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.

The largest study in the above meta-analysis was a 2020 double-blind RCT (n = 382) that evaluated the effectiveness and safety of bempedoic acid in patients receiving maximally tolerated statin therapy.³ The study enrolled patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and those with either multiple cardiovascular risk factors (three of the following: men 45 years or older; women 55 years or older; hypertension; low HDL cholesterol; a family history of coronary heart disease; smoking; or a coronary calcium score above the 95th percentile for the patient's age, sex, and race or ethnicity) or diabetes and one risk factor.

Patients were assigned 2: 2: 2: 1 randomly to daily bempedoic acid (180 mg), ezetimibe (10 mg) plus bempedoic acid (180 mg), ezetimibe (10 mg), or placebo, respectively. The participants were a mean age of 64 years, 50.5% were women, and 62.5% had atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia. The primary end point was a 12-week change in LDL cholesterol levels. Compared with placebo, the group taking bempedoic acid plus ezetimibe had the most effective reduction in LDL cholesterol (−38%) vs. bempedoic acid only (−19%) and ezetimibe only (−25%; P < .001, for all comparisons to baseline and differences between groups). The most common adverse effects in the combination group included blood uric acid elevation and constipation (2.4% each; no P value provided).

The second largest primary prevention study in the above meta-analysis was a 2018 double-blind RCT (n = 269) that evaluated 180 mg of bempedoic acid daily for 12 weeks compared with placebo. All patients were permitted to continue study-provided ezetimibe, 10 mg once daily (started during the run-in phase), and background antihyperlipidemic therapy (taken before the study).⁴ Participants were adults with statin intolerance taking no or low-dose statin therapy and having LDL cholesterol levels greater than 100 mg per dL (2.59 mmol per L). Reasons for exclusion were significant cardiovascular disease (i.e., uncontrolled hypertension, class IV heart failure, history of an interventional cardiovascular procedure), an estimated glomerular filtration rate less than 30 mL per minute, body mass index greater than 50 kg per m², and proprotein convertase subtilisin/kexin type 9 inhibitor use within the past 4 months. The patients had a mean age of 64 years, 89.2% were White, and 61% were female. Most (75%) were prescribed treatment for the primary prevention of cardiovascular disease, had hypertension (60%), had chronic kidney disease (84%), and were taking other lipid-lowering therapy (31%). The primary outcome was a change in the LDL cholesterol level. Bempedoic acid added to ezetimibe reduced LDL cholesterol by 23.5%, whereas placebo added to ezetimibe increased LDL cholesterol by 5.0% (P < .001). No statistically significant adverse effects were noted in the bempedoic acid group vs. the placebo group.

The National Institute for Health and Care Excellence guidelines include the 2020 and 2018 double-blind RCTs and recommend bempedoic acid with ezetimibe in patients who cannot tolerate statins and when ezetimibe alone does not control LDL cholesterol.^3–5 The International Lipid Expert Panel evidence-based guidelines recommend using bempedoic acid to lower LDL cholesterol, preferably in a fixed-dose combination with ezetimibe.⁶