FDA APPROVEDAcylated GLP-1 receptor agonist peptide

Semaglutide

Also known as Ozempic, Wegovy, Wegovy HD, Rybelsus

A once-weekly GLP-1 receptor agonist and one of the most extensively trialed peptides in metabolic research, including a 17,604-person cardiovascular outcomes trial.

  • Body weight reduction
  • Glycemic control
  • Cardiovascular outcomes
  • Liver fat and fibrosis

What it is

Semaglutide is a synthetic analogue of the gut hormone glucagon-like peptide-1 (GLP-1), modified with a fatty acid side chain that binds serum albumin and slows its clearance. Novo Nordisk developed it as a longer-acting successor to liraglutide, and Lau et al. (2015) described the design work behind once-weekly dosing. It is available as a weekly subcutaneous injection and as a once-daily oral tablet.

Mechanism of action

Semaglutide binds and activates the GLP-1 receptor, the same receptor used by the native hormone that the gut releases after meals. Native GLP-1 is cleared within minutes. Lau et al. (2015) described how structural modifications make semaglutide resistant to metabolic degradation and how a fatty acid moiety, attached through a linker, raises its affinity for serum albumin and slows elimination. In that work its GLP-1 receptor affinity was about threefold lower than liraglutide's, a trade-off accepted for stronger albumin binding, and its plasma half-life after intravenous dosing in mini-pigs was 46.1 hours. GLP-1 receptor activation increases glucose-dependent insulin secretion, lowers glucagon release and slows gastric emptying. Receptors in brain regions that regulate appetite are thought to account for the reduced food intake and body weight seen in trials. Whether the cardiovascular findings reflect weight loss alone or additional effects on the heart and blood vessels is still being studied.

What it’s most studied for

Semaglutide is most studied for body weight reduction and glycemic control. The STEP program tested the 2.4 mg weekly injection in adults with obesity, and later trials examined a higher 7.2 mg weekly dose and a 25 mg daily oral tablet. Researchers have also used it to ask whether a GLP-1 receptor agonist changes outcomes beyond weight: cardiovascular events in people with established heart disease (SELECT), liver histology in biopsy-defined steatohepatitis (ESSENCE), and pain in knee osteoarthritis (STEP 9). This body of trials makes it the reference compound against which newer incretin-based peptides, such as tirzepatide, retatrutide and cagrilintide combinations, are usually compared.

Notable findings

Each finding carries the species or population it was observed in and the dose that study used. Doses are reported as research context, exactly as published. They are not guidance.

Humans Randomized, placebo-controlled trial (n=1,961)

Weight reduction over 68 weeks (STEP 1)

Wilding et al. (2021) randomized adults with a BMI of 30 or more (or 27 or more with a weight-related condition) and no diabetes 2:1 to semaglutide or placebo, alongside lifestyle intervention. Mean body-weight change at 68 weeks was −14.9% with semaglutide versus −2.4% with placebo. Nausea and diarrhea were the most common adverse events, and 4.5% of the semaglutide group stopped treatment because of gastrointestinal events, versus 0.8% on placebo.

Dose studied
Semaglutide 2.4 mg once weekly, subcutaneous injection, adults, 68 weeks

[2] Wilding JPH et al. · 2021 · PMID 33567185 ↗

Humans Randomized, double-blind, placebo-controlled outcomes trial (n=17,604)

Cardiovascular events in established heart disease (SELECT)

Lincoff et al. (2023) enrolled adults aged 45 or older with established cardiovascular disease and a BMI of 27 or more but no diabetes. Over a mean follow-up of 39.8 months, the composite of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 6.5% of the semaglutide group and 8.0% of the placebo group (hazard ratio 0.80, 95% CI 0.72 to 0.90). Permanent discontinuation for adverse events was more frequent with semaglutide (16.6% vs 8.2%).

Dose studied
Semaglutide 2.4 mg once weekly, subcutaneous injection, adults, mean follow-up 39.8 months

[3] Lincoff AM et al. · 2023 · PMID 37952131 (NCT03574597) ↗

Humans Randomized, placebo- and active-controlled phase 3b trial (n=1,407)

7.2 mg versus 2.4 mg dose (STEP UP)

Wharton et al. (2025) randomized 1,407 adults with obesity and without diabetes to semaglutide 7.2 mg, semaglutide 2.4 mg or placebo for 72 weeks, with lifestyle intervention in all groups. Counting all participants regardless of adherence, mean weight change was −18.7% with 7.2 mg, −15.6% with 2.4 mg and −3.9% with placebo; the sponsor's estimate for participants who stayed on treatment was −20.7% with 7.2 mg. Gastrointestinal adverse events and dysesthesia (altered skin sensation) were more frequent at the higher dose.

Dose studied
Semaglutide 7.2 mg or 2.4 mg once weekly, subcutaneous injection, adults, 72 weeks

[5] Wharton S et al. · 2025 · PMID 40961952 (NCT05646706) ↗

Humans Randomized, double-blind, placebo-controlled trial (n=307)

Daily oral 25 mg tablet (OASIS 4)

Wharton et al. (2025) randomized 307 adults with overweight or obesity and without diabetes 2:1 to oral semaglutide or placebo, plus lifestyle intervention. At week 64, estimated mean weight change was −13.6% versus −2.2% with placebo; the sponsor reported −16.6% versus −2.7% for participants who adhered to treatment. Gastrointestinal adverse events occurred in 74.0% of the semaglutide group and 42.2% of the placebo group.

Dose studied
Oral semaglutide 25 mg once daily, adults, 64 weeks of treatment including a 12-week dose-escalation period

[6] Wharton S et al. · 2025 · PMID 40934115 (NCT05564117) ↗

Humans Randomized, double-blind, placebo-controlled trial (n=407)

Knee osteoarthritis pain (STEP 9)

Bliddal et al. (2024) studied adults with obesity and moderate knee osteoarthritis with at least moderate pain, at 61 sites in 11 countries. Body weight fell 13.7% with semaglutide versus 3.2% with placebo, and the WOMAC pain score (0 to 100, higher is worse) changed by −41.7 versus −27.5 points. Discontinuation for adverse events was 6.7% versus 3.0%, mostly gastrointestinal.

Dose studied
Semaglutide 2.4 mg once weekly, subcutaneous injection, adults, 68 weeks

[4] Bliddal H et al. · 2024 · PMID 39476339 (NCT05064735) ↗

Humans Randomized, double-blind, placebo-controlled phase 3 trial (interim analysis, n=800)

Liver histology in steatohepatitis (ESSENCE)

Sanyal et al. (2025) reported the planned 72-week analysis of the first 800 participants with biopsy-defined MASH and stage 2 or 3 fibrosis. Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of the semaglutide group versus 34.3% on placebo, and fibrosis improved without worsening of steatohepatitis in 36.8% versus 22.4%. The trial continues to 240 weeks to assess clinical outcomes such as progression to cirrhosis.

Dose studied
Semaglutide 2.4 mg once weekly, subcutaneous injection, adults, 72 weeks (interim analysis)

[7] Sanyal AJ et al. · 2025 · PMID 40305708 ↗

Study quality

The evidence for semaglutide is strong: several large randomized, placebo-controlled phase 3 trials in humans, a cardiovascular outcomes trial in 17,604 adults, and FDA approval for multiple indications. Weight trials ran 64 to 72 weeks, and SELECT followed participants for a mean of nearly 40 months, long by the standards of peptide research. The limitations are worth stating plainly. The trials summarized here were sponsored by the manufacturer, Novo Nordisk. Weight results differ depending on whether they count everyone randomized or only participants who stayed on treatment, so headline figures should be read with the analysis method in mind. Gastrointestinal adverse events (nausea, diarrhea, vomiting) are the most common safety finding and drive most discontinuations; in SELECT, 16.6% stopped the drug for adverse events versus 8.2% on placebo. STEP UP reported more dysesthesia at 7.2 mg, and semaglutide labeling carries a boxed warning about thyroid C-cell tumors.

On the research desk

Recent records on Semaglutide from the Alpha Helix research feed, each with its evidence tier and citation.

References

  1. 1
    Lau J, Bloch P, Schäffer L, et al. (2015). Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. Journal of Medicinal Chemistry. PMID 26308095
  2. 2
    Wilding JPH, Batterham RL, Calanna S, et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. PMID 33567185
  3. 3
    Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. New England Journal of Medicine. PMID 37952131 (NCT03574597)
  4. 4
    Bliddal H, Bays H, Czernichow S, et al. (2024). Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis. New England Journal of Medicine. PMID 39476339 (NCT05064735)
  5. 5
    Wharton S, Freitas P, et al. (2025). Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. The Lancet Diabetes & Endocrinology. PMID 40961952 (NCT05646706)
  6. 6
    Wharton S, Lingvay I, Bogdanski P, et al. (2025). Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity. New England Journal of Medicine. PMID 40934115 (NCT05564117)
  7. 7
    Sanyal AJ, Newsome PN, Kliers I, et al. (2025). Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis. New England Journal of Medicine. PMID 40305708

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