1. The concept of Diabetes & CV risk: A lifetime risk challenge The Clinical Significance of LDL-Cholesterol: No Longer a Hypothesis? John J.P. Kastelein, MD PhD Academic Medical Center University of Amsterdam Dept. Vascular Medicine Amsterdam, The Netherlands Master Class Lipid Innovations Prague, Czech Republic May 27-28, 2011 Slide lecture prepared and held by: Presentation topic

2. Mortality from Ischemic Heart Disease and Cholesterol 3,020 Deaths Prospective Studies Collaboration. Lancet 2007;370:1829 128 64 32 16 8 4 2 1 1.01.5 Usual HDL-C (mmol/L)Usual non-HDL-C (mmol/L)Usual total/HDL-C (mmol/L) 3.04.05.06.03.04.05.06.07.0 0.5 A. HDL-CB. non-HDL-CC. Total/HDL-C Age at risk (years) 70-89 60-69 40-69 Age at risk (years) 70-89 60-69 40-69 70-89 HR 0.69 (0.63-0.74) 60-69 HR 0.60 (0.56-0.64) 40-69 HR 0.56 (0.51-0.60) Age at risk (years)

3. Discovery of statins Discovery of LDL receptors Endo, 1976 Brown and Goldstein, 1974 Statins raise LDL receptors in the liver Plasma LDL is reduced

4. Primary prevention trials Secondary prevention trials 507011013015017019090210 % Patients with CHD Event LDL cholesterol CARE-Rx 4S-Rx LIPID-PL 4S-PL CARE-PL LIPID-Rx AFCAPS-Rx WOSCOPS-Rx WOSCOPS-PL AFCAPS-PL 25 20 15 10 5 0 ASCOT-PL ASCOT-Rx HPS-Rx HPS-PL HPS LRC-PL LRC-Rx POSCH-PL POSCH-Rx non statin trials Statin trials (mg/dL) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L) TNT-80A TNT-10A Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy

5. Correlation Between LDL-C Lowering and Decreased CHD Risk According to Treatment Modality in a Meta-Regression Analysis Adapted from Robinson JG, et al. J Am Coll Cardiol. 2005;46(10):1855–1862 LDL-C Reduction, % 402530351520 Nonfatal MI and CHD Death Relative Risk Reduction, % –20 100 80 60 40 20 0 London Oslo MRC Los Angeles Upjohn LRC NHLBI POSCH 4S a WOSCOPS a CARE a LIPID a AF/TexCaps a HPS a ALERT a PROSPER a ASCOT-LLA a CARDS a CTTC: 23% reduction in major vascular events for 1mmol/L lower LDL-C with statins

6. Deaths Due to Suicide, Cancer, and Hemorrhagic Stroke Number (%) of patients Quintile 1 <64 mg/dL (114/1722) * Quintile 2 64–<77 mg/dL (529/1403) * Quintile 3 77–<90 mg/dL (1019/968) * Quintile 4 90–<106 mg/dL (1515/515) * Quintile 5 106 mg/dL (1718/266) * Suicide1 (0.1)0 (0.0)1 (0.1)1 (0.0)1 (0.1) Cancer21 (1.1)37 (1.9)34 (1.7)32 (1.6)30 (1.5) Hemorrhagi c stroke † 6 (0.3)5 (0.3)6 (0.3)8 (0.4)7 (0.4) * Number of patients: atorvastatin 10 mg/atorvastatin 80 mg † Fatal and non-fatal

7. Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receivestatin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests Lancet, 2010; 376; 9756

8. GREACE: Enzyme Activity in Patients with Raised Liver Enzymes. A) On Statins B) Not On Statins Lancet, 2010; 376; 9756

10. Study Treatment comparison N Target population Entry lipid criteria PROVE-IT A 80 vs. P 40 4162ACS TC ≤240 mg/dL A to Z S 40 then S 80 vs. placebo then S 20 4497ACS TC ≤250 mg/dL TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL TG ≤600 mg/dL IDEAL A 80 vs. S 20-40 8888 Prior CHD TG ≤600 mg/dL SEARCH S 80 vs. S 20 12,064 Prior CHD TC ≥4.5 mmol/L or ≥3.5 if on statins Second CTT Cycle: More vs Less Intensive Statin Therapy

11. Study Treatment comparison N Target population Entry lipid criteria ALLIANCE A 10-80 (until LDL <80 mg/dL) vs. usual care 2442 Prior CHD LDL-C 110-200 mg/dL on lipid lowering drugs, 130-250 mg/dL if not 4D A 20 vs. placebo 1255 Type 2 DM + haemodialysis LDL-C 80-190 mg/dL TG <1000 mg/dL ASPEN A 10 vs. placebo 2410 Type 2 DM + CHD or risk factors LDL-C <150, TG ≤445 mg/dL with CHD; LDL-C <159, TG ≤600 mg/dL without MEGA P 10-20 vs. usual care 8214 Primary prevention TC 220-270 mg/dL JUPITER R 20 vs. placebo 17 802 Primary prevention (but CRP>2 mg/dL) LDL-C <130 mg/dL, TG <500 mg/dL GISSI-HF R 10 vs. placebo 4574CHFNone AURORA 2773HaemodialysisNone Second CTT Cycle: Additional Trials of Statin vs Control

12. Absolute Effect of Statin Therapy on MAJOR VASCULAR EVENTS 012345 0 5 10 15 20 LDL cholesterol, mmol/L Five year risk of a major vascular event, % Control 21% relative risk reduction per mmol/L Statin 15% relative risk reduction per 0.5 mmol/L More statin Combined evidence: ~33% relative risk reduction per 1.5 mmol/L

13. Less statin Proportional Effects on MAJOR VASCULAR EVENTS per mmol/L Reduction in LDL Cholesterol 0.40.60.8 1 1.21.4 No. of events (% pa) Statin/ More statin Contr ol/ Relative risk (CI) Statin/more statin better Control/less statin better Nonfatal MI CHD death Any major coronary event CABG PTCA Unspecified Any coronary revascularisation Ischaemic stroke Haemorrhagic stroke Unknown stroke Any stroke Any major vascular event 3485 (1.0) 1887 (0.5) 5105 (1.4) 1453 (0.4) 1767 (0.5) 2133 (0.6) 5353 (1.5) 1427 (0.4) 257 (0.1) 618 (0.2) 2302 (0.6) 10973 (3.2) 4593 (1.3) 2281 (0.6) 6512 (1.9) 1857 (0.5) 2283 (0.7) 2667 (0.8) 6807 (2.0) 1751 (0.5) 220 (0.1) 709 (0.2) 2680 (0.8) 13350 (4.0) 0.73 (0.69 - 0.78) 0.80 (0.74 - 0.87) 0.76 (0.73 - 0.78) 0.75 (0.69 - 0.82) 0.72 (0.65 - 0.80) 0.76 (0.70 - 0.82) 0.75 (0.72 - 0.78) 0.79 (0.72 - 0.87) 1.12 (0.88 - 1.43) 0.88 (0.76 - 1.01) 0.84 (0.79 - 0.89) 0.78 (0.76 - 0.80) 99% or95% CI

14. Proportional effects on ALL CAUSE MORTALITY per mmol/L LDL-C Reduction

15. Proportional Effects on CANCER INCIDENCE per mmol/L Reduction in LDL Cholesterol 0.50.7511.251.5 No. of patients Statin/ More statin Control Less statin Relative risk (CI) Statin/more statin better Control/less statin better 0-1 year 1-2 years 2-3 years 3-4 years 4-5 years 5+ years All groups 982 (1.2%) 1088 (1.3%) 982 (1.4%) 873 (1.4%) 680 (1.3%) 455 (1.5%) 5060 (6.0%) 997 (1.2%) 1056 (1.3%) 999 (1.4%) 878 (1.4%) 645 (1.3%) 489 (1.6%) 5064 (6.0%) 0.98 (0.87 - 1.11) 1.03 (0.92 - 1.16) 0.98 (0.86 - 1.10) 0.97 (0.85 - 1.10) 1.05 (0.90 - 1.22) 0.98 (0.80 - 1.21) 1.00 (0.96 - 1.04) T rend  1 2 = 0.01; p=0.94 99% or 95% CI