Bempedoic Acid Associated with 20% Reduction in Total CV Events in Prespecified CLEAR Outcomes Analysis

New data on use of bempedoic acid to reduce cardiovascular (CV) risk in high-risk patients who are statin-intolerant show the ATP citrate lyase inhibitor associated with a 20% reduction in the relative risk of total CV events when compared with placebo.¹

The prespecified analysis of data from the landmark CLEAR Outcomes trial evaluated the effects of bempedoic acid on the total incidence of CV events observed during study and found statistically significant reductions in relative risk for 4-point major adverse cardiovascular events (MACE; 20%), 3-point MACE (17%), myocardial infarction (MI; 31%), and coronary revascularization (22%).¹

Study authors, led by Steven Nissen, MD, of the Cleveland Clinic Coordinating Center for Clinical Research, wrote that based on the CLEAR Outcomes data, the projected clinical benefit of bempedoic acid could be 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 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,” the investigators wrote.

"...the projected clinical benefit of bempedoic acid could be 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."

CLEAR Outcomes was designed to assess the potential for CV risk reduction with bempedoic acid among individuals with, or at high risk for, CV disease, with elevated LDL-C, and unable to tolerate or unwilling to take guideline-recommended statin therapy. Results showed bemepdoic acid was associated with a 13% reduction in 4-point MACE, with a hazard ratio (HR) of 0.87 (95% CI, 0.79-0.96; P = .004) relative to placebo therapy.²

Bempedoic acid, marketed as Nexletol by Esperion Therapeutics, was originally approved by the US Food and Drug Administration in February 2020 as the first oral nonstatin cholesterol lowering agent for the treatment of hypercholesterolemia. Subsequently, in December 2023 and based on the CLEAR Outcomes findings above, the indication was expanded to include treatment of primary hyperlipidemia and language was removed from the label that required a patient be treated unsuccessfully on maximally tolerated statin therapy before qualifying for treatment.

Nissen and colleagues designed this prespecified analysis to evaluate the effects of bempedoic acid on CV events in addition to 4-point MACE in the CLEAR Outcomes study cohort.¹ During a median follow-up of 3.4 years, investigators recorded 1746 positively adjudicated first 4-point MACE events and 915 additional MACE events among 612 patients. Of the 1746 adjudicated events, coronary revascularizations accounted for 32.8% of first events and 69.4% of additional events, according to the study.¹

When they assessed the impact of bempedoic acid vs placebo on the total incidence of CV events, the team found use of the drug associated with relative risk reductions of¹:

• 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 MI (HR, 0.69; 95% CI, 0.58-0.83; P < .001)
• 22% for coronary revascularization (HR, 0.78; 95% CI, 0.68-0.89; P <.001)

They observed no statistically significant difference for stroke (HR, 0.80; 95% CI, 0.63-1.03)

Importantly, additional analysis suggested that the magnitude of treatment benefit with bempedoic acid increased with an increasing number of patients’ MACE events. Relative risk reductions recorded were¹:

• First event 13% (HR, 0.87; 95% CI, 0.79-0.96; P = .004)
• Second event 26% (HR, 0.74; 95% CI, 0.63-0.87; P <.001)
• Third event 31% (HR, 0.69; 95% CI, 0.51-0.93; P = .02),
• Fourth event 49% (HR, 0.51; 95% CI, 0.31-0.88; P = .02)

Their findings in this analysis, the researchers wrote, “highlight the importance of lipid lowering in patients at high cardiovascular risk. 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

Full FDA label approvals for bempedoic acid for CV risk reduction are pending, according to Esperion, with a PDUFA date set by the agency of March 31, 2024.²

References

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. US FDA updates LDL-C lowering indication for Esperion's Nexletol (bempedoic acid) and Nexlizet (bempedoic acid and ezetimibe) tablet. News release. Esperion. December 13, 2023. Accessed January 18, 2024. https://www.esperion.com/news-releases/news-release-details/us-fda-updates-ldl-c-lowering-indication-esperions-nexletolr