Bempedoic Acid Reduces Major Adverse Cardiovascular Events in Patients Who Cannot Tolerate Statins

Bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein-cholesterol.

New positive results from the CLEAR Outcomes trial of bempedoic acid (Nexletol; Esperion) showed a reduction in the combined rate of major adverse cardiovascular events (MACE) by 13%. These findings were reported during a session at the American College of Cardiology 2023 Scientific Sessions.

With the new data, bempedoic acid is the first adenosine 5’-triphosphate (ATP) citrate lyase inhibitor and first oral non-statin to meet the MACE-4 primary endpoint. The trial was the first to assess whether bempedoic acid could reduce adverse cardiovascular outcomes.

“We’re very pleased with the results,” said study chair Steven E. Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic, in a press release. “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.”

Bempedoic acid is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of low-density lipoprotein-cholesterol (LDL-C). Its effect on cardiovascular morbidity and mortality had not previously been determined.

Bempedoic acid affects the same biological pathway as statins but is not activated until it reaches the liver. This limits the drug’s effects on muscle, the brain, and other tissues or organs and minimizes some of the adverse effects associated with statins.

An analysis of different types of cardiac events found that bempedoic acid led to a 23% reduction in heart attacks and a 19% reduction in coronary revascularization, both of which were statistically significant. These results were seen in patients who had previously experienced a cardiac event, as well as those who had not.

The study enrolled more than 14,000 statin-intolerant patients between December 2016 and August 2019 at more than 1200 sites in 32 countries. Participants and their clinicians were required to acknowledge in writing their awareness of the benefits of statins and confirm that the patient was unable to tolerate statin therapy. All participants had LDL levels of 100 mg/dL or higher at baseline and either a previous cardiac event or other risk factors for heart disease.

On average, patients were 65 years of age, nearly half were women (48%), and approximately 70% had experienced a previous cardiac event. Participants were randomized to either 180 mg bempedoic acid or a placebo daily and were followed for more than 3 years, on average.

The combined rate of cardiovascular death, heart attack, stroke, or coronary revascularization occurred in 11.7% of participants taking bempedoic acid and 13.3% of those taking a placebo. There was no significant difference in rates of death between the 2 study arms.

On average, participants receiving bempedoic acid saw their LDL-C levels drop by between 20% to 25% over the course of the study. Participants taking a placebo saw a modest reduction in LDL-C, up to 10% on average, which the researchers said likely reflects closer monitoring and the addition of other cholesterol-lowering agents as part of their background therapy.

Participants taking bempedoic acid did see higher rates of several adverse events (AEs) compared to those taking a placebo, including renal impairment, gout, and gallstones, as well as elevated hepatic enzymes, likely caused by the drug’s activity in the liver. However, these AEs did not lead to a higher rate of drug discontinuation, according to the study.

The investigators did note that the 20% to 25% reduction in LDL-C reported for bempedoic acid is less than the 40% to 50% reductions typically achieved with statins. This is in line with previous studies indicating that bempedoic acid is not as effective at lowering cholesterol as statins or other therapies such as PCSK9 inhibitors. However, the study also showed that even this smaller degree of change can make a significant difference in the overall risk of cardiac events for patients who cannot tolerate statins.

“Statins are the cornerstone of risk reduction in patients with elevated LDL-C,” Nissen said in the press release. “Most people can take statins, but some cannot. This is the first study that directly addressed the problem of statin-intolerant patients. We achieved what we hoped we would get—a very positive result in a population of people who just could not tolerate statins.”


Bempedoic Acid Improves Outcomes in Statin-Intolerant Patients. News release. American College of Cardiology; March 4, 2023. Accessed March 4, 2023.

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