Efficacy and safety of semaglutide for weight management: evidence from the STEP program

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ABSTRACT

Obesity is a global health challenge. It is a multifactorial, complex, and progressive disease associated with various health complications and increased mortality. Lifestyle modifications are central to weight management but may be insufficient to maintain clinically meaningful weight loss. Pharmacotherapies are recommended as an adjunct to lifestyle interventions to induce and sustain clinically meaningful weight loss and reduce the risk of comorbidities in appropriate patients. Glucagon-like peptide-1 is an incretin metabolic hormone responsible for a range of physiological effects, including glucose and appetite regulation. Several glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the treatment of type 2 diabetes since 2005 including exenatide (short- and extended-release), lixisenatide, liraglutide, dulaglutide, albiglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently US Food and Drug Administration (FDA)-approved for chronic weight management in patients with or without diabetes. The phase 3 Semaglutide Treatment Effect in People with obesity (STEP) program was designed to investigate the effect of semaglutide versus placebo on weight loss, safety, and tolerability in adults with overweight or obesity. Following the submission of the results of the STEP 1–4 trials, the FDA approved once-weekly subcutaneous semaglutide 2.4 mg for chronic weight management in people with overweight or obesity in April 2021. Data from the program demonstrated that semaglutide (2.4 mg once weekly) achieved significant and sustained weight loss, together with improvements in cardiometabolic risk factors compared with placebo, and was generally well tolerated, with a safety profile consistent with other GLP-1RAs. The most common adverse events reported in STEP 1–5 were gastrointestinal events, which were transient, mild-to-moderate in severity, and typically resolved without permanent treatment discontinuation. This article reviews the data from STEP 1–5 and highlights clinically relevant findings for primary care providers.

KEYWORDS:

• Obesity
• glucagon-like peptide-1 receptor agonist
• semaglutide
• primary care

Abbreviations

AE, adverse event

AV, atrioventricular

BMI, body mass index

CI, confidence interval

CVD, cardiovascular disease

DPP-4, dipeptidyl peptidase-4

EOT, end of trial

ETD, estimated treatment difference

FDA, US Food and Drug Administration

GI, gastrointestinal

GLP-1, glucagon-like peptide-1

GLP‑1RA, glucagon-like peptide-1 receptor agonist

HbA_1c, glycated hemoglobin

IBT, intensive behavioral therapy

IWQOL-Lite-CT, Impact of Weight on Quality of Life-Lite Clinical Trials

MTC, medullary thyroid carcinoma

NR, not reported

OW, once weekly

SAEs, serious adverse events

SF-36, 36-Item Short Form Health Survey

STEP, Semaglutide Treatment Effect in People with obesity

T2D, type 2 diabetes

WL, weight loss

Acknowledgments

Medical writing support was provided by Laura Moore, PhD, of Axis, a division of Spirit Medical Communications Group Limited, and Gemma Hall, a contract writer working on behalf of Axis, and funded by Novo Nordisk Inc., in accordance with Good Publication Practice 3 (GPP3) guidelines (www.ismpp.org/gpp3).

Declaration of financial/other relationships

Anastassia Amaro: advisory boards and consultant – Medality Medical, Novo Nordisk, and Pfizer, and research support – Altimmune, Eli Lilly, Fractyl Health, and Novo Nordisk.

Danny Sugimoto: grants – AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Merck, and Novo Nordisk.

Sean Wharton: research funding, advisory/consulting fees, and/or other support – AstraZeneca, Bausch Health Inc., Boehringer Ingelheim, CIHR, Janssen, Lilly, and Novo Nordisk.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This peer-reviewed article was supported by Novo Nordisk Inc.; the company was provided with the opportunity to perform a medical accuracy review.