Bempedoic acid also reduces MACE in obese patients with high CVD risk

In a secondary analysis of CLEAR Outcomes among statin-intolerant patients with high CVD risk and BMI ≥30 kg/m², bempedoic acid reduced MACE risk and LDL-c and hs-CRP levels compared with placebo, with no significant safety concerns.

This summary is based on the publication of Bays HE, Bloedon L, Brennan D, et al. - Bempedoic Acid for Prevention of Cardiovascular Events in People With Obesity: A CLEAR Outcomes Subset Analysis. J Am Heart Assoc. 2025 Feb 18;14(4):e037898. doi: 10.1161/JAHA.124.037898.

Introduction and methods

Background

Given that obesity and hypercholesterolemia independently increase CVD risk, it is important to address both excess body fat and elevated levels of LDL-c or non-HDL-c at an early stage [1,2]. Recently, the CLEAR (Cholesterol Lowering via Bempedoic Acid (ECT1002), an ACL-Inhibiting Regimen) Outcomes trial demonstrated bempedoic acid reduced MACE and lowered LDL‐c and hs‐CRP levels compared with placebo in statin-intolerant patients with or at high risk of CVD [3].

Aim of the study

To further characterize the efficacy and safety of bempedoic acid specifically in patients with obesity and high CVD risk, the authors performed a prespecified secondary analysis of the CLEAR Outcomes trial among participants with BMI ≥30 kg/m².

Methods

The CLEAR Outcomes trial was an international, multicenter, double-blind, placebo-controlled, event-driven, phase 3 RCT in which 13,970 patients with a history of CVD (secondary prevention cohort) or increased CVD risk (primary prevention cohort) and LDL-c ≥100 mg/dL (≥2.6 mmol/L) who were unwilling or unable to take guideline-recommended statin therapy were randomized to oral bempedoic acid 180 mg once daily or placebo. In the current analysis, 6179 patients (44.2%) with BMI ≥30 kg/m² were included, with a median follow-up time of 40.7 months.

Outcomes

The primary efficacy endpoint was a 4-component composite outcome of MACE, defined as the time to CV death, nonfatal MI, nonfatal stroke, or coronary revascularization. Key secondary endpoints included a 3-component composite MACE outcome (defined as the time to CV death, nonfatal MI, or nonfatal stroke), the individual components of the composite outcomes, and changes in LDL-c and other biomarker levels from baseline to 6 or 12 months.

Safety assessment included the frequency of adverse events and changes in uric acid and serum creatinine levels from baseline to 6 months.

Main results

Efficacy

• At 6 months, the mean placebo-corrected change in LDL-c levels from baseline was −30.6 mg/dL (95%CI: ‐32.2 to −29.1), which represented a percent change of −22.5% (95%CI: −23.7% to −21.2%).
• The median placebo-corrected change in hs-CRP levels from baseline to 6 months was −23.2% (95%CI: −26.1% to −20.3%).
• The mean ± SD change in body weight from baseline was −1.1 ± 4.3 kg in patients treated with bempedoic acid (n=3075) and −0.5 ± 4.1 kg in those receiving placebo (n=3104) at 12 months and −2.3 ± 6.3 kg and −1.4 ± 6.1 kg, respectively, at 36 months.
• During follow-up. the primary 4-component MACE endpoint occurred in 357 patients (11.6%) in the bempedoic acid group and 459 (14.8%) of those in the placebo group (HR: 0.77; 95%CI: 0.67–0.89).
• Bempedoic acid treatment also reduced the risks of the 3-component MACE endpoint (HR: 0.73; 95%CI: 0.62–0.86), fatal and nonfatal MI (HR: 0.68; 95%CI: 0.53–0.86), coronary revascularization (HR: 0.76; 95%CI: 0.63–0.92), and fatal and nonfatal stroke (HR: 0.64; 95%CI: 0.45–0.89) compared with placebo.

Safety

• The frequency of adverse events was 87.4% in the bempedoic acid group and 86.7% in the placebo group.
• The rate of study drug discontinuation due to treatment-emergent adverse events was 10.6% in the bempedoic acid group and 10.3% in the placebo group.
• The observed mean ± SD change in uric acid levels from baseline to 6 months was 0.81 ± 1.26 mg/dL in bempedoic acid–treated patients and –0.04 ± 1.05 mg/dL in placebo-treated patients, whereas the mean ± SD change in serum creatinine levels was 0.05 ± 0.17 mg/dL and 0.02 ± 0.15 mg/dL, respectively.

Conclusion

In this prespecified secondary analysis of the CLEAR Outcomes trial among statin-intolerant patients with obesity and high CVD risk, treatment with bempedoic acid reduced MACE risk and LDL-c and hs-CRP levels compared with placebo. There were no significant safety concerns. The authors note that “this analysis was not powered to compare treatment effects between people living with obesity and those living without.” Still, they conclude that “in addition to reduction in excess adiposity, bempedoic acid may be a clinically relevant option to improve CVD outcomes in people who are statin intolerant and living with obesity who have elevated LDL‐c and are at high cardiovascular risk.”

Find this article online at J Am Heart Assoc.

References

1. Domanski MJ, Tian X, Wu CO, Reis JP, Dey AK, Gu Y, Zhao L, Bae S, Liu K, Hasan AA, et al. Time course of LDL cholesterol exposure and cardiovascular disease event risk. J Am Coll Cardiol. 2020;76:1507–1516. doi: 10.1016/j.jacc.2020.07.059
2. Bays HE, Kirkpatrick C, Maki KC, Toth PP, Morgan RT, Tondt J, Christensen SM, Dixon D, Jacobson TA. Obesity, dyslipidemia, and cardiovascular disease: a joint expert review from the Obesity Medicine Association and the National Lipid Association 2024. Obesity Pillars. 2024;10:100108. doi: 10.1016/j.obpill.2024.100108
3. Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, Thompson PD, Libby P, Cho L, Plutzky J, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353–1364. doi: 10.1056/NEJMoa2215024