1. The results of the Study of Heart and Renal Protection (SHARP) Colin Baigent, Martin Landray on behalf of the SHARP Investigators Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC, British Heart Foundation, and Australian NHMRC. Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

2. SHARP: Rationale  Risk of vascular events is high among patients with chronic kidney disease  Lack of clear association between cholesterol level and vascular disease risk  Pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic  Previous trials of LDL-lowering therapy in chronic kidney disease are inconclusive  Risk of vascular events is high among patients with chronic kidney disease  Lack of clear association between cholesterol level and vascular disease risk  Pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic  Previous trials of LDL-lowering therapy in chronic kidney disease are inconclusive Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

3. SHARP: Eligibility  History of chronic kidney disease Not on dialysis: elevated creatinine on 2 occasions ► Men:≥1.7 mg/dL (150 µmol/L) ► Women:≥1.5 mg/dL (130 µmol/L) On dialysis: haemodialysis or peritoneal dialysis  Age ≥40 years  No history of myocardial infarction or coronary revascularization  Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

4. SHARP: Assessment of LDL-lowering

5. SHARP: Baseline characteristics Age (years)62 ± 12 Men63% Systolic BP (mmHg)139 ± 22 Diastolic BP (mmHg)79 ± 13 Body mass index (kg/m 2 )27 ± 6 Current smoker13% Vascular disease15% Diabetes mellitus23% Non-dialysis patients only (n=6247) eGFR (ml/min/1.73m 2 )27 ± 13 Albuminuria80% Age (years)62 ± 12 Men63% Systolic BP (mmHg)139 ± 22 Diastolic BP (mmHg)79 ± 13 Body mass index (kg/m 2 )27 ± 6 Current smoker13% Vascular disease15% Diabetes mellitus23% Non-dialysis patients only (n=6247) eGFR (ml/min/1.73m 2 )27 ± 13 Albuminuria80% Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

6. SHARP: Compliance and LDL-C reduction at study midpoint ~2/3 compliance LDL-C reduction of 32 mg/dL with 2/3 compliance, equivalent to 50 mg/dL with full compliance LDL-C reduction of 32 mg/dL with 2/3 compliance, equivalent to 50 mg/dL with full compliance Eze/simvaPlacebo Compliant66%64% Non-study statin5%8% Any lipid-lowering71%8% Eze/simvaPlacebo Compliant66%64% Non-study statin5%8% Any lipid-lowering71%8% Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

7. SHARP: Baseline paper and data analysis plan  1-year LDL-C reduction of 30 mg/dL with simvastatin 20 mg alone and of 43 mg/dL with eze/simva 10/20 mg  Confirmation of safety of ezetimibe when added to simvastatin (1-year results)  Revised data analysis plan published as an appendix before unblinding of main results  1-year LDL-C reduction of 30 mg/dL with simvastatin 20 mg alone and of 43 mg/dL with eze/simva 10/20 mg  Confirmation of safety of ezetimibe when added to simvastatin (1-year results)  Revised data analysis plan published as an appendix before unblinding of main results Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease SHARP Collaborative Group. Am Heart J 2010 (in press)

8. SHARP: Main outcomes  Key outcome Major atherosclerotic events (coronary death, MI, non-haemorrhagic stroke, or any revascularization)  Subsidiary outcomes Major vascular events (cardiac death, MI, any stroke, or any revascularization) Components of major atherosclerotic events  Main renal outcome End-stage renal disease (dialysis or transplant)  Key outcome Major atherosclerotic events (coronary death, MI, non-haemorrhagic stroke, or any revascularization)  Subsidiary outcomes Major vascular events (cardiac death, MI, any stroke, or any revascularization) Components of major atherosclerotic events  Main renal outcome End-stage renal disease (dialysis or transplant) Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

9. SHARP: Major atherosclerotic events 0 0 1 1 2 2 3 3 4 4 5 5 Years of follow-up 0 0 5 5 10 15 20 25 Proportion suffering event (%) Risk ratio 0.83 (0.74-0.94) Logrank 2P=0.0022 Placebo Eze/simva Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

10. Proportional reduction in atherosclerotic event rate (95% CI) Proportional reduction in atherosclerotic event rate (95% CI) 0 0 5 5 10 15 20 25 30 Statin vs. control (21 trials) Mean LDL-C difference between treatment groups (mg/dL) More vs. less (5 trials) SHARP 32 mg/dL 20 40 10 30 CTT: Effects on major atherosclerotic events 0 0 Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010 SHARP 17% risk reduction

11. SHARP: Major atherosclerotic and vascular events Risk ratio (95% CI) Placebo (n=4620) Placebo (n=4620) Eze/simva (n=4650) Eze/simva (n=4650) Major coronary event Non-haemorrhagic stroke Any revascularization Major atherosclerotic event Other cardiac death Haemorrhagic stroke Other major vascular events Major vascular event Major coronary event Non-haemorrhagic stroke Any revascularization Major atherosclerotic event Other cardiac death Haemorrhagic stroke Other major vascular events Major vascular event 213 131 284 526 162 45 207 701 213 131 284 526 162 45 207 701 (4.6%) (2.8%) (6.1%) (11.3%) (3.5%) (1.0%) (4.5%) (15.1%) (4.6%) (2.8%) (6.1%) (11.3%) (3.5%) (1.0%) (4.5%) (15.1%) 230 174 352 619 182 37 218 814 230 174 352 619 182 37 218 814 (5.0%) (3.8%) (7.6%) (13.4%) (3.9%) (0.8%) (4.7%) (17.6%) (5.0%) (3.8%) (7.6%) (13.4%) (3.9%) (0.8%) (4.7%) (17.6%)  16.5% SE 5.4 (P=0.0022)  5.4% SE 9.4 (P=0.57)  15.3% SE 4.7 (P=0.0012) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

12. SHARP: Effects in subgroups  Among 8384 patients originally randomized to ezetimibe/simvastatin vs. placebo, major vascular events risk ratio = 0.84 (95% CI 0.75-0.93; P=0.0010)  Similar reductions in major atherosclerotic events in all subgroups studied (including non-dialysis and dialysis patients)  Among 8384 patients originally randomized to ezetimibe/simvastatin vs. placebo, major vascular events risk ratio = 0.84 (95% CI 0.75-0.93; P=0.0010)  Similar reductions in major atherosclerotic events in all subgroups studied (including non-dialysis and dialysis patients) Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

13.  16.5% SE 5.4 (P=0.0022) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better SHARP: Major atherosclerotic events by renal status at randomization Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010 Non-dialysis (n=6247) Dialysis (n=3023) Major atherosclerotic event Non-dialysis (n=6247) Dialysis (n=3023) Major atherosclerotic event 296 230 526 296 230 526 (9.5%) (15.0%) (11.3%) (9.5%) (15.0%) (11.3%) 373 246 619 373 246 619 (11.9%) (16.5%) (13.4%) (11.9%) (16.5%) (13.4%) No significant heterogeneity between non-dialysis and dialysis patients (P=0.25) Risk ratio (95% CI) Placebo (n=4620) Placebo (n=4620) Eze/simva (n=4650) Eze/simva (n=4650)

14. Risk ratio (95% CI) Placebo (n=4620) Placebo (n=4620) Eze/simva (n=4650) Eze/simva (n=4650) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010 Coronary Other cardiac Subtotal: Any cardiac Stroke Other vascular Subtotal: Any vascular Cancer Renal Other non-vascular Subtotal: Any non- vascular Unknown cause Total: Any death Coronary Other cardiac Subtotal: Any cardiac Stroke Other vascular Subtotal: Any vascular Cancer Renal Other non-vascular Subtotal: Any non- vascular Unknown cause Total: Any death 91 162 253 68 40 361 150 164 354 668 113 1142 91 162 253 68 40 361 150 164 354 668 113 1142 (2.0%) (3.5%) (5.4%) (1.5%) (0.9%) (7.8%) (3.2%) (3.5%) (7.6%) (14.4%) (2.4%) (24.6%) (2.0%) (3.5%) (5.4%) (1.5%) (0.9%) (7.8%) (3.2%) (3.5%) (7.6%) (14.4%) (2.4%) (24.6%) 90 182 272 78 38 388 128 173 311 612 115 1115 90 182 272 78 38 388 128 173 311 612 115 1115 (1.9%) (3.9%) (5.9%) (1.7%) (0.8%) (8.4%) (2.8%) (3.7%) (6.7%) (13.2%) (2.5%) (24.1%) (1.9%) (3.9%) (5.9%) (1.7%) (0.8%) (8.4%) (2.8%) (3.7%) (6.7%) (13.2%) (2.5%) (24.1%) ↓ 7.4% SE 8.4 (P=0.38) ↓ 7.3% SE 7.0 (P=0.30) ↑ 8.6% SE 5.8 (P=0.14) ↑ 1.9% SE 4.2 (P=0.65) SHARP: Cause-specific mortality

15. 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Main renal outcome End-stage renal disease (ESRD) Tertiary renal outcomes ESRD or death ESRD or 2 x creatinine Main renal outcome End-stage renal disease (ESRD) Tertiary renal outcomes ESRD or death ESRD or 2 x creatinine 1057 1477 1190 1057 1477 1190 (33.9%) (47.4%) (38.2%) (33.9%) (47.4%) (38.2%) 1084 1513 1257 1084 1513 1257 (34.6%) (48.3%) (40.2%) (34.6%) (48.3%) (40.2%) 0.97 (0.89-1.05) 0.97 (0.90-1.04) 0.94 (0.86-1.01) SHARP: Renal outcomes Risk ratio (95% CI) Placebo (n=3130) Placebo (n=3130) Eze/simva (n=3117) Eze/simva (n=3117) Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

16. SHARP: Cancer incidence Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010 0 0 1 1 2 2 3 3 4 4 5 5 Years of follow-up 0 0 5 5 10 15 20 25 Proportion suffering event (%) Placebo Eze/simva Risk ratio 0.99 (0.87-1.13) Logrank 2P=0.89

17. Oropharynx/oesophagus Stomach Bowel Pancreas Hepatobiliary Lung Other respiratory Skin cancer Breast Prostate Kidney Bladder & urinary tract Genital Haematological Other known site Unspecified site Any incident cancer Oropharynx/oesophagus Stomach Bowel Pancreas Hepatobiliary Lung Other respiratory Skin cancer Breast Prostate Kidney Bladder & urinary tract Genital Haematological Other known site Unspecified site Any incident cancer 14 11 53 9 8 42 3 136 29 39 31 26 12 26 9 13 438 14 11 53 9 8 42 3 136 29 39 31 26 12 26 9 13 438 16 14 35 10 4 35 4 153 21 52 23 32 14 27 12 7 439 16 14 35 10 4 35 4 153 21 52 23 32 14 27 12 7 439 No significant differences SHARP: Cancer incidence by site Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010 Eze/simva (n=4650) Eze/simva (n=4650) Placebo (n=4620) Placebo (n=4620) (9.5%) (9.4%)

18. SHARP: Safety  Myopathy CK >10 x but ≤40 x ULN CK >40 x ULN  Hepatitis  Persistently elevated ALT/AST >3x ULN  Complications of gallstones  Other hospitalization for gallstones  Pancreatitis without gallstones  Myopathy CK >10 x but ≤40 x ULN CK >40 x ULN  Hepatitis  Persistently elevated ALT/AST >3x ULN  Complications of gallstones  Other hospitalization for gallstones  Pancreatitis without gallstones 16 (0.3%) 5 (0.1%) 18 (0.4%) 26 (0.6%) 76 (1.6%) 30 (0.6%) 17 (0.4%) 16 (0.3%) 5 (0.1%) 18 (0.4%) 26 (0.6%) 76 (1.6%) 30 (0.6%) 17 (0.4%) 4 (0.1%) 21 (0.5%) 30 (0.6%) 85 (1.8%) 21 (0.5%) 12 (0.3%) 17 (0.4%) 4 (0.1%) 21 (0.5%) 30 (0.6%) 85 (1.8%) 21 (0.5%) 12 (0.3%) Eze/simva (n=4650) Eze/simva (n=4650) Placebo (n=4620) Placebo (n=4620) Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010

19. SHARP: Conclusions  No increase in risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality  No substantial effect on kidney disease progression  Two-thirds compliance with eze/simva reduced the risk of major atherosclerotic events by 17% (consistent with meta-analysis of previous statin trials)  Similar proportional reductions in all subgroups (including among dialysis and non-dialysis patients)  Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30-40 events per 1000 treated for 5 years  No increase in risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality  No substantial effect on kidney disease progression  Two-thirds compliance with eze/simva reduced the risk of major atherosclerotic events by 17% (consistent with meta-analysis of previous statin trials)  Similar proportional reductions in all subgroups (including among dialysis and non-dialysis patients)  Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30-40 events per 1000 treated for 5 years Presented at the Am. Soc. Nephrology, Denver, Nov 20 th 2010