Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance

BACKGROUND: Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP‐citrate lyase, an enzyme upstream of β‐hydroxy β‐methylglutaryl‐coenzyme A reductase in the cholesterol biosynthesis pathway. METHODS AND RESULTS: The phase 3, double‐blind, placebo‐controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL‐Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low‐density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low‐density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin‐associated muscle symptoms. Bempedoic acid treatment significantly reduced low‐density lipoprotein cholesterol from baseline to week 12 (placebo‐corrected difference, −21.4% [95% CI, −25.1% to −17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non–high‐density lipoprotein cholesterol (−17.9%), total cholesterol (−14.8%), apolipoprotein B (−15.0%), and high‐sensitivity C‐reactive protein (−24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle‐related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. CONCLUSIONS: Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02988115.