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

Abstract

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: NCT 02988115.

Trial registration: ClinicalTrials.gov NCT02988115.

Keywords: hypercholesterolemia; lipids; low‐density lipoprotein cholesterol; muscle; statin.

Figures

Figure 1

Study design.

Figure 2

Patient disposition.

Figure 3

Effect of bempedoic acid in patients with statin intolerance: percent change from baseline to week 12 in lipid parameters and biomarkers. Data for low‐density lipoprotein cholesterol (LDL‐C), non–high‐density lipoprotein cholesterol (non–HDL‐C), total cholesterol (TC), and apolipoprotein B (apoB) are means±standard error. Data are medians for high‐sensitivity C‐reactive protein (hsCRP). LDL‐C, non–HDL‐C, TC, and apoB were analyzed using analysis of covariance, with percent change from baseline as the dependent variable, treatment and cardiovascular disease risk category (primary prevention, secondary prevention) as fixed effects, and baseline as a covariate. hsCRP was analyzed using nonparametric Wilcoxon rank sum test. *P<0.001 vs placebo.

Figure 4

Effect of bempedoic acid in patients with statin intolerance: LDL‐C (low‐density lipoprotein cholesterol), apolipoprotein B, and hsCRP (high‐sensitivity C‐reactive protein) from baseline through week 24. Data for (A) LDL‐C and (B) apolipoprotein B are means±standard errors. (C) For hsCRP, data are medians, with error bars indicating Q1 and Q3.

Figure 5

Effect of bempedoic acid in patients with statin intolerance: change from baseline to week 12 in LDL‐C by patient subgroup. BMI indicates body mass index; CVD, cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; LDL‐C, low‐density lipoprotein cholesterol; LMT, lipid‐modifying therapy; LS, least‐squares.