The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial

Abstract

SummaryBackgroundLowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.MethodsThis randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607.Findings4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13).InterpretationReduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.FundingMerck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

Etiology and management of dyslipidemia in children with chronic kidney disease and end-stage renal disease

“…In the absence of randomized controlled clinical trials of dyslipidemia in CKD patients, these guidelines recommended following the 1992 National Cholesterol Education Program guidelines [89] for dyslipidemia goals in adults and adolescents with estimated glomerular filtration rates (eGFR) values of 15 ml./min/1.73 m 2 or greater (formerly known as CKD stages 1 to 4) and also recommended treatment in dyslipidemic adults and adolescents with eGFR values below 15 ml/min/1.73 m 2 (formerly known as stage 5 CKD) [90]. Recognizing that CKD is associated with pathological and/or clinical evidence of coronary disease before the age of 30 years and that multiple prospective studies show childhood lipid and lipoprotein profiles are predictive of future adult lipoprotein profiles with the strongest statistical correlation occurring between late childhood and the third and fourth decades of life [18,83], two expert pediatric panels published evidence-based guidelines for intensive cardiovascular risk reduction in children with CKD after the 2003 publication of the KDOQI guidelines [18,78].…”

“…Since publication of the KDOQI, AHA, and NHBLI guidelines, results from more than a dozen randomized controlled trials, including three landmark trials [88][89][90], have better informed dyslipidemia management in the adult CKD population and resulted in publication of the 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD [78]. This guideline focuses on lipid management for adults and children with CKD and contains substantial changes in dyslipidemia management in adult CKD from the KDOQI guidelines including the following:…”

“…The follow-up period was 4.9 years, and it showed a significant reduction in major atherosclerotic events, stroke, and arterial revascularization procedures in the treatment group. However, this effect was not observed in ESRD patients alone [27]. The AURORA trial [28] was a RCT that included more than 2,700 patients receiving hemodialysis.…”

Treatment and impact of dyslipidemia in diabetic nephropathy

“…The effect on renal protection was not demonstrated in the Study of Heart and Renal Protection (SHARP) which included 2,094 (33 %) patients with diabetes [34], and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) which included 3,638 (36 %) patients with diabetes [35]. A meta-analysis also showed that regression of albuminuria [31] and changes in eGFR [36] were not observed in patients with diabetes treated with statins.…”

“…There is sufficient evidence, such as SHARP [34], to show that statins reduce the risk of cardiovascular events. Considering these facts, many diabetic patients might benefit from statin treatment.…”