Why should cardiologist be concerned about cardio metabolic risk?

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

2. Intra-Abdominal (Visceral) Fat Visceral Subcutaneous

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

4. High waist circumference is associated with multiple cardio vascular risk factors US population age >20 years 30 20 Prevalence of high waistcircumferenceassociated with (%) 10 0 LowHDL-Ca HighTGb HighFPGc HighBPd >2 riskfactorse 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 3rd National Health and Nutrition Survey. JAMA 2002; 287:356-359.

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

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

9. Dyslipidaemia in Type 2 Diabetes and Metabolic Syndrome Triglycerides Insulin resistance Small, dense LDL Remnants HDL2

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

11. Apo B More apo B The Absolute Concentration of LDL-C Can be Misleading in Subjects with Small, Dense LDL? Large, buoyant particles Small, dense particles 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 DM-TG 2.95 mmol/l DJB-TG 0.9 mmol/l III I II Increasing density Decreasing size

13. UKPDS:Risk Factors for MI. • LDL cholesterol • HDL cholesterol • HbA1c • Systolic blood pressure • Smoking Baseline Epidemiology Data Turner et al BMJ 1998

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

15. CHD Prevention Trials with Statins in Diabetic Patients Subgroup Analyses. CHD % Risk Reduction Secondary prevention CARE Pravastatin 586 23 25 (p=0.05) 4S Simvastatin 202 32 55 (p=0.002) LIPID Pravastatin 782 24 19 (NS) 4S reanalysis Simvastatin 483 32 42 (p=0.001) HPS Simvastatin 3050 24 18.4 (p<0.0001) Diabetes Overall 51 Atorvastatin 313 GREACE 58 (p<0.0001)

16. Atorvastatin 10 mg Atorvastatin 80 mg Time to First Major Cardiovascular Event Patients With DiabetesTNT Study HR = 0.75 (95% CI 0.58, 0.97) P=0.026 0.20 Atorvastatin 10mg HR = 0.75 (95% CI 0.58, 0.97) P=0.026 0.15 Cumulative incidence of major cardiovascular events* Atorvastatin 80mg 0.10 0.05 Relative risk reduction = 25% Relative risk reduction = 25% 0 0 1 2 3 4 5 6 Time (years) Shepherd et al Diabetes Care 2006

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; HR 0.75 p= 0.03 HR 0.76 p= 0.002 Event Rate Non Diabetes Diabetes n=978 No Diabetes n=3184 Ahmed et al European Heart Journal Sept 5th 2006

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

19. TNT StudyPrevalence of Metabolic Syndrome With metabolic syndrome Without metabolic syndrome 5584 (56%) 4417 (44%) 22% with DM 2005 NCEP-based criteria (Circulation 2005 112: 2735) • BMI 28 • 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) • Blood pressure 130/85 mm Hg • Fasting glucose 100 mg/dL (5.6 mmol/L) Deedwania et al Lancet In Press

20. Atorvastatin 10 mg Atorvastatin 80 mg TNT Time to First Major Cardiovascular Event Patients With Metabolic Syndrome 0.20 HR 0.71 (95%CI 0.61,0.84) p<0.0001 HR = 0.71 (95% CI 0.61, 0.84) P < 0.0001 0.15 Atovastatin 10mg/day Proportion of patients experiencing major cardiovascular event* 0.10 Atovastatin 80mg/day 0.05 Relative risk reduction 29% 0 0 1 2 3 4 5 6 Time (years) Deedwania et al 2006 Lancet In Press

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

22. Median Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Average difference 40% 1.20 mmol/L (46mg/dL) p<0.0001 Average difference 26% 1.40 mmol/L (54mg/dL) p<0.0001 6 4 3 4 2 2 1 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin

23. Median Lipid Levels by Treatment Triglycerides (mmol/L) HDL cholesterol (mmol/L) Average difference 19% 0.39 mmol/L, 35mg/dL p<0.0001 Average difference 1% 0.02 mmol/L,0.8mg/dL p=0.0002 1.4 2 1.2 1 .8 1 .6 .4 .2 0 0 0 1 2 3 4 4.5 0 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin

24. CARDSPrimary Prevention of CVD in Type 2 Diabetes with Atorvastatin 10mgCumulative Hazard for Primary Endpoint 15 Relative Risk -37% (95% CI: -52, -17) Placebo 127 events P=0.001 10 Atorvastatin 83 events Cumulative Hazard (%) 5 0 0 1 2 3 4 4.75 Years Number at risk Placebo 1410 651 1351 1306 305 1022 Atorva 1428 694 1392 1361 328 1074

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

26. Cumulative Hazard for Stroke Relative Risk -48% (95% CI: -69, -11) 0.04 Placebo 39 events 0.03 Atorvastatin 21 events Cumulative Hazard (%) 0.02 0.01 0 Years 0 1 2 3 4 4.75 Number at risk 1410 1370 1342 1061 677 321 Placebo 1428 1402 1378 1093 716 344 Atorva

27. 15 Placebo Atorvastatin 10 mg 10 Cumulative hazard (%) 5 0 0 1 2 3 4 Years Cumulative Hazard for Primary Endpoint in Older People 62 events ≥65 years Relative Risk -38% (95% CI -58, -8)P=0.017 41 events 65 events 42 events <65 years Relative Risk-37% (95% CI-57,-7) P=0.019

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 glomerularfitration 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/1.73m2/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/1.73m2atorvastatin reduced major CVD events by 42% with 61% reduction in stroke

29. Yearly mean within person change in estimated GFR (MDRD) by treatment group and baseline albuminuria Mean within person change in est GFR from baseline Net effect 0.38ml/min/1.73m2/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 Targets Total chol <4mmol/l LDL-chol <2mmol/l Heart, 2005; 91 Suppl V

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 VascDis Res 2008; 5: 177-183

33. CARDS: Safety Overview AtorvastatinPlacebo 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 VascDis Res 2008; 5: 177-183

34. CARDS: Safety OverviewMuscle-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 VascDis Res 2008; 5: 177-183

35. CARDS: Safety OverviewMuscle-related Adverse Events AtorvastatinPlacebo 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 VascDis Res 2008; 5: 177-183

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

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.