Semaglutide: Uses, Mechanism, and Reported Side Effects

Semaglutide is one of the most widely prescribed GLP-1 receptor agonists, with hundreds of clinical trials examining its effects beyond its original approval. For people managing type 2 diabetes or researching GLP-1 therapies, understanding what the label actually covers, and what side effects are most commonly reported, matters more than marketing claims.

Key takeaways

• Semaglutide is a GLP-1 receptor agonist approved as OZEMPIC and RYBELSUS.
• It is indicated for glycemic control in type 2 diabetes and to reduce major cardiovascular event risk in adults with type 2 diabetes at high cardiovascular risk.
• The label carries a boxed warning.
• Over 800 registered trials have studied semaglutide, including investigations in obesity and other conditions.
• The most frequently reported adverse events involve the gastrointestinal system, led by nausea.

What Semaglutide Is

Semaglutide is a GLP-1 analogue that shares 94% sequence homology with human GLP-1. It works by selectively binding to and activating the GLP-1 receptor, the same receptor targeted by the body's natural GLP-1 hormone, which has multiple effects on glucose regulation. Its long duration of action comes from albumin binding, which slows its clearance from the body. It is classified as a GLP-1 receptor agonist (pubchem CID 56843331).

What Semaglutide Is Approved For

Under the brand names OZEMPIC and RYBELSUS, semaglutide tablets are approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also approved to reduce the risk of major adverse cardiovascular events, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke, in adults with type 2 diabetes who are at high risk for these events. The label carries a boxed warning.

What the Evidence Shows

More than 800 trials have been registered studying semaglutide, spanning its approved use and other areas of interest. A Phase 4 trial is examining oral semaglutide in people who are overweight or have obesity, while another Phase 4 study is enrolling postmenopausal women to evaluate GLP-1 agonists for physical and vascular health. A Phase 2 trial exploring semaglutide for cannabis use disorder has not yet begun recruiting.

Reported Side Effects

FAERS reports associated with semaglutide are dominated by gastrointestinal complaints: nausea (11,150 reports), vomiting (7,332), diarrhoea (6,833), and constipation (4,976). Decreased appetite (5,107), weight decreased (4,777), and impaired gastric emptying (4,175) were also commonly reported, consistent with the drug's effects on digestion and metabolism. Off label use was reported 7,890 times. These figures represent counts of submitted reports, not confirmed incidence rates or evidence of causation.