Bempedoic Acid Found Comparable to Statins for Lowering LDL-C, Reducing Major CV Event Risk

Bempedoic acid (Nexletol, Esperion) demonstrated a reduction in risk of major cardiovascular (CV) events comparable to that of statin drugs based on an analysis of per unit decrease in LDL-C as observed in the CLEAR Outcomes study, according to a new analysis presented at ENDO 2023, the Endocrine Society's annual meeting.

Specifically, the latest analysis of data from the landmark CLEAR Outcomes trial demonstrated that 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

As such the ATP citrate lyase inhibitor may be considered an alternative to statin therapy for individuals at high risk for CV events who cannot tolerate the drugs or for those who require additional LDL-C lowering despite treatment with statins, suggested A. Michael Lincoff, MD, co-author of the study and vice chair for research, Department of Cardiovascular Medicine at the Cleveland Clinic in Ohio in an Endocrine society statment.²

The data presented at ENDO 2023 are the result of a new analysis of the CLEAR Outcomes trial, which enrolled 13 970 statin-intolerant patients who had, or were at high risk for, CV disease. The original CLEAR Outcomes findings, published in March 2023 in the New England Journa of Medicine,³ showed that compared to placebo, treatment with bempedoic acid was associated with a 21% decrease in LDL-C and with a 13% relative reduction in the risk of major adverse cardiovascular events (MACE).³ The question left open after the findings were published was whether the relationship between LDL-C reduction and the magnitude of the CV events seen in CLEAR Outcomes with bempedoic acid were comparable to levels of the same outcomes for statin therapy.

For their comparison, Lincoff and colleagues referred to findings from a landmark meta-analysis of statin trials by the Cholesterol Treatment Trialists (CTT) Collaboration and to the methodology used to calculate the CV event outcomes. The CTT meta-analysis showed that each 1 mmol/L (39 mg/dL) reduction in LDL-C was associated with a 22% reduction in major vascular events (MVE). The CTT analysis also found that the benefit increased with cumulative treatment.

Lincoff et al thus used the CTT methodology to assess whether the effects of bempedoic acid on reduction of risk for a composite endpoint of CV outcomes are similar to that of statins, per unit decrease in LDL-C after 12 months of treatment.

FINDINGS

According to the study abstract, participants assigned to treatment with bempedoic acid achieved a placebo-corrected lowering of LDL-C of 0.58 mmol/L (22.43 mg/dL) at month 12, with an associated 15% reduction (HR 0.85; 95%CI 0.77-0.94) in the risk of the CTT MVE endpoint.¹

When normalized to a 1.0 mmol/L LDL-C reduction as was performed in the CTT, the CV risk reduction with bempedoic acid was comparable to the normalized risk reduction with statins observed in the CTT meta-analyses of 22% (risk ratio 0.78, 95% CI 0.76- 0.80]. The beneficial effect of bempedoic acid on MVE reduction generally improved over time, similar to what was observed in statin cardiovascular outcomes trials. Specifically, the cumulative normalized hazard ratio for major CV events improved from 0.77 at year 1 to 0.72 by year 4 of treatment with bempedoic acid.¹

"The benefit of bempedoic acid treatment is consistent with the event reduction predicted by the CTT analysis, and generally improved over time, similar to what was observed in statin outcomes trials, with greater major adverse cardiovascular events benefit seen in those patients who remain on the study drug for the duration of the study," commented Sheldon Koenig, Esperion president and CEO in a company release.⁴ "Patients unable to tolerate statins or achieve their LDL-C goals on statins alone represent approximately one-third of all primary and secondary prevention patients, making the significant benefits of bempedoic acid in this patient population both evident and important.”⁴

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. Abstract presented at ENDO 2023; Chicago, Il; June 15-18, 2023.

2. Statin alternative lowers risk of cardiac events as well as cholesterol levels. News release. The Endocrine Society. 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. Nissen SE, Lincoff AM, Brennan D, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353-1364. doi:10.1056/NEJMoa2215024

4. Esperion presents results from new analysis on cardiovascular benefits with bempedoic acid treatment at ENDO 2023. Press release. Esperion; June 15, 2023. Accessed June 15, 2023.