Semaglutide

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist and an approved medicine — the highest evidence tier on this site. It is marketed as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for chronic weight management and cardiovascular risk reduction. No other compound in this catalog comes close to its evidence base: randomized trials in tens of thousands of participants have measured its effects not just on glucose and weight, but on heart attacks, strokes, kidney failure, and liver disease.

That evidence applies to the regulated pharmaceutical product. Vials sold as "research-grade" semaglutide are not the approved drug, and the FDA has documented specific concerns with unapproved semaglutide products, including different salt forms and dosing errors that have led to hospitalizations.

Semaglutide is a modified analog of human GLP-1, an intestinal hormone released after eating. Two engineering changes define it: an amino-acid substitution that protects it from the enzyme DPP-4, and a fatty-diacid chain that binds it tightly to albumin in the blood. Together these stretch its half-life to roughly one week, compared with about two minutes for native GLP-1 (Knudsen & Lau, Frontiers in Endocrinology 2019).

Acting on GLP-1 receptors in the pancreas, gut, and brain, semaglutide:

• Stimulates insulin secretion only when glucose is elevated (which is why hypoglycemia is uncommon with semaglutide alone)
• Suppresses glucagon when glucose is high
• Slows gastric emptying, prolonging fullness after meals
• Acts on appetite-regulating centers in the hypothalamus and brainstem, reducing hunger and energy intake

In the United States, semaglutide's labeled indications are:

• Type 2 diabetes — as an adjunct to diet and exercise (Ozempic injection, Rybelsus tablets; Ozempic prescribing information)
• Chronic weight management — in adults and adolescents meeting BMI criteria (Wegovy; Wegovy prescribing information)
• Cardiovascular risk reduction — to reduce major adverse cardiovascular events in adults with established cardiovascular disease and overweight or obesity, an indication added after the SELECT trial (Wegovy label)

Beyond these approvals, semaglutide is being studied in chronic kidney disease, metabolic liver disease, and other conditions — several of which now have completed outcome trials described in the research snapshot below.

Semaglutide carries a boxed warning for thyroid C-cell tumors: it caused these tumors in rodents at clinically relevant exposures, and it is unknown whether the finding applies to humans. Because of it, semaglutide is contraindicated in people with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2 (Ozempic label).

The dominant day-to-day side effects are gastrointestinal. In the pooled 68-week Wegovy trials, versus placebo (Wegovy label):

• Nausea: 44% vs 16%
• Diarrhea: 30% vs 16%
• Vomiting: 25% vs 6%
• Severe gastrointestinal reactions: 4.1% vs 0.9% on placebo
• Permanent discontinuation because of a gastrointestinal reaction: 4.3% vs 0.7% on placebo

Less common but clinically important risks include acute pancreatitis, gallbladder disease (gallstones and cholecystitis, partly linked to rapid weight loss), dehydration-related kidney injury after severe vomiting or diarrhea, and hypoglycemia when combined with insulin or sulfonylureas. In the SUSTAIN-6 diabetes trial, diabetic retinopathy complications were more frequent with semaglutide (hazard ratio 1.76), so people with existing retinopathy are monitored (NEJM 2016).

Semaglutide's roughly one-week half-life is what allows once-weekly subcutaneous injection; steady-state levels build over 4–5 weeks. An oral formulation exists but has low bioavailability and is taken daily on an empty stomach under strict conditions.

A practical safety point unique to the gray market: approved pens deliver a fixed, verified dose, while raw peptide vials require reconstitution and syringe math. The FDA has received multiple reports of hospitalizations from dosing errors with compounded and unapproved semaglutide products.

Semaglutide is sold in three branded formulations, each with its own label:

• Ozempic — once-weekly subcutaneous pen for type 2 diabetes, maintenance doses up to 2 mg.
• Wegovy — the higher-dose (2.4 mg weekly) product for weight management and cardiovascular risk reduction; the current label also includes once-daily oral Wegovy tablets.
• Rybelsus — once-daily oral tablets for type 2 diabetes. Oral semaglutide's cardiovascular safety was established in PIONEER 6 (n=3,183, NEJM 2019).

The most advanced combination is cagrilintide–semaglutide (CagriSema), which pairs semaglutide with a long-acting amylin analog. In the phase 3 REDEFINE 1 trial (n=3,417), the combination produced a mean weight change of −20.4% vs −3.0% for placebo at 68 weeks — several points beyond semaglutide alone (NEJM 2025; see the cagrilintide–semaglutide page).

Compounded semaglutide is a separate category: the FDA notes that some compounders have used salt forms (semaglutide sodium, semaglutide acetate) that are different active ingredients from the approved drug (FDA).

The headline trials, by organ system:

• Weight — STEP 1 (n=1,961): 2.4 mg weekly produced −14.9% mean body weight vs −2.4% with placebo over 68 weeks (NEJM 2021).
• Maintenance — in STEP 4, participants switched to placebo after 20 weeks regained weight (+6.9%) while those continuing lost a further 7.9% (JAMA 2021). A year after stopping, STEP 1 participants had regained about two-thirds of what they lost (Diabetes, Obesity and Metabolism 2022).
• Heart — SELECT (n=17,604, obesity without diabetes): 20% relative reduction in major cardiovascular events, hazard ratio 0.80 (NEJM 2023); SUSTAIN-6 showed hazard ratio 0.74 in type 2 diabetes (NEJM 2016).
• Kidney — FLOW (n=3,533, diabetic kidney disease): 24% lower risk of major kidney disease events, hazard ratio 0.76 (NEJM 2024).
• Liver — phase 2 in biopsy-confirmed NASH: resolution of steatohepatitis in 59% at the highest dose vs 17% on placebo, though fibrosis stage did not significantly improve (NEJM 2021).

A fuller trial-by-trial walkthrough lives on the research and evidence page.

For focused semaglutide guides, see:

• Semaglutide benefits and areas of clinical focus
• Semaglutide side effects and safety context
• Semaglutide dosing concepts and titration overview
• Semaglutide research and evidence overview
• Semaglutide vs tirzepatide, head to head

Is semaglutide a peptide? Yes. It is a 31-amino-acid analog of the natural hormone GLP-1, chemically modified so it survives in the body for about a week instead of minutes (Knudsen & Lau 2019). See also "Is Ozempic a peptide?"

How much weight do people lose on semaglutide? In STEP 1, the average was 14.9% of body weight over 68 weeks at 2.4 mg weekly, vs 2.4% with placebo — with wide individual variation around that average (NEJM 2021).

What happens when you stop taking it? Weight largely comes back. In the STEP 1 extension, participants regained about two-thirds of their lost weight within a year of stopping (Diabetes, Obesity and Metabolism 2022), and in STEP 4 those switched to placebo regained weight while those continuing kept losing (JAMA 2021). Trials treat it as a chronic therapy, not a course.

What is the difference between Ozempic, Wegovy, and Rybelsus? All three are semaglutide. Ozempic is the weekly injection labeled for type 2 diabetes (up to 2 mg); Wegovy is the higher-dose weekly injection (2.4 mg) labeled for weight management and cardiovascular risk reduction; Rybelsus is a daily tablet for diabetes.

How does semaglutide compare with tirzepatide? Tirzepatide activates two receptors (GIP and GLP-1) rather than one and produced larger average weight loss in its own trials. The two have been compared directly — see semaglutide vs tirzepatide.

Is compounded or "research-grade" semaglutide the same as the approved drug? No. The FDA warns that some compounded products use different salt forms (semaglutide sodium or acetate) that are not the approved active ingredient, and has received reports of hospitalizations from dosing errors with unapproved products (FDA).

Does semaglutide cause thyroid cancer? Unknown. It caused thyroid C-cell tumors in rodents, which drives the boxed warning and the contraindication in people with a personal or family history of medullary thyroid carcinoma or MEN 2 — but whether the rodent finding translates to humans has not been determined (Ozempic label).