The lancet. Diabetes & endocrinologyAug 1, 2024

Safety and effectiveness of weekly semaglutide 2.4 mg compared to placebo in people with obesity and prediabetes

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Feb 21, 2026

Abstract

Participants receiving semaglutide 2·4 mg experienced a 13·9% reduction in body weight at week 52 compared to a 2·7% reduction in the placebo group.

A significantly greater proportion of participants on semaglutide reverted to normoglycaemia at week 52 (81%) compared to those on placebo (14%).
The estimated treatment difference in body weight reduction between semaglutide and placebo was -11·2%.
Serious adverse events were reported in 9% of participants in both the semaglutide and placebo groups.
Treatment discontinuation due to adverse events occurred in 6% of the semaglutide group compared to 1% in the placebo group.
No new safety signals were identified during the study.

Simplified

BACKGROUND: There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes.

METHODS: STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/mor higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbAof 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA<6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete. 2 1c1c

FINDINGS: Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m(6·9), waist circumference 120·1 cm (14·7), HbA5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported. 2 1c

INTERPRETATION: Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia.

FUNDING: Novo Nordisk.

TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

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Declaration of interests AV, HAKM, and MQ are employees and shareholders of Novo Nordisk. BMM received a research grant from Novo Nordisk; received honoraria as a consultant or speaker for Eli Lilly, Amgen, Novo Nordisk, Pfizer, and Johnson & Johnson; and is a shareholder of Reset Health. DCWL received clinical trial funding from Amgen and Novo Nordisk, and honoraria as a consultant or speaker for Amgen, Bayer, Boehringer Ingelheim, CME at Sea, Canada Collaborative Research Network, Eli Lilly, Novartis, Novo Nordisk, Viatris, and Zealand Pharma. JMB is a member of speakers bureaus for Merck, Boehringer Ingelheim, and Novo Nordisk, and has received research grants from the Novo Nordisk Foundation. KHP received honoraria for attendance or talks at meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk, and research funding from the Novo Nordisk Foundation. MC received research grants and honoraria as a speaker for and member of advisory boards, and support to attend meetings from Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. SDP received consulting fees from AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, Bayer, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, GSK, Janssen, Boehringer Ingelheim, Sanofi, Merck, Abbott, Dexcom, HLS, Bayer, and Pfizer; support for attending meetings or travel from AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, and Bayer; and participation on data safety monitoring boards or advisory boards for AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, and Bayer.

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Safety and effectiveness of weekly semaglutide 2.4 mg compared to placebo in people with obesity and prediabetes

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