PCSK9 inhibitor appears more effective than ezetimibe for short-term LDL lowering in small, randomized trial
The authors of an accompanying editorial noted that PCSK9 inhibitors like evolocumab are not approved for the indication in the trial and have not yet been shown to reduce cardiovascular events.
Evolocumab may lead to significantly greater reduction in LDL cholesterol levels at 24 weeks in patients who cannot tolerate statins because of muscle-related adverse effects, reported a study funded by the drug's manufacturer.
In the study, published online April 3 by the Journal of the American Medical Association, researchers performed a 2-stage randomized clinical trial to compare the efficacy of lipid-lowering therapy with ezetimibe and evolocumab in patients with confirmed muscle symptoms due to statins. The study was funded by Amgen, which manufactures evolocumab.
In phase A of the trial, a 24-week crossover procedure with atorvastatin, 20 mg, or placebo was used to identify patients who had symptoms only while on the statin. In phase B, which took place after a 2-week washout period, patients were randomly assigned to 24 weeks of therapy with ezetimibe, 420 mg/mo, or evolocumab, 10 mg/d. The end points were mean percentage change in LDL cholesterol level from baseline to the mean of levels at week 22 and 24 and from baseline to the level at week 24.
Four hundred ninety-one patients entered phase A, and of these, 50.1% were women and 34.6% had coronary heart disease. Mean age was 60.7 years, and mean LDL cholesterol level at entry was 212.3 mg/dL. Two hundred nine (42.6%) had muscle symptoms while taking atorvastatin but not while taking placebo. One hundred ninety-nine of these patients entered phase B, along with 19 patients who proceeded directly to phase B because they had elevated levels of creatine kinase.
Seventy-three patients were randomly assigned to ezetimibe, and 145 patients were randomly assigned to evolocumab; the mean LDL cholesterol level at entry was 219.9 mg/dL. Greater change was seen in LDL cholesterol levels at 24 weeks with evolocumab compared with ezetimibe (mean percentage change, −52.8% vs. −16.7%; absolute change, −102.9 mg/dL vs. −31.2 mg/dL). Between-group difference in LDL cholesterol at week 24 was −36.1%, with an absolute difference of −71.7 mg/dL. A total of 28.8% of patients in the ezetimibe group and 20.7% of patients in the evolocumab group reported muscle symptoms. Five of 73 patients in the ezetimibe group (6.8%) and 1 of 145 patients in the evolocumab group (0.7%) stopped the study drug because of muscle symptoms.
The authors noted that the study was relatively small and that its design did not allow a common management strategy to be used for patients with muscle-related symptoms, among other limitations. However, they concluded that evolocumab led to significantly greater reduction in LDL cholesterol levels at 24 weeks in patients who cannot tolerate statins because of muscle-related adverse effects. They called for more studies to assess efficacy and safety over the long term.
The authors of an accompanying editorial noted that PCSK9 inhibitors like evolocumab are not approved for the indication in the trial and have not yet been shown to reduce cardiovascular events. In addition, they wrote, one-fifth of the study patients taking evolocumab because of statin intolerance continued to report muscle-related adverse effects, and PCSK9 inhibitors are expensive, with a current cost of approximate $14,000 for a 1-year supply.
The editorialists noted that it would be inappropriate to conclude that PCSK9 inhibitors should never be used in statin-intolerant patients and that such treatment should be considered in those at very high risk for a cardiovascular event who have intolerable muscle symptoms on even a low dose of statins. “Less than 1% of all ‘statin-intolerant’ patients might belong in this group at present,” the editorialists wrote. “For other patients with statin intolerance, the appropriateness of the use of these agents is less clear.”