Overall, 9270 patients were randomly assigned to simvastatin plus ezetimibe (4650 patients, 4193 initially plus 457 after 1 year) versus placebo (4620 patients, 4191 initially plus 429 after 1 year; ). Among these patients, all variables were well balanced between randomised groups (). Mean age was 62 years (SD 12), 5800 (63%) were male, mean blood pressure was 139/79 mm Hg, mean body-mass index was 27 (SD 6) kg/m2, 2094 (23%) had diabetes, and 1393 (15%) had a history of vascular disease (angina, stroke, or peripheral vascular disease). Self-reported ethnic origin was 6646 (72%) white, 264 (3%) black, 2086 (23%) Asian, and 274 (3%) other or unspecified. Mean baseline non-fasting plasma concentrations were 4·9 (SD 1·2) mmol/L for total cholesterol, 2·8 (SD 0·9) mmol/L for directly measured LDL cholesterol, 1·1 (SD 0·3) mmol/L for HDL cholesterol, and 2·3 (SD 1·7, IQR 1·3–2·8) mmol/L for triglycerides ().
Baseline demographic features and laboratory measurements by treatment allocation
3023 (33%) patients were receiving maintenance dialysis at randomisation (2527 [27%] haemodialysis and 496 [5%] peritoneal dialysis; ). Mean LDL cholesterol concentration was lower in patients on dialysis than in those who were not (2·6 [SD 0·9] vs
2·9 [SD 0·9] mmol/L; p<0·0001). Among the 6029 (97%) of 6247 patients not on dialysis with centrally measured creatinine, the average eGFR estimated with the Modification of Diet in Renal Disease equation17
was 26·6 (SD 13·0) mL/min per 1·73 m2
(): 2155 (36%) had Kidney Disease Outcomes Quality Initiative18
stage 3 disease (eGFR 30–59 mL/min per 1·73 m2
), 2565 (43%) stage 4 disease (eGFR 15–29 mL/min per 1·73 m2
), and 1221 (20%) stage 5 disease (eGFR <15 mL/min per 1·73 m2
). Among the 5574 (89%) of 6247 patients not on dialysis with a centrally measured urinary albumin-to-creatinine ratio (ACR), 1107 (20%) had ACR lower than 30 mg/g, 2108 (38%) had ACR 30–300 mg/g, and 2359 (42%) had ACR higher than 300 mg/g ().
The median duration of follow-up was 4·9 years for surviving patients. During the scheduled treatment period, slightly fewer patients allocated simvastatin plus ezetimibe discontinued study treatment (1533 [33·0%] simvastatin plus ezetimibe vs 1669 [36·1%] placebo); this finding was chiefly attributable to slightly more placebo-allocated patients commencing non-study statin therapy (337 [9·6%] vs 513 [14·6%]; p<0·0001). Among patients allocated simvastatin plus ezetimibe, there were no significant excesses of discontinuations due to suspected serious adverse reactions (17 [0·4%] vs 12 [0·3%]), other serious adverse events (297 [6·4%] vs 307 [6·6%]), non-serious adverse events (165 [3·5%] vs 131 [2·8%]), or other reasons (1054 [22·7%] vs 1219 [26·4%]).
Compliance was defined as at least 80% of the scheduled simvastatin plus ezetimibe or placebo tablets having been taken since the previous follow-up. Among the patients allocated simvastatin plus ezetimibe, 3403 (77%) of 4435 at the end of the first year of follow-up and 2397 (68%) of 3512 at the end of the fourth year remained compliant or were taking a non-study statin and, at the study midpoint (2·5 years), 2864 (71%) of 4058 were taking simvastatin plus ezetimibe or a non-study statin (). By contrast, in patients allocated placebo, 124 (3%) of 4162 patients at the end of the first year and 447 (14%) of 3278 at the end of the fourth year were taking a non-study statin and, at the study midpoint, the average use was 9% (341 of 3735 patients). Hence, the average difference in the proportion taking simvastatin plus ezetimibe or non-study statin was 61% (). As a result, the intention-to-treat comparisons assess the effects of around two-thirds of participants actually taking LDL-cholesterol-lowering treatment daily, which yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; ). The average use of simvastatin plus ezetimibe or non-study statin did not vary much among different types of patient (webappendix p 1), except that the average use was lower in patients who were on dialysis than in those who were not (54% vs 65%), which, taken together with the lower baseline LDL cholesterol concentration in patients on dialysis (2·6 vs 2·9 mmol/L), yielded a smaller average LDL cholesterol reduction (0·60 vs 0·96 mmol/L; webappendix p 1).
Average use of study simvastatin plus ezetimibe or non-study statin and average change in plasma LDL cholesterol from baseline, by period of follow-up
During the scheduled treatment period, there were 526 (11·3%) first major atherosclerotic events (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or arterial revascularisation) among the 4650 participants allocated simvastatin plus ezetimibe compared with 619 (13·4%) among the 4620 allocated placebo, corresponding to a significant 17% proportional reduction (RR 0·83, 95% CI 0·74–0·94; log-rank p=0·0021; and ). There was also a significant one-sixth reduction in major vascular events (ie, major atherosclerotic events plus non-coronary cardiac deaths and haemorrhagic strokes: 701 [15·1%] vs 814 [17·6%]; RR 0·85, 95% CI 0·77–0·94; p=0·0012; webappendix p 2), even when the patients initially allocated simvastatin alone were excluded (639 [15·2%] vs 749 [17·9%]; RR 0·84, 0·75–0·93; p=0·001).
Life-table plot of effects of allocation to simvastatin plus ezetimibe versus placebo on major atherosclerotic events
Major atherosclerotic events subdivided by type
Allocation to simvastatin plus ezetimibe was associated with non-significantly fewer first major coronary events (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37), which reflected non-significantly fewer non-fatal myocardial infarctions (134 [2·9%] vs 159 [3·4%]; RR 0·84, 0·66–1·05; p=0·12; ), but no significant difference in coronary mortality (91 [2·0%] vs 90 [1·9%]; RR 1·01, 0·75–1·35; p=0·95).
Allocation to simvastatin plus ezetimibe produced a significant reduction in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01; ), due chiefly to a significant reduction in strokes that were definitely ischaemic (114 [2·5%] vs 157 [3·4%]; RR 0·72, 0·57–0·92; p=0·0073). There were non-significantly more patients with haemorrhagic stroke (45 [1·0%] vs 37 [0·8%]; RR 1·21, 95% CI 0·78–1·86; p=0·4; webappendix p 2). There was a significant reduction in the risk of any type of stroke (171 [3·7%] vs 210 [4·5%]; RR 0·81, 95% CI 0·66–0·99; p=0·04).
Allocation to simvastatin plus ezetimibe significantly reduced the incidence of any arterial revascularisation (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036; ), with no evidence of statistical heterogeneity (χ12=2·0, p=0·2) between the reductions in coronary revascularisations (149 [3·2%] vs 203 [4·4%]; RR 0·73, 0·59–0·90), which was statistically significant (p=0·0027), and non-coronary revascularisations (ie, carotid, aortic or leg, but not haemodialysis access procedures), which was not (154 [3·3%] vs 169 [3·7%]; RR 0·90, 0·73–1·12; p=0·36). Among coronary revascularisation procedures, there was no evidence of statistical heterogeneity (χ12=0·1, p=0·8) between the reductions in percutaneous coronary intervention procedures (106 [2·3%] vs 148 [3·2%]; RR 0·71, 95% CI 0·56–0·91; p=0·0063) and coronary artery bypass grafts (50 [1·1%] vs 66 [1·4%]; RR 0·75, 0·52–1·09; p=0·13).
SHARP was not expected to have sufficient statistical power to allow reliable estimation of effects on major atherosclerotic events in particular clinical circumstances, so subgroup analyses were planned only as tertiary assessments.12
There was not good evidence that the proportional effects on major atherosclerotic events differed between patients on dialysis and not (χ12
=1·3, p=0·25; ), and nor were there trends towards smaller proportional reductions in patients not on dialysis with lower eGFR (trend χ12
=0·12, p=0·73) or higher urinary albumin excretion (trend χ12
=0·38, p=0·54; ). Conventionally significant trends in the proportional effect of allocation to simvastatin plus ezetimibe were observed for subgroups defined by total cholesterol (trend χ12
=9·01, p=0·0027) and body-mass index (trend χ12
=4·04, p=0·04). After adjustment for the subgroup-specific LDL cholesterol reductions, the χ12
statistics were reduced but remained conventionally significant for total cholesterol (p=0·02; webappendix p 3).
Major atherosclerotic events by baseline characteristics
Allocation to simvastatin plus ezetimibe was associated with non-significantly fewer cardiac deaths (253 [5·4%] vs 272 [5·9%]; RR 0·93, 95% CI 0·78–1·10; p=0·38; ) and stroke deaths (68 [1·5%] vs 78 [1·7%]; RR 0·87, 0·63–1·20, p=0·39), but with similar numbers of deaths due to other vascular causes (40 [0·9%] vs 38 [0·8%]; RR 1·05, 0·67–1·64, p=0·83); overall, there were non-significantly fewer deaths due to any vascular cause (361 [7·8%] vs 388 [8·4%]; RR 0·93, 0·80–1·07; p=0·30; ). Simvastatin plus ezetimibe was associated with non-significantly more deaths from any non-vascular cause (668 [14·4%] vs 612 [13·2%]; RR 1·09, 95% CI 0·98–1·21, p=0·13), but was not associated with a significant excess of deaths from any particular non-vascular cause considered separately or with excess deaths from any unknown cause (113 [2·4%] vs 115 [2·5%]; RR 0·98, 0·76–1·27, p=0·87). There was no significant effect on deaths from any cause (1142 [24·6%] vs 1115 [24·1%]; RR 1·02, 95% CI 0·94–1·11; p=0·63).
Cause-specific and overall mortality
First post-randomisation cancers occurred in 877 (9%) patients during the scheduled follow-up period. There was no evidence that simvastatin plus ezetimibe increased the incidence of cancer (438 [9·4%] vs 439 [9·5%], RR 0·99, 95% CI 0·87–1·13, p=0·89; ) or of increasing hazard with length of follow-up (webappendix p 4). There was also no significantly increased incidence of, or mortality from, cancer at any particular site ().
Cancer incidence and cancer mortality by site
Allocation to simvastatin plus ezetimibe did not yield significant excesses of creatine kinase concentrations of 10–40 times the upper limit of normal (ULN) or greater than 40 times the ULN (). There were very few cases of myopathy of any severity (defined as creatine kinase greater than ten times the ULN with muscle symptoms: 9 [0·2%] simvastatin plus ezetimibe vs 5 [0·1%] placebo) or of more severe cases with rhabdomyolysis (defined as myopathy with creatine kinase greater than 40 times the ULN: 4 [0·1%] vs 1 [0·0%]). Nor were there significant excesses of persistently raised transaminases to greater than three times the ULN, hepatitis, or gallstones (with or without complications). Among patients allocated simvastatin plus ezetimibe, there were fewer cases of pancreatitis without gallstones ().
Effects of allocation to simvastatin plus ezetimibe on muscle and hepatobiliary system
Among the 6247 patients not on dialysis at randomisation, allocation to simvastatin plus ezetimibe did not produce significant reductions in any of the prespecified measures of renal disease progression: end-stage renal disease defined as commencement of maintenance dialysis or transplantation (1057 [33·9%] vs 1084 [34·6%]; RR 0·97, 95% CI 0·89–1·05, p=0·41); end-stage renal disease or death (1477 [47·4%] vs 1513 [48·3%]; RR 0·97, 0·90–1·04, p=0·34); and end-stage renal disease or doubling of baseline creatinine (1190 [38·2%] vs 1257 [40·2%]; RR 0·93, 0·86–1·01; p=0·09).