Bempedoic Acid and Atherogenic Lipid Levels in Hypercholesterolemia Trials

Quick Takes

  • Bempedoic acid is a nonstatin that lowers the LDL-C by about 20 mg/dl in persons on maximally tolerated statins, and 37 mg/dl in statin-intolerant persons.
  • It increases hyperuricemia and gout (1.4% vs. 0.3%) by three-fold, does not cause myalgias or muscle weakness, and has no impact on glycemic status.

Study Questions:

What is the effect of bempedoic acid in patients with hypercholesterolemia who are on stable lipid-lowering therapy and high cardiovascular risk or hypercholesterolemia with statin intolerance?


A pooled analysis was conducted from four double-blind placebo-controlled randomized trials with 2:1 to 180 mg bempedoic acid (n = 2,425) or placebo (n = 1,198) once daily for 12-52 weeks. Primary efficacy endpoint was percent change from baseline in low-density lipoprotein cholesterol (LDL-C) at 12 weeks by intention-to-treat. Patients were assigned into two groups based on enrollment criteria: 1) hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) or both and receiving statins, and 2) patients with statin intolerance and hypercholesterolemia on maximally tolerated statins.


The mean (standard deviation) age was 65.2 (9.2) years and similar in the two groups. In those with ASCVD or HeFH or both, the baseline mean LDL-C was 107.6 (32.7) mg/dl. At week 12, the LDL-C was -16% from baseline on bempedoic acid versus 1.8% with placebo (difference -18%, p < 0.001). Patients with statin intolerance had a mean baseline LDL-C of 144.4 (38.8) mg/dl. At week 12, the percentage change was -23% with bempedoic acid versus 1.5% on placebo (difference -24%, p < 0.001). The decrease in LDL-C with bempedoic acid was sustained during long-term follow-up in both pools. Decreases in non–high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels were greater with bempedoic acid versus placebo. Adverse events were more frequent with bempedoic acid than with placebo and included increased blood uric acid level (2.1% vs. 0.5%), gout (1.4% vs. 0.4%), decreased glomerular filtration rate (0.7% vs. <0.1%), and increased levels of hepatic enzymes (2.8% vs. 1.3%).


Bempedoic acid added to maximally tolerated statins, including moderate- or high-intensity statins or no background statin, was associated with decreased LDL-C levels versus placebo in patients with hypercholesterolemia with an acceptable safety profile. As a nonstatin adjunct or statin alternative, bempedoic acid has potential for use in a broad spectrum of patients.


Bempedoic acid (Esperion Therapeutics Inc.) decreases LDL-C by inhibition of hepatic adenosine triphosphate–citrate lyase, a key enzyme in the cholesterol biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Similar to statins, by up-regulating hepatic LDL receptor expression, bempedoic acid lowers LDL-C blood levels by increasing clearance of circulating LDL-C particles. While it does not result in classic myalgias or weakness, compared to placebo, bempedoic acid does cause muscle spasms and “leg pain.” It does not result in new-onset or worsening of diabetes. When used in combination with statins, the benefit of bempedoic acid is greater than the anticipated 6% doubling of the dose of statins, and when combined with ezetimibe, the LDL-C lowering is additive. The degree to which the decrease in LDL-C level associated with bempedoic acid impacts ASCVD outcomes is being evaluated in the ongoing CLEAR Outcomes study.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins

Keywords: Atherosclerosis, Cholesterol, LDL, C-Reactive Protein, Dyslipidemias, Glomerular Filtration Rate, Gout, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Myalgia, Primary Prevention, Risk Factors, Uric Acid

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