Bempedoic Acid for the Prevention of Cardiovascular Disease

Is bempedoic acid (Nexletol) effective for the primary prevention of cardiovascular disease?

Bempedoic acid can be used to effectively treat hyperlipidemia. (Strength of Recommendation [SOR]: B, single, high-quality, randomized controlled trial [RCT].) Bempedoic acid decreases the incidence of major adverse cardiovascular events, with insignificant increases in liver enzyme and creatine kinase levels, gout, myalgia, and cholelithiasis. When bempedoic acid is used for the primary and secondary prevention of cardiovascular disease, it is more effective than placebo at lowering non–high-density lipoprotein (HDL), low-density lipoprotein (LDL), and total cholesterol. (SOR: C, disease-oriented evidence based on a single meta-analysis of RCTs.) In patients prescribed a maximum dosage of tolerated statins, bempedoic acid added to ezetimibe, compared with either agent alone, is more effective at lowering LDL cholesterol. (SOR: C, disease-oriented evidence based on a single RCT.)

A 2023 subgroup analysis of a double-blind RCT evaluated the benefit of bempedoic acid (180 mg) vs. placebo for primary cardiovascular disease prevention in patients with statin intolerance.¹ The subgroup analysis included 4,206 patients (59% were female between 18 and 85 years of age; 92% identified as White) who met the criteria for high cardiovascular risk without a previous cardiovascular event and intolerance to the guideline-recommended dosage of statins. Most patients had diabetes mellitus (66%) or hypertension (88%). Patients were permitted to continue adjunct antihyperlipidemic agents; 19.3% took a very low-dose statin (defined as less than 10 mg daily of simvastatin or atorvastatin), and 8% took ezetimibe. The primary outcome was the time to first incidence of a four-component major adverse cardiovascular event (i.e., death from cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization).

Secondary outcomes included the time to other cardiovascular end points and all-cause mortality. After 36 months of follow-up, bempedoic acid significantly decreased the primary outcome (adjusted hazard ratio [HR] = 0.70; 95% CI, 0.55 to 0.89]; number needed to treat [NNT] = 44) compared with placebo. Bempedoic acid also decreased the risk of all-cause mortality (adjusted HR = 0.73; 95% CI, 0.54 to 0.98; NNT = 63). Compared with placebo, the bempedoic acid–only cohort had insignificant increases in liver enzyme and uric acid levels, kidney injury, myalgia, gout, and cholelithiasis. Study limitations included underpowered subgroup analysis.

A 2020 meta-analysis of 10 phase 2 and 3 RCTs (n = 3,788) evaluated the benefit and safety profile of bempedoic acid compared with placebo in treating hypercholesterolemia for the primary and secondary prevention of cardiovascular disease.² The study outcome measures were lipid and high-sensitivity C-reactive protein levels, treatment discontinuation, and drug-related adverse effects.

Compared with placebo, bempedoic acid reduced the levels of total cholesterol (mean difference [MD] = −14.94%; 10 studies; n = 3,485), non-HDL cholesterol (MD = −18.17%; nine studies; n = 3,485), LDL cholesterol (MD = −22.94%; 10 studies; n = 3,483), apolipoprotein B (MD = −15.18%; eight studies; n = 3,402), HDL cholesterol (MD = −5.83%; nine studies; n = 3,453), and high-sensitivity C-reactive protein (MD = −27.03%; five studies; n = 3,179). Compared with placebo, bempedoic acid had no significant effect on triglycerides, very low LDL cholesterol, and apolipoprotein A-1 levels. Bempedoic acid increased liver enzymes (odds ratio [OR] = 4.28; 95% CI, 1.34 to 13.71; five studies; n = 2,363), creatine kinase levels (OR = 3.79; 95% CI, 1.06 to 13.51; four studies; n = 2,718), and treatment discontinuation rates (OR = 1.37; 95% CI, 1.06 to 1.76; nine studies; n = 3,731). There was significant heterogeneity between studies for most outcomes.