CLEAR Outcomes Subanalysis Shows Bempedoic Acid’s Clinical Benefits Apply Equally to Women and Men

When the Cleveland Clinic-led CLEAR Outcomes study was published last year in the New England Journal of Medicine (2023;388:1353-1364), it was notable for showing for the first time that bempedoic acid (Nexletol^®) significantly reduced major cardiovascular events (MACE) in statin-intolerant patients treated for primary or secondary cardiovascular prevention.

Less well appreciated was another point of distinction for the trial: with women constituting 48% of study participants, CLEAR Outcomes had the highest percentage enrollment of females among all contemporary outcomes studies of lipid-lowering therapies.

Now the CLEAR Outcomes investigators have leveraged that large cohort of female patients to publish a prespecified subgroup analysis that represents one of the most robust — and encouraging — reports on the clinical effectiveness of lipid-lowering therapy in women to date.

“Data on clinical outcomes of lipid-lowering therapies in women have been limited,” says Leslie Cho, MD, first author of the new prespecified analysis, published in Circulation (Epub 6 Apr 2024). “Moreover, prior research has shown that, in the United States, women are less likely than men to have hypercholesterolemia diagnosed and more likely to report statin intolerance. We viewed CLEAR Outcomes, which assessed clinical outcomes among more than 6,700 women, as presenting a singular opportunity to evaluate whether clinical effects of lipid lowering — in this case, with bempedoic acid — varied by patient sex.”

Essentials of CLEAR Outcomes and the subgroup analysis

As detailed in the primary CLEAR Outcomes study report, the trial randomized 13,970 patients in 32 countries to oral bempedoic acid 180 mg/d or placebo in a double-blind manner. All patients had cardiovascular disease or were at high risk for it and were unable or unwilling to take statin therapy at guideline-recommended doses. Of the study’s 13,970 patients, 6,740 (48.2%) were women. A large majority of patients (91%) identified racially as white, and 17% identified as being of Hispanic/Latino ethnicity.

The current analysis by patient-reported sex was specified in the study protocol for the composite primary efficacy endpoint (death from cardiovascular cause, nonfatal myocardial infarction [MI], nonfatal stroke or coronary revascularization; MACE-4) and a key secondary endpoint (death from cardiovascular cause, nonfatal MI or nonfatal stroke; MACE-3). Median patient follow-up was 3.4 years. Hazard ratios (HRs) were estimated relative to placebo within each sex using a Cox regression model with post hoc adjustment for demographic and baseline characteristics.

Results

The analysis showed that bempedoic acid lowered cardiovascular risk comparably in females and males, specifically:

• Among females, the primary endpoint (MACE-4) occurred in 8.4% of the bempedoic acid group versus 9.7% of the placebo group (adjusted HR = 0.89) and MACE-3 occurred in 6.1% versus 7.2%, respectively (adjusted HR = 0.88).
• Among males, MACE-4 occurred in 14.8% of the bempedoic acid group versus 16.6% of the placebo group (adjusted HR = 0.86) and MACE-3 in 10.2% versus 11.6%, respectively (adjusted HR = 0.84).
• P values for the interaction by sex were not statistically significant for MACE-4 (P = .82) or for MACE-3 (P = .84).

Similarly, analysis of safety results showed no meaningful differences by sex in rates of serious adverse events, rates of overall adverse events or changes in laboratory measures.

Takeaways from the analysis

“It’s reassuring that reductions in clinical events with bempedoic acid were similar among women and men in CLEAR Outcomes and that adverse events were comparable as well,” says Dr. Cho, Director of the Women’s Cardiovascular Center at Cleveland Clinic and Co-Section Head of Preventive Cardiology. She notes that the notably lower cardiovascular event rates among women versus men in both the active and placebo study arms are characteristic of other cardiovascular outcomes trials, particularly cholesterol-lowering studies.

“The results of this new analysis are welcome because experience shows that lipid-lowering alternatives to statin therapy, given alone or in combination, are needed by a sizeable number of patients,” Dr. Cho says. “We can now have confidence that these patients can achieve reductions in cardiovascular risk and events with bempedoic acid irrespective of their sex.”

“This subgroup is analysis is important because some prominent physicians have questioned the value of cholesterol lowering in women,” adds co-author Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute. “Dr. Cho’s analysis confirms that women have comparable benefits to men. Because statin intolerance is more common in women, having an alternative for treatment of elevated cholesterol in women is particularly valuable.”