近日，英国伦敦大学学院John Deanfield团队研究了司美格鲁肽治疗与心血管结局的基线和肥胖测量变化。该研究于2025年10月22日发表在《柳叶刀》杂志上。

SELECT试验发现，司美格鲁肽可降低超重或肥胖合并心血管疾病但无糖尿病患者的重大不良心血管事件（MACE）。研究组报告了一项预先指定的SELECT试验分析，分析了基线肥胖测量、治疗引起的肥胖变化和随后的MACE风险之间的关系。

在41个国家（804个站点）招募年龄≥45岁，BMI≥27kg/m²的患者入组，并按1:1随机分组至每周一次的司美格鲁肽2.4 mg或安慰剂。主要终点是首次MACE（心血管死亡、非致死性心肌梗死或非致死性卒中的综合）发生的时间。肥胖测量包括体重和腰围。在该分析中，通过前20周的肥胖变化来评估患者在20周后发生MACE的风险，在另一项分析中，通过超过104周的肥胖变化来评估患者之间所有试验中的MACE。

与安慰剂相比，司美格鲁肽显著降低了17604名患者入组SELECT，所有基线体重和腰围类别均有一致的获益。在司美格鲁肽组中，线性趋势分析显示，基线体重和腰围越低，MACE的发生率越低——体重每降低5公斤（风险比[HR] 0.96; p= 0.001）和腰围每减小5厘米（风险比[HR] 0.96 [0.93 - 0.99]; p= 0.004）， MACE的发生率平均降低4%。在安慰剂组中，较低的基线腰围（0.96 [0.94 - 0.99]；p= 0.007）与较低的MACE风险相关，而体重（0.99 [0.97 - 1.01]；p= 0.28）与较低的MACE风险相关，体重减轻与MACE风险增加矛盾地相关。在接受司美格鲁肽治疗的患者中，第20周体重减轻与随后的MACE风险之间没有线性趋势，但第20周腰围减小与随后的MACE风险降低相关，第104周腰围减小与试验中MACE风险降低相关。据估计，33%的MACE获益是通过腰围减小介导的（调整腰围时变变化后的HR为0.86）。

研究结果表明，司美格鲁肽的心脏保护作用与基线肥胖和体重减轻无关，与腰围只有很小的关联，这表明除了减少肥胖之外，还有其他的益处机制。

附：英文原文

Title: Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial

Author: John Deanfield, A Michael Lincoff, Steven E Kahn, Scott S Emerson, Ildiko Lingvay, Benjamin M Scirica, Jorge Plutzky, Robert F Kushner, Helen M Colhoun, G Kees Hovingh, Signe Stensen, Peter E Weeke, Ole Kleist Jeppesen, Rafael Bravo, Chau-Chung Wu, Issei Komuro, Ferruccio Santini, Jran Hjelmesth, Miguel Urina-Triana, Silvio Buscemi, Donna H Ryan

Issue&Volume: 2025-10-22

Abstract:

Background

The SELECT trial found semaglutide reduced major adverse cardiovascular events (MACE) in patients with overweight or obesity with cardiovascular disease but without diabetes. We report a prespecified analysis of the SELECT trial on the relationships between baseline adiposity measures, treatment-induced adiposity changes, and subsequent MACE risk.

Methods

Patients aged at least 45 years, with a BMI of at least 27 kg/m2 were enrolled in 41 countries (804 sites) and randomised 1:1 to once-weekly semaglutide 2·4 mg or placebo. The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke). Adiposity measures included weight and waist circumference. In this analysis, risk of MACE occurring after 20 weeks was assessed between patients by adiposity changes in the first 20 weeks and, in a separate analysis, all in-trial MACE were assessed between patients by adiposity changes over 104 weeks. This trial is registered with ClinicalTrials.gov, NCT03574597.

Findings

Semaglutide significantly reduced MACE incidence compared with placebo among 17604 patients enrolled in SELECT, with consistent benefits across all baseline weight and waist circumference categories. In the semaglutide group, analyses for linear trends showed lower baseline bodyweight and waist circumference were associated with lower incidence of MACE—an average 4% reduction in risk per 5 kg lower bodyweight (hazard ratio [HR] 0·96 [95% CI 0·94–0·99]; p=0·001) and per 5 cm smaller waist circumference (0·96 [0·93–0·99]; p=0·004). In the placebo group, lower baseline waist circumference (0·96 [0·94–0·99]; p=0·007), but not bodyweight (0·99 [0·97–1·01]; p=0·28), was associated with a lower MACE risk and weight loss was paradoxically associated with increased MACE risk. In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk, but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk, and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE. An estimated 33% of the observed benefit on MACE was mediated through waist circumference reduction (HR 0·86 [95% CI 0·77–0·97] after adjustment for time-varying changes in waist circumference).

Interpretation

The cardioprotective effects of semaglutide were independent of baseline adiposity and weight loss and had only a small association with waist circumference, suggesting some mechanisms for benefit beyond adiposity reduction.

DOI: 10.1016/S0140-6736(25)01375-3

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01375-3/abstract