CLEAR Outcomes Analysis Finds Bempedoic Acid Reduces Total Cardiovascular Events by 20%

Published on: 

In the CLEAR Outcomes trial, bempedoic acid was associated with a 20% reduction in relative risk for total cardiovascular events, with further analysis shining light on the effects of specific types of events.

A prespecified analysis of data from the landmark CLEAR Outcomes trial suggests use of bempedoic acid (Nexletol) was associated with a 20% reduction in relative risk of total cardiovascular events compared with placebo therapy.

An analysis of the trial examining the totality of events from within the trial, which included more than 13,900 patients, results indicate use of bempedoic acid was associated with statistically significant relative risk reductions of 20%, 17%, 31%, and 32% for 4-point major adverse cardiovascular events (MACE), 3-point MACE, myocardial infarction, and coronary revascularization.1

“This prespecified analysis of the CLEAR Outcomes trial demonstrated that the previously described benefit of treatment with bempedoic acid on the time to first MACE was extended to the occurrence of recurrent cardiovascular events,” wrote investigators.1

Presented at the American College of Cardiology 2023 Scientific Sessions, the CLEAR Outcomes trial was designed to assess the potential for cardiovascular risk reduction with bempedoic acid among a cohort of patients with, or at high risk for, cardiovascular disease, with hypercholesterolemia and an inability to take guideline-recommended statins. Results of the trial, which were presented by Steve Nissen, MD, of the Cleveland Clinic, suggested use of bempedoic acid was associated with a 13% reduction in 4-point MACE (Hazard ratio [HR], 0.87 [95% confidence interval [CI], 0.79-0.96]; P=.004) relative to placebo therapy.2

Presented more than 3 years after the agent received approval for lowering LDL-C in February 2020, the trial would go on to serve as the basis for an expanded indication allowing use in primary hyperlipidemia and removing the maximally tolerated statin requirement. In a December 2023 release from Esperion, the company notes the FDA has accepted applications for label expansions denoted the effect on cardiovascular risk and a decision is expected by March 31, 2024.2

Since the initial presentation of CLEAR Outcomes, multiple analyses have emerged shedding further light on the effects of the first in a class ATP citrate lyase inhibitor with presentations at ENDO 2023, ADA 2023, and ESC Congress 2023 providing evidence of the effects according to LDL-C reduction achieved, among a primary prevention cohort, and according to glycemic control, respectively.3,4,5

In this prespecified analysis, investigators sought to determine the effect of use on total cardiovascular events among trial participants. During a median follow-up of 3.4 (Interquartile Range, 3.1-3.9) years, a total of 1746 positively adjudicated first 4-point MACE events and 915 additional MACE events were recorded among 612 patients. Of the 1746 adjudicated events, coronary revascularizations accounted for 32.8% of first events and 69.4% of additional events.1

When assessing impact on total incidence of cardiovascular events, results indicated use of bempedoic acid was associated with relative risk reductions of 20% for 4-point MACE (HR, 0.80; 95% CI, 0.72-0.89; P <.001), 17% for 3-point MACE (HR, 0.83; 95% CI, 0.73-0.93; P = .002), 31% for myocardial infarction (HR, 0.69; 95% CI, 0.58-0.83; P < .001), and 22% for coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001) compared to placebo therapy. In contrast, no statistically significant difference was observed for stroke (HR, 0.80; 95% CI, 0.63-1.03).1

Further analysis revealed the magnitude of benefit with bempedoic acid appeared to increase with increasing number of MACE events experienced by patients. Specifically, relative risk reductions of 13%, 26%, 31%, and 49% were observed for the first (HR, 0.87; 95% CI, 0.79-0.96; P = .004), second (HR, 0.74; 95% CI, 0.63-0.87; P <.001), third (HR, 0.69; 95% CI, 0.51-0.93; P = .02), and fourth (HR, 0.51; 95% CI, 0.31-0.88; P = .02) events, respectively.1

According to investigators, the projected clinical benefit derived from the results of the CLEAR Outcomes trial indicate use of bempedoic acid could result in 66 fewer primary 4-point MACE events, 25 fewer myocardial infarctions, 32 fewer coronary revascularizations, and 7 fewer strokes over a 5-year period among 1000 patients.1

“This prespecified analysis of the CLEAR Outcomes trial demonstrated favorable reductions in the total number of cardiovascular events in patients treated with bempedoic acid. This finding highlights the importance of lipid lowering in patients at high cardiovascular risk,” investigators wrote.1 “More effective clinical models are required to achieve more sustainable adherence to optimized lipid-lowering strategies in order to produce greater reductions in cardiovascular risk.”


  1. Nicholls SJ, Nelson AJ, Lincoff AM, et al. Impact of Bempedoic Acid on Total Cardiovascular Events: A Prespecified Analysis of the CLEAR Outcomes Randomized Clinical Trial. JAMA Cardiol. Published online January 17, 2024. doi:10.1001/jamacardio.2023.5155
  2. Campbell P. Bempedoic acid reduces risk of mace by 13% but proves no benefit on cardiovascular death. HCP Live. March 4, 2023. Accessed January 18, 2024.
  3. Campbell P. Clear outcomes data at Endo 2023 provides further insight into effects of Bempedoic acid. HCP Live. June 15, 2023. Accessed January 18, 2024.
  4. Campbell P. Study suggests bempedoic acid could find role in primary prevention. HCP Live. June 30, 2023. Accessed January 18, 2024.
  5. Campbell P. Bempedoic acid proves cardiovascular benefit across glycemic spectrum in new analysis. HCP Live. August 30, 2023. Accessed January 18, 2024.