 1 (0.1) 1 (0.1) Treatment associated 1 (0.1) 0 Newman et al Diabetes Vasc Dis Res 2008; 5: 177-183

36. h Association between Statin Therapy and Incident Diabetes in 13 Major Cardiovascular Trials Odds Ratio 1.09 (1.02-1.17) Treatment of 255 (95%CI 150-852) patients with statins for 4years resulted in one extra case of diabetes

38. Objective: To characterize IVUS defined coronary atherosclerosis progression in diabetic patients Methods: Systematic analysis, 2,237 subjects in RCTs of atherosclerosis progression, Reversal, Camelot, Activate, Asteroid and Illustrate. All patients had CAD, at least one lumen narrowing >20% on diagnostic arteriogram. The pattern of disease progression was compared in subjects with and without diabetes Diabetic patients had a greater percent atheroma volume 40.2 ± 0.9% vs 37.5 ± 0.8% on multivariate analysis, p<0.0001 at baseline.