Bempedoic Acid Proves Cardiovascular Benefit Across Glycemic Spectrum in New Analysis

Data from an analysis of the landmark CLEAR Outcomes trial suggests bempedoic acid could prove useful in the treatment algorithms for statin-intolerant patients with diabetes mellitus.

Results of the study, which were presented at the European Society of Cardiology (ESC) Congress 2023, indicate use of bempedoic acid significantly reduced cardiovascular risk as a monotherapy, with the greatest absolute benefit observed in patients with diabetes and no adverse effect on glycemic measures observed.¹

“Patients with diabetes have twice the risk of cardiovascular disease and lose on average half a decade of life compared to those without and when cardiovascular disease also co-exists this loss of life years is a decade and a half” said Kausik Ray, MBChB, MD, professor of public health and a consultant cardiologist at Imperial College London.² “Lowering LDL-C with statins is beneficial in people with diabetes and reduces cardiovascular disease. To date most treatments have been as add on to statins in people with diabetes so the present findings with bempedoic acid are noteworthy for several reasons.”

Launched in 2016 as a double-blind, randomized, placebo-controlled trial, CLEAR Outcomes was an event-driven trial aimed at assessing the effects of bempedoic acid use on LDL-C levels and risk of major adverse cardiovascular outcomes (MACE). 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

The trial’s primary outcome of interest was incidence of 3-point MACE, which was defined as a composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction.³

Initial results of the trial were presented at the American College of Cardiology 72nd Annual Scientific Sessions in March 2023. Data presented at the meeting detailed a significantly lower rate of 3-point MACE 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).³

Presented by Ray at ESC Congress 2023, the current study was a prespecified analysis examining endpoints according to glycemic status. Among the 13,970 patients included in the study:

• 1801 were considered normoglycemic (937 received bempedoic acid, 864 received placebo)
• 5796 met criteria for prediabetes (2911 received bempedoic acid, 2885 received placebo)
• 6373 had diabetes (3144 received bempedoic acid, 3229 received placebo)

The prespecified analysis had multiple outcomes of interest. For the efficacy outcomes, investigators examined incidence of 3- and 4-point MACE. Of note, 3-point MACE consisted of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke and 4-point MACE included these 3 endpoints plus coronary revascularization. The clinical outcomes of interest included change in HBA1c and fasting glucose at 1 year as well as incident diabetes at the end of the study.¹

Compared to their counterparts in the normoglycemia group, those in the diabetes group had a 25% greater risk of 4-point MACE (HR, 1.58; 95% CI, 1.21-1.55; P =.042) and a 58% greater risk of 3-point MACE (HR, 1.58; 95% CI, 1.21-2.06; P < .001). Analysis of LDL-C and non-HDL-C reductions from the trial suggested reductions achieved with bempedoic acid were similar across the different groups stratified by glycemic status.¹

Further analysis suggested use of bempedoic acid was associated with similar relative benefits on the 4-point MACE endpoint, with the greatest absolute benefits observed in those with diabetes (HR, 0.83; 95% CI, 0.72-0.95; P =.42; absolute risk reduction, 2.4%; 95% CI, 0.7-4.0; P =.0063). Similarly, analysis of 3-point MACE demonstrated use of bempedoic acid was associated with similar relative, but greater absolute benefits in those with diabetes mellitus (HR, 0.80; 95% CI, 0.68-0.93; P =.41; Absolute risk reduction, 2.1%; 95% CI, 0.7-3.6; P =.010).¹

Analysis of clinical outcomes of interest revealed use of bempedoic acid was not associated with a worsening of HbA1c or glucose levels in those without diabetes. Additionally, there was no increase in risk of new onset diabetes observed among those using bempedoic acid during the trial.¹

“Importantly, bempedoic acid use was not associated with an increased rate of new onset diabetes, which is a key differentiating feature compared to statins. We continue to believe bempedoic acid will have an increasingly important place in the treatment paradigm to reduce cardiovascular risk in a broad range of high-risk patients,” said Sheldon Koenig, President and CEO of Esperion.²

References:

1. KK Ray, SJ Nicholls, N Li, et al. Cardiovascular Benefits and Risk of New Onset Diabetes by Glycaemic Status with Bempedoic Acid: Prespecified Analyses of the CLEAR OUTCOMES trial. Presented at: European Society of Cardiology (ESC) Congress 2023. Amsterdam, the Netherlands. August 25-28, 2023.
2. Esperion Therapeutics, Inc. Esperion presents two clear outcomes study late-breakers at European Society of Cardiology Congress 2023. Esperion Therapeutics, Inc. August 26, 2023. Accessed August 30, 2023. https://www.esperion.com/news-releases/news-release-details/esperion-presents-two-clear-outcomes-study-late-breakers.
3. Campbell P. Bempedoic acid reduces risk of mace by 13%, but proves no benefit on cardiovascular death. HCP Live. March 4, 2023. Accessed August 30, 2023. https://www.hcplive.com/view/bempedoic-acid-reduces-risk-of-mace-by-13-but-proves-no-benefit-on-cardiovascular-death.