Background

Bempedoic acid, an ATP citrate lyase inhibitor, is known to reduce LDL cholesterol levels. It is particularly useful for patients who are unable to tolerate statins due to adverse effects. The drug’s impact on cardiovascular outcomes remains uncertain.

Summary

The CLEAR Outcomes trial investigated the effects of bempedoic acid in patients unable or unwilling to take statins due to adverse effects. A total of 13,970 patients were randomly assigned to receive either bempedoic acid or placebo.

Primary endpoint was a composite of major adverse cardiovascular events, including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

During a median follow-up of 40.6 months, bempedoic acid led to a significant reduction in LDL cholesterol levels by 29.2 mg per deciliter compared to placebo. The primary endpoint occurred in 11.7% of the bempedoic acid group and 13.3% of the placebo group, resulting in a hazard ratio of 0.87 with a 95% confidence interval (CI) of 0.79 to 0.96. Other key secondary endpoints, such as a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction, were also significantly lower in the bempedoic acid group.

Analysis

The trial was well-designed, involving a double-blind, randomized, placebo-controlled approach. The patient population consisted of those at high risk for cardiovascular disease who were intolerant to statins. The observed reduction in LDL cholesterol levels was substantial and consistent with previous studies of bempedoic acid. The study’s endpoints were clinically relevant, focusing on major adverse cardiovascular events that impact patient outcomes. The results suggest that bempedoic acid offers significant cardiovascular benefits for statin-intolerant patients.

Subcomponents of the primary endpoint:

• Death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction occurred in 8.2% of patients in the bempedoic acid group and 9.5% in the placebo group, with a hazard ratio of 0.85 (95% CI: 0.76 to 0.96; p-value: 0.006).
• Fatal or nonfatal myocardial infarction occurred in 3.7% of patients in the bempedoic acid group and 4.8% in the placebo group, with a hazard ratio of 0.77 (95% CI: 0.66 to 0.91; p-value: 0.002).
• Coronary revascularization occurred in 6.2% of patients in the bempedoic acid group and 7.6% in the placebo group, with a hazard ratio of 0.81 (95% CI: 0.72 to 0.92; p-value: 0.001).

Even though bempedoic acid reduced cardiovascular events it had no significant effect on reducing mortality. The trial also revealed a higher incidence of certain adverse events, such as gout and cholelithiasis, in the bempedoic acid group compared to placebo.

Incidences of hepatic enzyme elevations (4.5% vs. 3.0%), renal events (11.5% vs. 8.6%), hyperuricemia (10.9% vs. 5.6%), gout (3.1% vs. 2.1%), and cholelithiasis (2.2% vs. 1.2%) were higher with bempedoic acid.

This indicates potential trade-offs between cardiovascular benefits and certain side effects. Close monitoring of hepatic and renal functions, uric acid levels, and musculoskeletal symptoms is recommended in clinical practice.

Implications

The CLEAR Outcomes trial demonstrates that bempedoic acid can effectively reduce major adverse cardiovascular events in patients unable to tolerate statins. Viable alternative for managing cardiovascular risk in such individuals.

The full Research paper can be found on NEJM

Reference

Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, Thompson PD, Libby P, Cho L, Plutzky J, Bays HE, Moriarty PM, Menon V, Grobbee DE, Louie MJ, Chen CF, Li N, Bloedon LA, Robinson P, Horner M, Sasiela WJ, McCluskey J, Davey D, Fajardo-Campos P, Petrovic P, Fedacko J, Zmuda W, Lukyanov Y, Nicholls SJ, et al. (2023). Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 388(15):1353-1364. doi:10.1056/NEJMoa2215024