Bempedoic Acid May be Effective Alternative for Statin-intolerant Patients, According to Data from CLEAR Outcomes Trial

Among patients who had, or were at high risk for, cardiovascular disease (CVD) who were deemed statin intolerant, bempedoic acid reduced their risk for major adverse cardiovascular events (MACE) by 13% compared with placebo, according to data from the CLEAR Outcomes trial.

Findings were presented at the American College of Cardiology’s (ACC) 72nd Annual Scientific Session Together with the World Congress of Cardiology, being held March 4-6, 2023, in New Orleans, and simultaneously published in NEJM.

In 2020, bempedoic acid (Nexletol®, Esperion Therapeutics) became the first oral, once-daily, non-statin cholesterol lowering medication to receive approval from the US Food and Drug Administration since 2002. The effects of the drug on cardiovascular (CV) outcomes, however, remain uncertain, according to study authors.

“Statin intolerance remains a vexing clinical problem that can prevent patients who are guideline-eligible for statin treatment from reaching LDL cholesterol levels associated with clinical benefits. Accordingly, alternative nonstatin therapies are needed to manage the LDL cholesterol level in these patients,” wrote first author and chair of the study, Steven E. Nissen, MD, MACC, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic, and colleagues. “This is the first study that directly addressed the problem of statin-intolerant patients,” said Nissen in an ACC press release.

Nissen and colleagues analyzed data from 13 970 adults from 1250 sites across 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects (aka statin-intolerant patients) and had or were at high risk for CVD. To enroll, prospective participants and their clinicians were required to provide written confirmation that they were statin intolerant and aware of the benefits of statins in reducing the risk of CV outcomes.

Researchers randomly assigned patients to receive 180 mg oral bempedoic acid once daily (n=6992) or placebo (n=6978) and followed the cohort for a median of 40.6 months. The mean age of participants was 65.5 years and nearly half (48.2%) were women, 45.6% had diabetes, 69.9% had had a previous CV event, 22.7% were taking a statin, and 11.5% were receiving ezetimibe. Mean baseline LDL-cholesterol was 139 mg/dL in both groups.

The primary endpoint was a 4-component composite of MACE, defined as CV death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.

Results

After 6 months, the reduction in the level of LDL-cholesterol was greater with bempedoic acid than with placebo by 29.2 mg/dL; the observed difference in the percent reductions was 21.1 percentage points in favor of bempedoic acid.

The incidence of a primary endpoint event was lower in the bempedoic acid group than the placebo group (11.7% vs. 13.3%; hazard ratio [HR] 0.87, 95% CI 0.79-0.96, P=.004). Similarly, incidences of CV death, nonfatal MI, and nonfatal stroke were lower with bempedoic acid than placebo (HR 0.85, 95% CI, 0.76-0.96, P=.006), as was fatal or nonfatal MI (HR 0.77, 95% CI 0.66-0.91, P=.002) and coronary revascularization (HR 0.81, 95% CI 0.72-0.92, P=.001).

Investigators observed that bempedoic acid had no significant effects on fatal or nonfatal stroke, CV death, and death from any cause. The incidences of gout and cholelithiasis were higher with bempedoic acid than with placebo (3.1% vs 2.1% and 2.2% vs 1.2%, respectively), as were the incidences of small increases in serum creatinine, uric acid and hepatic-enzyme levels. However, these adverse events did not lead to a higher rate of drug discontinuation.

A major limitation to the current study was the inclusion of only patients who had reported that they were unable or unwilling to take statins, which resulted in a high mean LDL cholesterol level at baseline, noted researchers. The effects of bempedoic acid on CV events in populations with lower LDL cholesterol levels and in patients taking conventional therapeutic doses of statins were not included in the study.

“We’re very pleased with the results,” said Nissen. “People who couldn’t tolerate a statin did tolerate bempedoic acid and had a very good outcome. We are glad that we were able to demonstrate this level of efficacy on the outcomes that really matter to patients.”

Reference: Nissen SE, Lincoff M, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. NEJM. Published online March 4, 2023. Doi: 10.1056/NEJMoa2215024.