CLEAR Outcomes Trial Evaluates Bempedoic Acid to Lower Cholesterol in Statin-Intolerant Patients

March 4, 2023—The American College of Cardiology announced the presentation of findings from the CLEAR Outcomes study showing that the cholesterol-lowering drug bempedoic acid reduced the combined rate of major adverse cardiovascular events by 13%, meeting its primary endpoint in this large study of patients with high cholesterol who were unable to tolerate statins.

The findings were presented at ACC.23/WCC, the ACC's annual scientific session together with the World Congress of Cardiology held March 4-6, 2023, in New Orleans, Louisiana. The study was simultaneously published online by Steven E. Nissen, MD, et al in The New England Journal of Medicine.

According to the ACC press release, bempedoic acid is approved by the FDA as an additional treatment to help lower cholesterol in patients with certain conditions who have high cholesterol despite receiving maximally tolerated statin therapy. It affects the same biological pathway that statins target but is not activated until it reaches the liver, thus limiting the drug’s effects on muscle, brain, and other tissues or organs. Because of this, it does not have the same side effects reported with statins.

ACC noted that CLEAR Outcomes is the first trial to assess whether bempedoic acid could reduce cardiovascular outcomes. The study was funded by Esperion Therapeutics, developer of bempedoic acid.

As summarized by ACC, the trial showed the drug was associated with significant reductions in the trial’s primary endpoint, a composite of cardiovascular death, heart attack, stroke, or coronary revascularization.

An analysis of different types of cardiac events found bempedoic acid led to a 23% reduction in heart attacks and a 19% reduction in coronary revascularizations, both of which were statistically significant. These benefits were seen both in patients who had previously experienced a cardiac event and in patients who had not, advised ACC.

"We’re very pleased with the results," commented Dr. Nissen, the study chair, in the ACC 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." Dr. Nissen is chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic in Cleveland, Ohio.

The press release stated that the CLEAR Outcomes study enrolled more than 14,000 statin-intolerant patients between December 2016 and August 2019 at more than 1,200 sites in 32 countries. To participate, patients and their clinicians were required to acknowledge in writing their awareness of the benefits of statins and confirm the patient was unable to tolerate statin therapy.

In CLEAR Outcomes, all enrolled patients had low-density lipoprotein (LDL) levels of ≥ 100 mg/dL at baseline and either a previous cardiac event or other risk factors for heart disease. Average age of the patients was 65 years. Approximately half of patients were women (48%) and approximately 70% had experienced a previous cardiac event. The patients were randomly assigned to take 180 mg of bempedoic acid or a placebo daily and were followed, on average, for more than 3 years.

The investigators found that the combined rate of cardiovascular death, heart attack, stroke, or coronary revascularization occurred in 11.7% of patients taking bempedoic acid and 13.3% of patients assigned to a placebo. There was no significant difference in rates of death between the two study arms.

In patients who received bempedoic acid, LDL cholesterol levels dropped by approximately 20% to 25% on average over the course of the study.

Patients who received a placebo also saw a modest reduction in LDL cholesterol (up to 10% on average), which likely reflects closer monitoring and the addition of other cholesterol-lowering agents as part of their background therapy, reported the investigators.

Patients taking bempedoic acid experienced higher rates of several adverse events than those taking a placebo, including renal impairment, gout, and gallstones, as well as elevated hepatic enzymes, likely because of the drug’s activity in the liver. However, these side effects did not lead to a higher rate of drug discontinuation.

The investigators advised that the 20% to 25% reduction in LDL cholesterol reported for bempedoic acid is less of an impact than the 40% to 50% reductions typically achieved with statins. This finding 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 shows that this degree of change can still make a difference in the overall risk of cardiac events for patients who cannot tolerate statins, stated Dr. Nissen.

"Statins are the cornerstone of risk reduction in patients with elevated LDL cholesterol," concluded Dr. Nissen in the ACC 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."