Elsevier

The Lancet

Volume 397, Issue 10278, 13–19 March 2021, Pages 971-984
The Lancet

Articles
Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(21)00213-0Get rights and content

Summary

Background

This trial assessed the efficacy and safety of the GLP-1 analogue once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for weight management in adults with overweight or obesity, and type 2 diabetes.

Methods

This double-blind, double-dummy, phase 3, superiority study enrolled adults with a body-mass index of at least 27 kg/m2 and glycated haemoglobin 7–10% (53–86 mmol/mol) who had been diagnosed with type 2 diabetes at least 180 days before screening. Patients were recruited from 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia. Patients were randomly allocated (1:1:1) via an interactive web-response system and stratified by background glucose-lowering medication and glycated haemoglobin, to subcutaneous injection of semaglutide 2·4 mg, or semaglutide 1·0 mg, or visually matching placebo, once a week for 68 weeks, plus a lifestyle intervention. Patients, investigators, and those assessing outcomes were masked to group assignment. Coprimary endpoints were percentage change in bodyweight and achievement of weight reduction of at least 5% at 68 weeks for semaglutide 2·4 mg versus placebo, assessed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03552757 and is closed to new participants.

Findings

From June 4 to Nov 14, 2018, 1595 patients were screened, of whom 1210 were randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403) and included in the intention-to-treat analysis. Estimated change in mean bodyweight from baseline to week 68 was −9·6% (SE 0·4) with semaglutide 2·4 mg vs −3·4% (0·4) with placebo. Estimated treatment difference for semaglutide 2·4 mg versus placebo was −6·2 percentage points (95% CI −7·3 to −5·2; p<0·0001). At week 68, more patients on semaglutide 2·4 mg than on placebo achieved weight reductions of at least 5% (267 [68·8%] of 388 vs 107 [28·5%] of 376; odds ratio 4·88, 95% CI 3·58 to 6·64; p<0·0001). Adverse events were more frequent with semaglutide 2·4 mg (in 353 [87·6%] of 403 patients) and 1·0 mg (329 [81·8%] of 402) than with placebo (309 [76·9%] of 402). Gastrointestinal adverse events, which were mostly mild to moderate, were reported in 256 (63·5%) of 403 patients with semaglutide 2·4 mg, 231 (57·5%) of 402 with semaglutide 1·0 mg, and 138 (34·3%) of 402 with placebo.

Interpretation

In adults with overweight or obesity, and type 2 diabetes, semaglutide 2·4 mg once a week achieved a superior and clinically meaningful decrease in bodyweight compared with placebo.

Funding

Novo Nordisk.

Introduction

More than 90% of people with type 2 diabetes also have overweight or obesity,1 and more than 20% of people with obesity also have type 2 diabetes.2 Some medications used to treat type 2 diabetes are associated with weight gain,3 aggravating this common comorbidity. Weight loss is an important tool in the management of type 2 diabetes, because it improves glycaemic control and associated metabolic comorbidities.4

GLP-1 receptor agonists have shown efficacy in lowering glycated haemoglobin (HbA1c) and decreasing weight in patients with type 2 diabetes, and are recommended as a second-line therapy after metformin, and as the first injectable treatment after failure of oral glucose-lowering agents.5, 6, 7 Furthermore, the GLP-1 receptor agonist liraglutide is available for the treatment of overweight and obesity in people with or without type 2 diabetes.8 Among GLP-1 receptor agonists currently available for the treatment of diabetes, semaglutide 1·0 mg has shown the greatest weight loss effect in patients with type 2 diabetes,9, 10, 11 and is currently being investigated at the higher dose of 2·4 mg for weight management. The aim of this study, part of the Semaglutide Treatment Effect in People With Obesity (STEP) programme,12 was to evaluate the efficacy and safety of once a week subcutaneous semaglutide 2·4 mg versus semaglutide 1·0 mg (the dose approved for diabetes treatment) and placebo for bodyweight management in adults with overweight or obesity, and type 2 diabetes.

Research in context

Evidence before this study

Weight loss has been shown to improve glycaemic control and reverse disease progression in people with type 2 diabetes. GLP-1 receptor agonists have shown efficacy in lowering glycated haemoglobin (HbA1c) and decreasing weight in patients with type 2 diabetes. Once a week semaglutide 2·4 mg is currently being investigated as an obesity pharmacotherapy.

We searched PubMed on Nov 24, 2020, for articles published in the past 5 years, with no language restrictions, using the search terms “glucagon-like peptide-1 receptor agonist”, “obesity”, and “overweight”. The SCALE Diabetes trial of once a day liraglutide 3·0 mg as an adjunct to lifestyle intervention in patients with overweight or obesity, and type 2 diabetes (n=846) reported a reduction in bodyweight of 5·4% from baseline. In a phase 2, dose-finding trial (n=957), once a day subcutaneous semaglutide 0·4 mg showed effective weight loss and an acceptable safety profile.

Added value of this study

In adults with overweight or obesity and type 2 diabetes, once a week semaglutide 2·4 mg achieved a superior decrease in mean bodyweight (−9·6% [SE 0·4]) compared with semaglutide 1·0 mg (−7·0% [SE 0·4]) and placebo (−3·4% [SE 0·4]), with clinically meaningful reductions (at least 5%) reported in more than two-thirds of patients on semaglutide 2·4 mg. Furthermore, more than two-thirds of patients treated with semaglutide 2·4 mg achieved a target HbA1c of 6·5% or lower. Semaglutide 2·4 mg also resulted in improvement in cardiometabolic risk factors compared with placebo. The safety profile of semaglutide 2·4 mg was typical of a GLP-1 receptor agonist.

Implications of all the available evidence

This is the first trial to show that in adults with overweight or obesity and type 2 diabetes, once a week subcutaneous semaglutide 2·4 mg produces clinically meaningful reductions in bodyweight. The magnitude of weight loss achieved with semaglutide 2·4 mg in STEP 2 was greater than that seen with liraglutide and other approved anti-obesity medications in similar patient populations. Semaglutide 2·4 mg is a promising treatment option for weight management in patients with overweight or obesity and type 2 diabetes.

Section snippets

Trial design and participants

This phase 3, randomised, double-blind, double-dummy, placebo-controlled, multicentre superiority study was done at 149 outpatient clinics in 12 countries across Europe, North America, South America, the Middle East, South Africa, and Asia, as described in a previous publication and listed in the appendix (p 2).12 The trial complied with the International Conference on Harmonization Good Clinical Practice guidelines13 and the Declaration of Helsinki. The protocol and amendments were approved by

Results

Of 1595 patients screened from June 4 to Nov 14, 2018, 1210 were enrolled, randomly assigned to semaglutide 2·4 mg (n=404), semaglutide 1·0 mg (n=403), or placebo (n=403), and included in the intention-to-treat analysis (figure 1). There was high completion of treatment (1058 [87%] of 1210) and the trial (1164 [96%] of 1210; figure 1). 24 patients received obesity rescue medication (four in the semaglutide 2·4 mg group, seven with semaglutide 1·0 mg, and 13 with placebo). One patient in the

Discussion

The STEP 2 study showed that in adults with overweight or obesity and type 2 diabetes, once a week subcutaneous semaglutide 2·4 mg as adjunct to lifestyle intervention was significantly more effective at reducing bodyweight than either semaglutide 1·0 mg or placebo, reducing it by 9·6% from baseline (6·2 percentage points more than placebo and 2·7 percentage points more than semaglutide 1·0 mg). Also, more than two-thirds of patients treated with semaglutide 2·4 mg achieved a target HbA1c of

Data sharing

Data will be shared with bona fide researchers who submit a research proposal approved by the independent review board. Individual patient data will be shared in data sets in a de-identified and anonymised format. Data will be made available after research completion and approval of the product and product use in the EU and the USA. Information about data access request proposals can be found at novonordisk-trials.com.

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