Semaglutide: Uses, Mechanism, Evidence, and Side Effects

Anyone managing type 2 diabetes has likely heard of semaglutide, sold under brand names like Ozempic and Rybelsus. Here is what the FDA label, clinical trial registry, and adverse event reports actually say about it.

Key takeaways

• Semaglutide is a GLP-1 receptor agonist approved to improve glycemic control in adults with type 2 diabetes.
• It also carries an approved indication to reduce major cardiovascular events in adults with type 2 diabetes at high risk.
• The label carries a boxed warning.
• Over 780 registered clinical trials have studied semaglutide, including completed phase 3 diabetes trials.
• The most frequently reported adverse events involve the gastrointestinal system, led by nausea and vomiting.

What Semaglutide Is

Semaglutide is a GLP-1 analogue that shares 94% of its sequence with human GLP-1, a hormone the body uses to regulate glucose. It works as a GLP-1 receptor agonist, binding to and activating the same receptor that native GLP-1 targets. This activation influences multiple glucose-related processes in the body. Semaglutide's albumin binding slows its clearance from the kidneys, which gives it a long half-life.

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. The label also covers reducing 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 outcomes. The FDA label for semaglutide includes a boxed warning.

What The Evidence Shows

More than 780 clinical trials have been registered involving semaglutide. A completed phase 3 trial evaluated the efficacy and safety of semaglutide injection for treating type 2 diabetes mellitus. Separately, a phase 2 trial currently recruiting is examining semaglutide for weight management following smoking cessation, and a completed phase 1 study compared drug levels in participants with reduced versus normal kidney function.

Reported Side Effects

Adverse event reports for semaglutide are dominated by gastrointestinal symptoms: nausea (10,674 reports), vomiting (6,964), diarrhoea (6,462), and constipation (4,724). Decreased appetite (4,905 reports), weight decreased (4,487), and impaired gastric emptying (3,558) were also commonly reported. Off label use was reported 7,325 times. These figures reflect the number of reports submitted to a surveillance database, not confirmed incidence rates or proof that semaglutide caused the event.