Key Points
Bempedoic acid, an ATP citrate lyase inhibitor, has been shown to reduce LDL cholesterol concentrations by 17% to 28% in clinical trials. However, data on whether bempedoic acid reduces cardiovascular events has been lacking.
The CLEAR Outcomes trial enrolled 13,970 statin-intolerant individuals at risk for, or with established cardiovascular disease, and randomized them to 180 mg of bempedoic acid per day or placebo.
Over a median follow-up of 40.6 months, treatment with bempedoic acid resulted in a 13% relative reduction in the composite primary endpoint of CV death, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization).
Musculoskeletal adverse effects are reported among 5-20% of patients prescribed statins in clinical practice resulting in poor adherence or medication discontinuation. Accordingly, non-statin alternatives are an important contribution to the LDL-C lowering armamentarium, particularly for individuals at high-risk for or with established cardiovascular disease. Bempedoic acid, an ATP citrate lyase inhibitor, has been shown to reduce LDL cholesterol concentrations by 17 to 29% in clinical trials, and was approved by the FDA in 2020 for individuals with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C as an adjunct to diet and maximally tolerated statin therapy. However, data on whether bempedoic acid reduces cardiovascular events has been lacking.
The Clear Outcomes trial (NCT02993406) was a double-blind, randomized, placebo-controlled trial conduced at 1250 sites in 32 countries which evaluated the effect of 180 mg of bempedoic acid daily on major adverse cardiovascular events (defined as cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization) as compared to placebo. The trial enrolled individuals aged 18 years or older deemed at high risk for a cardiovascular event or with established cardiovascular disease. Eligible patients had to be unable or unwilling to receive statins due to an adverse effect (i.e. “statin-intolerant”). Women who were pregnant or lactating, and individuals with a recent (within 90 days) major cardiovascular event, transient ischemic attack, or unstable or symptomatic arrhythmia were not candidates for the study . A total of 13,970 participants underwent randomization. The mean age of the participants was 65 years, 48% were women, and the majority had a prior cardiovascular event (69.9%). Approximately 23% were taking a statin and 12% were receiving ezetimibe at the time of enrollment. The mean baseline LDL cholesterol concentration was 139 mg/dl.
The median follow-up was 40.6 months. There was a 21% greater reduction in LDL cholesterol levels with bempedoic acid treatment as compared to placebo at 6 months; the time-averaged difference in LDL cholesterol reduction between the two groups over the course of the trial was 15.9% in favor of bempedoic acid. The primary endpoint occurred in 11.7% participants in the bempedoic acid group and in 13.3% of individuals in the placebo group (hazard ratio, 0.87; 95% CI 0.79 to 0.96; p=0.004). The incidence of the secondary endpoint of three components (cardiovascular death, non-fatal MI, or non-fatal stroke) was also reduced with bempedoic acid as compared to placebo (8.2% vs. 9.5%; hazard ratio, 0.85; 95% CI 0.76 to 0.96; p=0.006). There was no difference in cardiovascular mortality or all-cause mortality between the two groups. There were small absolute increases in the incidence of gout (3.1% vs 2.1%) and cholelithiasis (2.2% vs 1.2%) among individuals treated with bempedoic acid compared to placebo, respectively. The incidence of musculoskeletal adverse events did not differ between the two randomization groups.
The authors noted that these findings establish bempedoic acid as an effective approach to reduce major cardiovascular events in statin intolerant patients.
