Once-Weekly Semaglutide in Adults with Overweight or Obesity.

The New England journal of medicine · March 2021 · John P H Wilding, Rachel L Batterham, Salvatore Calanna, Melanie Davies, Luc F Van Gaal, et al.

What this study found

In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight. (Funded by Novo Nordisk; STEP 1 ClinicalTrials.gov number, NCT03548935).

Open on PubMed DOI

Landmark studyrctNCT03548935

Why this trial matters

Semaglutide body composition

How RAGMD uses this study

Clinical questions this paper informs

Synthesis lives on the evidence question — this page shows where the study sits in that analysis.

Core study

How does tirzepatide compare with semaglutide for weight loss?

Head-to-head trials suggest tirzepatide produces greater average weight loss than semaglutide at studied doses, with broadly similar gastrointestinal side-effect profiles. Long-term cardiovascular outcome comparisons are ongoing.

Open evidence analysis

Primary study

Does GLP-1 treatment cause meaningful muscle loss?

GLP-1 therapies reduce weight through fat and lean mass loss; lean loss is partly proportional to total weight lost. Resistance training and adequate protein may mitigate but not eliminate lean mass decline.

Open evidence analysis

Primary study

Can resistance training and protein intake preserve muscle during GLP-1 weight loss?

Exercise and higher protein intake are biologically plausible strategies to attenuate lean mass loss during significant GLP-1-mediated weight reduction, though dedicated outcome trials are still emerging.

Open evidence analysis

Supporting literature

Do GLP-1 receptor agonists reduce major cardiovascular events?

GLP-1 receptor agonists with cardiovascular outcome trials (including liraglutide and semaglutide in selected populations) reduce major adverse cardiovascular events beyond glucose lowering in high-risk patients with type 2 diabetes or obesity.

Open evidence analysis

Supporting literature

Do patients regain weight after stopping GLP-1 therapy?

Clinical trials and observational follow-up show substantial weight regain after GLP-1 discontinuation, suggesting chronic therapy may be needed to maintain benefit unless durable lifestyle changes are established.

Open evidence analysis

Supporting literature

Do GLP-1 agonists increase pancreatitis risk?

Early signals raised pancreatitis concern, but large trials and post-marketing data have not confirmed a strong causal increase at population level. Caution remains reasonable in patients with prior pancreatitis.

Open evidence analysis

Supporting literature

Do GLP-1 drugs increase thyroid cancer risk in humans?

Rodent C-cell tumor signals led to contraindications in medullary thyroid carcinoma and MEN2. Human epidemiologic data have not established a clear excess of thyroid cancer, but long-term surveillance continues.

Open evidence analysis

Read the evidence analysis Research library