A double-blind, randomized, 12 week study was performed in patients with a clinical and/or genotypic diagnosis of HoFH. Data were analyzed from a subgroup of patients (n = 14) receiving simvastatin 40 mg at baseline. Increasing the dose of simvastatin from 40 mg to 80 mg (n = 5) produced a reduction of LDL-C of 13% from baseline on simvastatin 40 mg. Coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/40 mg and 10 mg/80 mg pooled, n = 9), produced a reduction of LDL-C of 23% from baseline on simvastatin 40 mg. In those patients coadministered ezetimibe and simvastatin equivalent to ezetimibe and simvastatin tablets (10 mg/80 mg, n = 5), a reduction of LDL-C of 29% from baseline on simvastatin 40 mg was produced.
The Study of Heart and Renal Protection (SHARP) was a multinational, randomized, placebo-controlled, double-blind trial that investigated the effect of ezetimibe and simvastatin on the time to a first major vascular event (MVE) among 9438 patients with moderate to severe chronic kidney disease (approximately one-third on dialysis at baseline) who did not have a history of myocardial infarction or coronary revascularization. An MVE was defined as nonfatal MI, cardiac death, stroke, or any revascularization procedure. Patients were allocated to treatment using a method that took into account the distribution of 8 important baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups.
For the first year, 9,438 patients were allocated 4:4:1, to ezetimibe and simvastatin tablets, 10 mg/20 mg, placebo, or simvastatin 20 mg daily, respectively. The 1 year simvastatin arm enabled the comparison of ezetimibe and simvastatin to simvastatin with regard to safety and effect on lipid levels. At 1 year the simvastatin-only arm was re-allocated 1:1 to ezetimibe and simvastatin tablets, 10 mg/20 mg or placebo. A total of 9,270 patients were ever allocated to ezetimibe and simvastatin tablets, 10 mg/20 mg (n = 4,650) or placebo (n = 4,620) during the trial. The median follow-up duration was 4.9 years. Patients had a mean age of 61 years; 63% were male, 72% were Caucasian, and 23% were diabetic; and, for those not on dialysis at baseline, the median serum creatinine was 2.5 mg/dL and the median estimated glomerular filtration rate (eGFR) was 25.6 mL/min/1.73 m 2 , with 94% of patients having an eGFR < 45 mL/min/1.73m 2. Eligibility did not depend on lipid levels. Mean LDL-C at baseline was 108 mg/dL. At 1 year, the mean LDL-C was 26% lower in the simvastatin arm and 38% lower in the ezetimibe and simvastatin arm relative to placebo. At the midpoint of the study (2.5 years), the mean LDL-C was 32% lower for ezetimibe and simvastatin relative to placebo. Patients no longer taking study medication were included in all lipid measurements.
In the primary intent-to-treat analysis, 639 (15.2%) of 4,193 patients initially allocated to ezetimibe and simvastatin and 749 (17.9%) of 4,191 patients initially allocated to placebo experienced an MVE. This corresponded to a relative risk reduction of 16% (p = 0.001) (see Figure 1). Similarly, 526 (11.3%) of 4,650 patients ever allocated to ezetimibe and simvastatin and 619 (13.4%) of 4620 patients ever allocated to placebo experienced a major atherosclerotic event (MAE; a subset of the MVE composite that excluded non-coronary cardiac deaths and hemorrhagic stroke), corresponding to a relative risk reduction of 17% (p = 0.002). The trial demonstrated that treatment with ezetimibe and simvastatin tablets, 10 mg/20 mg versus placebo reduced the risk for MVE and MAE in this CKD population. The study design precluded drawing conclusions regarding the independent contribution of either ezetimibe or simvastatin to the observed effect.
The treatment effect of ezetimibe and simvastatin on MVE was attenuated among patients on dialysis at baseline compared with those not on dialysis at baseline. Among 3,023 patients on dialysis at baseline, ezetimibe and simvastatin reduced the risk of MVE by 6% (RR 0.94: 95% CI 0.80 to 1.09) compared with 22% (RR 0.78: 95% CI 0.69 to 0.89) among 6,247 patients not on dialysis at baseline (interaction P = 0.08).
The individual components of MVE in all patients ever allocated to ezetimibe and simvastatin or placebo are presented in Table 12.
Ezetimibe and Simvastatin 10 mg/20 mg
(N = 4650)
(N = 4620)
Major Vascular Events
0.85 (0.77 to 0.94)
0.84 (0.66 to 1.05)
0.93 (0.78 to 1.10)
0.81 (0.66 to 0.99)
0.75 (0.60 to 0.94)
1.21 (0.78 to 1.86)
0.79 (0.68 to 0.93)
Among patients not on dialysis at baseline, ezetimibe and simvastatin did not reduce the risk of progressing to end-stage renal disease compared with placebo (RR 0.97: 95% CI 0.89 to 1.05).
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