CLEAR Outcomes Data at ENDO 2023 Provides Further Insight into Effects of Bempedoic Acid

A. Michael Lincoff, MD
Credit: Cleveland Clinic

Data from the CLEAR Outcomes trial presented at the Endocrine Society’s 2023 annual meeting suggests use of the lipid-lowering medication bempedoic acid (Nexletol) was associated with a reduction in major vascular events in the trial.

Less than 3 months after Steve Nissen, MD, presented the initial results of the CLEAR Outcomes trial at the American College of Cardiology 72nd Annual Scientific Sessions, the latest analysis of data from the landmark trial suggests use of bempedoic acid was associated with a 23% relative reduction in risk for major vascular events at 1 year and a 28% reduction in relative risk at 4 years compared to placebo therapy.¹

“Our findings indicate bempedoic acid may be a valuable therapy for patients who cannot tolerate adequate doses of statins or who need to further lower their LDL cholesterol levels,” said study investigator A. Michael Lincoff, MD, vice chair for Research in the Department of Cardiovascular Medicine at the Cleveland Clinic.²

The CLEAR Outcomes trial represents one of the most anticipated trials in recent memory for the lipidology community. Although bempedoic acid and bempedoic acid plus ezetimibe received approval from the US Food and Drug Administration 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, many in community expressed hesitancy around prescription with the lack of outcomes data.

To address these hesitancies, the CLEAR Outcomes trial was launched in 2016 as a double-blind, randomized, placebo-controlled trial aimed at assessing the effects of bempedoic acid use on LDL-C levels and risk of major adverse cardiovascular outcomes. The trial enrolled and randomized a cohort of 13,970 patient and randomize them to bempedoic acid 180 mg or matching placebo therapy. This cohort had a mean age of 65 (SD, 9.0) years, median duration of follow-up of 40.6 months, a mean baseline LDL-C of 139.0 mg/dL, and 48.2% were female.³

Results of the ACC 2022 study suggest use of bempedoic acid was associated with a lower 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).³

In the ENDO 2023 presentation, investigators offered further insight into the trial by assessing the effects of use on risk of a composite endpoint of major vascular endpoints and individual cardiovascular outcomes per 1 mmol/L LDL-C reduction at 1 year. For the purpose of analysis, this composite endpoint included fatal coronary heart disease, nonfatal myocardial infarction, stroke, or revascularization. Investigators pointed out plans to perform an intention-to-treat analysis to assess the treatment effect on cardiovascular events relative to LDL-C reduction and an on-treatment Per Protocol Set (PPS) analysis only including events occurring prior to 30 days after study drug discontinuation.¹

Upon analysis, results of the ITT analysis suggested the placebo-corrected absolute LDL-C reduction with bempedoic acid at month 12 was 0.58 mmol/L and the HR for major vascular events was 0.85 (95% CI, 0.77-0.94). In the PPS analysis, the mean LDL-C reduction was 0.71 mmol/L and the HR for major vascular events was 0.80 (95% CI, 0.71-0.89). Further analysis indicated the HRs for the ITT and PPS analyses were 0.75 (95% CI, 0.63-0.90) and 0.73 (95% CI, 0.62-0.85), respectively, when 1.0 mmol/L LDL-C-reduction. Investigators pointed out these were comparable to the normalized risk reduction with statins observed in the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analyses (risk ratio [RR], 0.78 [95% CI, 0.76-0.80]).¹

Investigators also noted the cumulative normalized HR for major vascular events improved from 0.77 at year 1 to 0.72 by year 4 of treatment with bempedoic acid. Additionally, results suggested the normalized HRs for individual endpoints of major coronary events, nonfatal myocardial infarction, revascularization, and stroke for bempedoic acid relative to placebo therapy in the trial were comparable to the RRs observed for the equivalent endpoints with statin therapy in the aforementioned CTT meta-analyses.¹

“Cardiovascular disease remains the most prevalent cause of mortality and morbidity in the world,” Lincoff added.² “Medications to lower cholesterol offer an important tool to diminish this risk.”

References:

1. Lincoff AM, Ray K, Sasiela W, et al. Comparison of the Cardiovascular Benefits of Bempedoic Acid with Statins—Analysis by the Cholesterol Treatment Trialists’ Methodology. Paper presented at: Endocrine Society 2023. Chicago, Il. June 15-18, 2023.
2. Statin alternative lowers risk of cardiac events as well as cholesterol levels. Newswise. June 15, 2023. Accessed June 15, 2023. https://www.newswise.com/articles/statin-alternative-lowers-risk-of-cardiac-events-as-well-as-cholesterol-levels.
3. Campbell P. Bempedoic acid reduces risk of mace by 13%, but proves no benefit on cardiovascular death. HCP Live. March 4, 2023. Accessed June 15, 2023. https://www.hcplive.com/view/bempedoic-acid-reduces-risk-of-mace-by-13-but-proves-no-benefit-on-cardiovascular-death.