減量薬が減量量に関係なく心臓に良い効果(‘Weight loss’ drug helps heart regardless of amount of weight lost)

2025-10-22 ユニバーシティ・カレッジ・ロンドン(UCL)

<関連情報>

• https://www.ucl.ac.uk/news/2025/oct/weight-loss-drug-helps-heart-regardless-amount-weight-lost
• https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01375-3/
• https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

セマグルチドと心血管アウトカム(ベースラインおよび肥満測定値の変化):SELECT試験の事前規定解析 Semaglutide and cardiovascular outcomes by baseline and changes in adiposity measurements: a prespecified analysis of the SELECT trial

Prof John Deanfield, MB BChir ∙ Prof A Michael Lincoff, MD ∙ Prof Steven E Kahn, MB ChB ∙ Prof Scott S Emerson, MD PhD ∙ Prof Ildiko Lingvay, MD ∙ Benjamin M Scirica, MD MPH ∙ et al.
The Lancet  Published: October 22, 2025
DOI:https://doi.org/10.1016/S0140-6736(25)01375-3

Summary

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 17 604 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.

糖尿病のない肥満におけるセマグルチドと心血管疾患の結果 Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

A. Michael Lincoff, M.D. , Kirstine Brown-Frandsen, M.D., Helen M. Colhoun, M.D., John Deanfield, M.D., Scott S. Emerson, M.D., Ph.D., Sille Esbjerg, M.Sc., Søren Hardt-Lindberg, M.D., Ph.D., +9 , for the SELECT Trial Investigators
The New England Journal of Medicine  Published: November 11, 2023
DOI: 10.1056/NEJMoa2307563

Abstract

Background

Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown.

Methods

In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed.

Results

A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).

Conclusions

In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.)