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?

Methods:

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.

Results:

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%).

Conclusions:

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.

Perspective:

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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