Once-Weekly Semaglutide in Adults with Overweight or Obesity

Abstract

BACKGROUNDObesity is a global health challenge with few pharmacologic options. Whether adults with obesity can achieve weight loss with once-weekly semaglutide at a dose of 2.4 mg as an adjunct to lifestyle intervention has not been confirmed. METHODSIn this double-blind trial, we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions. RESULTSThe mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo, for an estimated treatment difference of −12.4 percentage points (95% confidence interval [CI], −13.4 to −11.5; P<0.001). More participants in the semaglutide group than in the placebo group achieved weight reductions of 5% or more (1047 participants [86.4%] vs. 182 [31.5%]), 10% or more (838 [69.1%] vs. 69 [12.0%]), and 15% or more (612 [50.5%] vs. 28 [4.9%]) at week 68 (P<0.001 for all three comparisons of odds). The change in body weight from baseline to week 68 was −15.3 kg in the semaglutide group as compared with −2.6 kg in the placebo group (estimated treatment difference, −12.7 kg; 95% CI, −13.7 to −11.7). Participants who received semaglutide had a greater improvement with respect to cardiometabolic risk factors and a greater increase in participant-reported physical functioning from baseline than those who received placebo. Nausea and diarrhea were the most common adverse events with semaglutide; they were typically transient and mild-to-moderate in severity and subsided with time. More participants in the semaglutide group than in the placebo group discontinued treatment owing to gastrointestinal events (59 [4.5%] vs. 5 [0.8%]). CONCLUSIONSIn 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).

Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists

“…After 56 weeks of treatment with liraglutide 3.0 mg vs. placebo, patients had mean body weight reductions of -8.4 kg vs. -2.8 kg (ETD -5.6 kg; 95% confidence interval [CI] -6.0 to -5.1; p \ 0.001) [37]. In a recently published landmark phase III study in patients with overweight or obesity (STEP 1), greater reductions in body weight were observed after 68 weeks of treatment with onceweekly semaglutide 2.4 mg vs. placebo (mean change from baseline -14.9% vs. -2.4%; ETD -12.4%; 95 CI -13.4 to -11.5; p \ 0.001) [38]. Similarly, in a 68-week phase III study comparing the effects of semaglutide 2.4 mg vs. placebo in adults with overweight or obesity without diabetes (STEP 3), mean body weight decreased 16.0% with semaglutide compared with 5.7% with placebo, both as adjunct to intensive behavioral therapy (ETD -10.3%; 95% CI -12.0 to -8.6; p \ 0.0001) [39].…”

“…In the authors' anecdotal experience, when further uptitration is not tolerated, but treatment effects are noted, maintaining the patient at the lower tolerated dose may be preferable to discontinuation. This strategy was used for the STEP 1 trial of semaglutide 2.4 mg [38].…”

Benefits of Sustained Upregulated Unimolecular GLP-1 and CCK Receptor Signalling in Obesity-Diabetes

“…Image analysis was carried out using Cell F image analysis software (Olympus Soft Imaging Solutions, GmbH, Münster, Germany). To assess islet morphology, areas of insulin and glucagon positive staining were quantified using a "closed polygon" and expressed as islet/beta-/alpha-cell areas in µm 2 , as described previously (34). To assess beta-cell proliferation and apoptosis, co-staining of insulin with Ki-67 (1:400; ab15580, AbCam) or TUNEL (In situ cell death kit, Fluorescein; Roche Diagnostics) was conducted.…”

“…The increasing use of GLP-1 mimetics to treat diabetes and obesity highlights the therapeutic importance of this class of drugs (1). Indeed, weight loss recently reported using the GLP-1 mimetic semaglutide in humans with obesity is highly impressive (2). Nevertheless, the pronounced metabolic benefits of bariatric surgery, often resulting in remission of diabetes, unquestionably exceed positive effects of GLP-1 mimetics, highlighting the important interplay between gut-derived hormones to induce distinct and sustained benefits in obesity-diabetes (3).…”

Heart failure management; a perspective from diabetes care

“…The data also suggest that the GLP-1RA class should not be specifically targeted towards people with HF, always assuming that they are so targeted to people with CV disease in line with recent consensus recommendations [3,27]. However, the exceptional weight loss demonstrated by the newer GLP-1RA approaches might benefit quality of life of those with heart failure [57,58].…”