Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study

Atherosclerosis. 2018 Oct:277:195-203. doi: 10.1016/j.atherosclerosis.2018.06.002. Epub 2018 Jun 12.


Background and aims: Patients with hyperlipidemia who are unable to tolerate optimal statin therapy are at increased cardiovascular risk due to ongoing elevations in low-density lipoprotein cholesterol (LDL-C). The objective of CLEAR Tranquility (NCT03001076) was to evaluate the efficacy and safety of bempedoic acid when added to background lipid-modifying therapy in patients with a history of statin intolerance who require additional LDL-C lowering.

Methods: This phase 3, multicenter, randomized, double-blind, placebo-controlled study enrolled patients with a history of statin intolerance and an LDL-C ≥100 mg/dL while on stable lipid-modifying therapy. After a 4-week ezetimibe 10 mg/day run-in period, patients were randomized 2:1 to treatment with bempedoic acid 180 mg or placebo once daily added to ezetimibe 10 mg/day for 12 weeks. The primary endpoint was the percent change from baseline to week 12 in LDL-C.

Results: The study population comprised 269 patients (181 bempedoic acid, 88 placebo). Bempedoic acid added to background lipid-modifying therapy that included ezetimibe reduced LDL-C by 28.5% more than placebo (p < 0.001; -23.5% bempedoic acid, +5.0% placebo). Significant reductions in secondary endpoints, including non-high-density lipoprotein cholesterol (-23.6%), total cholesterol (-18.0%), apolipoprotein B (-19.3%), and high-sensitivity C-reactive protein (-31.0%), were observed with bempedoic acid vs. placebo (p < 0.001). Bempedoic acid was well tolerated; rates of treatment-emergent adverse events, muscle-related adverse events, and discontinuations were similar in the bempedoic acid and placebo treatment groups.

Conclusions: Bempedoic acid may provide an oral therapeutic option complementary to ezetimibe in statin intolerant patients who require additional LDL-C lowering.

Keywords: Cardiovascular disease; ETC-1002; Hyperlipidemia; Low-density lipoprotein cholesterol; Prevention; Statin intolerance; Statin-associated muscle symptoms.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / blood
  • Canada
  • Cholesterol, LDL / blood*
  • Dicarboxylic Acids / adverse effects
  • Dicarboxylic Acids / therapeutic use*
  • Double-Blind Method
  • Down-Regulation
  • Drug Therapy, Combination
  • Europe
  • Ezetimibe / adverse effects
  • Ezetimibe / therapeutic use*
  • Fatty Acids / adverse effects
  • Fatty Acids / therapeutic use*
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects*
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / drug therapy*
  • Hypolipidemic Agents / adverse effects
  • Hypolipidemic Agents / therapeutic use*
  • Male
  • Middle Aged
  • Time Factors
  • Treatment Outcome
  • United States


  • Biomarkers
  • Cholesterol, LDL
  • Dicarboxylic Acids
  • Fatty Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hypolipidemic Agents
  • 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
  • Ezetimibe

Associated data

  • ClinicalTrials.gov/NCT03001076