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

Deanfield J, Lincoff AM, Kahn SE, Emerson SS, Lingvay I, Scirica BM, Plutzky J, Kushner RF, Colhoun HM, Hovingh GK, Stensen S, Weeke PE and 9 more

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Jeppesen OK, Bravo R, Wu CC, Komuro I, Santini F, Hjelmesæth J, Urina-Triana M, Buscemi S, Ryan DH

Lancet (London, England)22 Oct 2025Cited by 103 (Europe PMC)

PMID41138739DOI10.1016/s0140-6736(25)01375-3PepBankPUB-41138739

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Summary

BackgroundThe 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.MethodsPatients 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.FindingsSemaglutide 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).InterpretationThe 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.FundingNovo Nordisk.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study8

8 results from studies that gave the peptide. 8 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with overweight or obesity and cardiovascular disease but no diabetes, semaglutide significantly reduced MACE incidence compared with placebo.
In plain wordsIn adults with overweight or obesity and heart disease, semaglutide cut major heart events more than placebo.
Peptide
Semaglutide
Outcome
DecreaseMACE incidence
Study
n = 17,604
Comparator
Placebo
Analysis
Primary
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873901
02HumanRandomized controlled trialEfficacy outcome
In SELECT, the MACE benefit of semaglutide over placebo was consistent across all baseline weight and waist circumference categories.
In plain wordsIn adults with overweight or obesity and heart disease, semaglutide's heart benefit over placebo was similar across baseline weight and waist size groups.
Peptide
Semaglutide
Outcome
DecreaseMACE reduction across baseline weight and waist circumference categories
Study
n = 17,604
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873902
03HumanRandomized controlled trialOther
In the semaglutide group, each 5 kg lower baseline bodyweight was associated with 4% lower MACE risk.
In plain wordsAmong people on semaglutide, lower starting body weight was linked to a lower risk of major heart events.
Peptide
Semaglutide
Outcome
DecreaseBaseline body weight and MACE risk (semaglutide group)
Study
n: not reported in source
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Measurements
Hazard ratio per 5 kg lower bodyweight
0.96
semaglutide group
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873903
04HumanRandomized controlled trialOther
In the semaglutide group, each 5 cm smaller baseline waist circumference was associated with 4% lower MACE risk.
In plain wordsAmong people on semaglutide, a smaller starting waist was linked to a lower risk of major heart events.
Peptide
Semaglutide
Outcome
DecreaseBaseline waist circumference and MACE risk (semaglutide group)
Study
n: not reported in source
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Measurements
Hazard ratio per 5 cm smaller waist
0.96
semaglutide group
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873904
05HumanRandomized controlled trialOther
In the semaglutide group, weight loss at week 20 showed no linear trend with subsequent MACE risk.
In plain wordsAmong people on semaglutide, how much weight they lost by week 20 was not linked to later heart-event risk.
Peptide
Semaglutide
Outcome
No significant changeWeek-20 weight loss and subsequent MACE (semaglutide group)
Study
n: not reported in source
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Source sentences
Summary
In those receiving semaglutide there was no linear trend linking weight loss at week 20 to subsequent MACE risk
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873905
06HumanRandomized controlled trialOther
In the semaglutide group, greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk.
In plain wordsAmong people on semaglutide, a bigger waist reduction by week 20 was linked to a lower later risk of major heart events.
Peptide
Semaglutide
Outcome
DecreaseWeek-20 waist circumference reduction and subsequent MACE (semaglutide group)
Study
n: not reported in source
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Source sentences
Summary
but greater waist circumference reduction at week 20 was associated with lower subsequent MACE risk
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873906
07HumanRandomized controlled trialOther
In the semaglutide group, waist circumference reduction by week 104 was associated with lower in-trial MACE risk.
In plain wordsAmong people on semaglutide, a bigger waist reduction by week 104 was linked to a lower risk of major heart events during the trial.
Peptide
Semaglutide
Outcome
DecreaseWeek-104 waist circumference reduction and in-trial MACE (semaglutide group)
Study
n: not reported in source
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Source sentences
Summary
and waist circumference reduction by week 104 was associated with lower in-trial risk of MACE.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873907
08HumanRandomized controlled trialMechanism
An estimated 33% of the MACE benefit of semaglutide was mediated through waist circumference reduction.
In plain wordsAbout one third of semaglutide's heart-event benefit was estimated to work through a smaller waist.
Peptide
Semaglutide
Outcome
Not applicableShare of MACE benefit mediated by waist circumference reduction
Study
n: not reported in source
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
2.4 mg once weeklyAs given in this study (human).
Measurements
Share of benefit mediated
33%
waist circumference reduction
Source sentences
Summary
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).
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
The primary outcome was time to first MACE (composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke).
Show in the study text Report a problemFND-4113873908

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3Results postedNCT03574597

Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity

Novo Nordisk A/Sn = 17,60424 Oct 2018 to 29 Jun 2023

Overweight · Obesity

Trial page ClinicalTrials.govUpdated 30 Aug 2024

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
11 Oct 2026, 00:04 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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