Evolocumab reduces MACE across BMI categories in ASCVD, with greatest benefit in severe obesity

In a prespecified analysis of the FOURIER trial, patients with obesity and ASCVD had a higher risk of MACE than those without obesity. Although LDL-c lowering with evolocumab was similar in patients with and without obesity, both the relative and absolute reductions in MACE increased with greater obesity severity.

This summary is based on the publication of Kang YM, Giugliano RB, Keech AC, et al. - Obesity-Associated Cardiovascular Risk and Benefit From PCSK9 Inhibition: A Prespecified Analysis From FOURIER. J Am Coll Cardiol. 2026 Jun 2;87(21):3016-3025. Epub 2025 Dec 10. doi: 10.1016/j.jacc.2025.10.036.

Introduction and methods

Background

Obesity is associated with an increased risk of ASCVD. Obesity contributes to atherosclerosis through multiple mechanisms, including insulin resistance, diabetes, abnormal lipid metabolism, hypertension, chronic inflammation, and a prothrombotic state [1-3]. Current clinical guidelines recommend weight loss, alongside optimal management of traditional cardiovascular risk factors, to reduce cardiovascular risk. However, achieving and maintaining weight loss remains challenging for many individuals with obesity [4-5]. Intensive lipid-lowering therapies may offer the potential to further reduce cardiovascular risk in high-risk individuals with obesity through complementary pathways.

Aim of the study

The aim of this study was to investigate the association between BMI, risk of MACE, and the clinical benefit of evolocumab in patients with established ASCVD.

Methods

This was a prespecified analysis of the randomized, double-blind, placebo-controlled FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial, which enrolled 27,564 patients with stable ASCVD and LDL-c ≥70 mg/dL (≥1.8 mmol/L) or non–HDL-c ≥100 mg/dL (≥2.6 mmol/L) despite high- or moderate-intensity statin therapy. Participants were randomized to subcutaneous evolocumab (140 mg every 2 weeks or 420 mg every 4 weeks) or matching placebo. Median follow-up duration was 2.2 years.

Of the 27,500 participants with available BMI data, 40% had obesity (BMI ≥30 kg/m²), including 13% with class 2 or 3 obesity (BMI ≥35 kg/m²).

Outcomes

The primary endpoint was a composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was a composite of CV death, MI, or stroke.

Main results

BMI and cardiovascular risk

• In the placebo group, every 5-unit increase in BMI above 30 kg/m² was associated with an 11% higher risk of the primary endpoint (adjusted HR: 1.11; 95%CI: 1.02–1.21).
• The risk of the key secondary endpoint (CV death, MI, or stroke) increased by 16% per 5-unit increase in BMI above 30 kg/m² (adjusted HR: 1.16; 95%CI: 1.04–1.28).

Effect of evolocumab

• Evolocumab reduced LDL-c by 60.8% in patients with BMI <30 kg/m² and by 56.3% in those with BMI ≥30 kg/m².
• The reduction in MACE risk with evolocumab was greater in participants with more severe obesity when BMI was modeled on a continuous basis (P for interaction=0.025 for BMI >30 kg/m²).
• Evolocumab also reduced the risk of the primary endpoint across all BMI categories, with progressively greater relative benefit as obesity severity increased. Hazard ratios were 0.89 (95%CI: 0.81–0.98) for BMI <30 kg/m², 0.86 (95%CI: 0.75–0.98) for BMI 30–<35 kg/m², and 0.71 (95%CI: 0.59–0.86) for BMI ≥35 kg/m². The corresponding absolute risk reductions were 1.4%, 1.8%, and 5.7%, respectively.

Conclusion

In this prespecified analysis of the FOURIER trial, obesity was associated with a higher risk of MACE in patients with ASCVD. Although evolocumab produced similar LDL-c reductions regardless of BMI, both the relative and absolute reductions in cardiovascular events were greater in patients with higher BMI, particularly those with a BMI of ≥35 kg/m².

Find this article online at J Am Coll Cardiol.

References

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