Bempedoic Acid Decreases CVD Events in One RCT, but Better Studies Needed

Jennifer Middleton, MD, MPH
Posted on March 13, 2023

The U.S. Preventive Services Task Force (USPSTF) recommends statin therapy for primary prevention in certain persons at elevated risk of cardiovascular disease (CVD), and solid evidence mandates statins for secondary prevention in most persons with a history of CVD. Although 5% to 10% of people taking statins report muscle aches and researchers disagree about how valid those symptoms are (with at least one study suggesting nocebo effect is to blame), they still lead to statin discontinuation for some patients. Although various alternatives to statins have been investigated over the years, none has been shown to reduce the risk of CVD events until now.

A randomized controlled trial (RCT) published earlier this month studied the efficacy of bempedoic acid (Nexletol) in people who self-identified as statin-intolerant to reduce the risk of CVD outcomes. Researchers enrolled nearly 14,000 participants across 32 countries between the 18 and 85 years of age if they had either a history of a CVD event (secondary prevention) or were determined to be at elevated risk of a first CVD event (primary prevention). The mean age of participants was 65.5 years of age, 48% of participants were women, and more than 90% of enrolled participants identified as White. The trial’s primary outcome was a “composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.” The researchers found that:

The incidence of a primary end-point event was significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P=0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P=0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P=0.001).

The researchers alluded to differences between the participants with and without a history of CVD in their discussion section (“the hazard ratio in the primary-prevention subgroup was lower than that in the secondary prevention population”); they did not provide details of their statistical analysis by subgroup. The most notable adverse events of bempedoic acid were gout and cholelithiasis (3.1% of intervention group vs. 2.1% of placebo and 2.2% of intervention group vs. 1.2% of placebo, respectively).

Bempedoic acid was approved for people with familial hyperlipidemia or documented CVD by the U.S. Food and Drug Administration in 2020 after disease-oriented studies showed it reduces LDL cholesterol levels; this RCT is the first to examine its effect on patient-oriented outcomes. Although this study’s findings seem promising, bempedoic acid may not be ready for widespread use. This trial studied bempedoic acid against placebo, but given that the preferred medication for CVD prevention is statins, a noninferiority trial of bempedoic acid vs. a statin is needed, along with transparent data about its benefit in primary prevention compared with secondary prevention. Trials with more diverse participants are also needed.  Finally, a month’s supply of Nexletol in the United States costs around $400, whereas most statin medications are now available in generic form in the United States for less than $20 a month.

While we wait for further studies on bempedoic acid, you can read more in the AFP By Topic on Coronary Artery Disease/Coronary Heart Disease and the AFP By Topic on Hyperlipidemia, both of which contain subheadings with content about both prevention and treatment. You can also read this STEPS article from 2021, which predates the above RCT but still provides useful information about bempedoic acid’s Safety, Tolerability, Effectiveness, Price, and Simplicity.