Bempedoic Acid Reduces Risk of MACE by 13%, But Proves No Benefit on Cardiovascular Death

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Results of the CLEAR Outcomes trial suggests adherence to bempedoic acid was associated with a 13% relative reduction in incidence of the trial's primary endpoint of 4-point MACE, but no benefit was observed for risk of cardiovascular death or all-cause mortality in the trial.

At long last, the cardiology community was given the answers they had been waiting years for with the presentation of CLEAR Outcomes data at the American College of Cardiology (ACC)’s 2023 Annual Scientific Session Together With the World Congress of Cardiology.

Results of the trial, which enrolled more than 14,000 statin-intolerant patients with a median duration of follow-up of 40.6 months, indicate use of bempedoic acid was associated with a 13% relative reduction in risk of 4-point major adverse cardiovascular events (MACE), with statistically significant reductions observed for both myocardial infarction and coronary revascularization but no reduction in death from cardiovascular causes.1

“Statins are the cornerstone of risk reduction in patients with elevated LDL cholesterol,” said Steven E. Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at Cleveland Clinic and chair of the study.2 “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.”

Approved in February 2020 as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or established atherosclerotic cardiovascular disease (ASCVD)3, the community waited nearly 3 more years before receiving confirmation the primary endpoint of CLEAR Outcomes had been met in an announcement from Esperion in December 2022.4

In the clinical trial program serving as the basis for this approval, use of the first-in-class, ATP citrate lyase inhibitor was associated with a 18% reduction in LDL-C when used as an adjunct to maximally-tolerated statin therapy and by 28% among statin-averse patients.3 Still, even with this safety and efficacy profile in 4 phase 3 clinical trials, many in the community expressed hesitancy around prescription of the agent without long-term cardiovascular outcomes data.

A double-blind, randomized, placebo-controlled trial, enrollment for CLEAR Outcomes occurred from December 2016-August 2019. a total of 13,970 patients underwent randomization in the trial, with 6992 assigned to bempedoic acid 180 mg and 6978 assigned to placebo therapy.1

Of note, inclusion criteria for the trial required participants to have LDL levels of 100 mg/dL or greater at baseline and either a previous cardiac event or other risk factors for heart disease. For the purpose of analysis, 4-point MACE was chosen as the primary outcome of interest, with 4-point MACE defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.1

The overall study cohort had a mean age of 65 (SD, 9.0) years, median duration of follow-up of 40.6 months, and a mean baseline LDL-C of 139.0 mg/dL. Investigators also pointed out 48.2% of participants were female, 45.6% had diabetes, 69.9% had a previous cardiovascular event, 22.7% were taking a statin, and 11.5% were receiving ezetimibe. After 6 months of follow-up LDL-C reductions observed in the bempedoic acid arm were 29.2 mg per deciliter greater than those observed in the placebo arm, which is a difference of 21.1 percentage points in favor of bempedoic acid.1

Analysis of outcomes revealed the incidence of a primary endpoint event was significantly lower with bempedoic acid (11.7%) than with placebo therapy (13.3%) (Hazard ratio [HR], 0.87 [95% confidence interval [CI], 0.79-0.96]; P=.004). Investigators pointed out the analyses also indicated use of bempedoic acid was associated with reductions in the incidences of composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (HR, 0.85 [95% CI, 0.76-0.96]; P=.006), fatal or nonfatal myocardial infarction (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).1

No statistically significant reductions were observed for cardiovascular mortality (HR, 1.04 [95% CI, 0.88-1.24]) or all-cause mortality (HR, 1.03 [95% CI, 0.90-1.18]) within the trial. Additionally, safety analyses indicated incidences of both gout (3.1% vs 2.1%) and cholelithiasis (2.2% vs 1.2%) were greater in the bempedoic acid arm than the placebo arm. Investigators also pointed out small increases in serum creatinine, uric acid, and hepatic-enzyme levels were observed with bempedoic acid.1

In an editorial published alongside the trial results in the New England Journal of Medicine, John Alexander, MD, MHS, of Duke Clinical Research Institute, offered historical perspective on the long-awaited CLEAR Outcomes trial and noted he expects the results to be practice-changing.5

“The compelling results of the CLEAR Outcomes trial will and should increase the use of bempedoic acid in patients with established atherosclerotic vascular disease and in those at high risk for vascular disease who are unable or unwilling to take statins,” Alexander wrote.5


  1. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. DOI: 10.1056/NEJMoa2215024.
  2. Clear outcomes: Bempedoic acid shows promise in lowering CVD risk in statin-intolerant patients. American College of Cardiology. Published March 4, 2023. Accessed March 4, 2023.
  3. Esperion announces FDA approval of NEXLETOL™ (bempedoic acid) tablet, an oral, once-daily, non-statin LDL-cholesterol lowering medicine. Esperion Therapeutics, Inc. Published February 21, 2020. Accessed March 4, 2023.
  4. Esperion announces clear cardiovascular outcomes trial of NEXLETOL® (bempedoic acid) meets primary endpoint. Esperion Therapeutics, Inc. Published December 7, 2022. Accessed March 4, 2023.
  5. Alexander J. Benefits of Bempedoic Acid — Clearer Now. New England Journal of Medicine. March 2023. doi:10.1056/NEJMe2301490