Semaglutide

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for the treatment of type 2 diabetes and, more recently, for chronic weight management. ^{[1] [2]} It is a long-acting GLP-1 analog developed by extending the half-life of GLP-1 through reversible binding to albumin, and is the only GLP-1RA currently available as both a subcutaneous and an oral formulation. ^{[3] [2]} Under the brand name Wegovy, once-weekly 2.4 mg subcutaneous semaglutide received US Food and Drug Administration approval for weight loss. ^[4]

Like other GLP-1 receptor agonists, semaglutide augments hyperglycemia-induced insulin secretion, suppresses glucagon secretion, decelerates gastric emptying, and reduces calorie intake and body weight. ^[5] The actions of GLP-1 to reduce food intake and body weight are highly conserved in obese animals and humans, and these effects informed the development of semaglutide 2.4 mg once weekly for obesity. ^[6] GLP-1 agonists act on diverse obesity-related processes including food intake regulation, insulin resistance, inflammation, endothelial dysfunction, lipid metabolism, and oxidative stress. ^[7]

Semaglutide has demonstrated the largest weight loss of any obesity medication to date, with reductions of approximately 15% of initial weight at 68 weeks, accompanied by improvements in cardiovascular risk factors and physical functioning. ^[1] In a systematic review of adults with overweight or obesity and without diabetes, once-weekly 2.4 mg semaglutide produced weight loss of up to 13.9% after 68 weeks compared with placebo. ^[8] Semaglutide was one of the agents evaluated in the SUSTAIN-6 cardiovascular outcome trial included in a meta-analysis showing beneficial cardiovascular, mortality, and kidney outcomes for GLP-1 receptor agonists in type 2 diabetes. ^[9] In a meta-analysis of cardiovascular outcome trials, GLP-1 receptor agonists as a class reduced major adverse cardiovascular events by 12% and all-cause mortality by 12% in patients with type 2 diabetes. ^[9]

Semaglutide induces mostly mild-to-moderate and transient gastrointestinal disturbances and increases the risk of biliary disease such as cholelithiasis. ^[2] Definitive conclusions about pancreatic and thyroid cancer risk cannot be drawn at this point owing to the low incidence of these conditions, and no unexpected safety issues have arisen to date. ^[2] After discontinuation of GLP-1 receptor agonist therapy, weight is regained in proportion to the amount originally lost, and participants taking semaglutide or tirzepatide regained a pooled mean of 9.69 kg, so these agents are considered chronic therapy. ^[11] Potent GLP-1 receptor agonists such as semaglutide achieve greater overall weight loss but are associated with a significant reduction in lean mass. ^[12]