Physicians' Academy for Cardiovascular Education

Safety of cholesterol biosynthesis inhibitor in high CV risk patients

Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol

Literature - Ray KK, Bays HE, Catapano AL et al. - NEJM 2019;380:1022-32.; DOI: 10.1056/NEJMoa1803917

Introduction and methods

Statin use alone is often insufficient to lower LDL-c to goal levels in patients with increased CV risk [1,2]. Therefore, additional therapies are needed that are safe and effective in lowering LDL-c on top of standard-of-care medical therapies.

Bempedoic acid has been shown to lower LDL-c by inhibiting ATP citrate lyase, a key enzyme in the cholesterol biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the target for statins. Bempedoic acid inhibits production of cholesterol in the liver, but not in muscles [3]. Results of 12 weeks treatment with bempedoic acid have been shown previously [4-8]. Now, patients were followed for 1 year.

The CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Harmony trial, was a randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial of bempedoic acid, in which safety, side-effect profile and efficacy was assessed over a 1-year intervention period (conducted from Jan 2016-Feb 2018). Patients with ASCVD or heterozygous FH were included, who were taking maximally tolerated statins alone or in combination with other lipid-lowering therapies, in addition they had LDL-c levels ≥70 mg/dL (1.8 mmol/L). Patients were assigned in a 2:1 ratio to receive bempedoic acid (n=1488) or placebo (n=742). Primary endpoint was safety.

Main results


The authors concluded that in the CLEAR Harmony trial, use of bempedoic acid in patients with high CV risk had an acceptable safety profile. Number of deaths was higher in the bempedoic acid group compared to placebo group, but the authors noted that deaths from cancer in general occurred early in the trial, suggesting preexisting cancers and they stated that these findings are likely a chance finding.


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