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EviPep

Semaglutide: Research Status, Evidence and Regulation

Status: Approved drug Evidence level: Human RCT

Last reviewed: Data retrieved:

Semaglutide is a modified human glucagon-like peptide-1 (GLP-1) analogue developed by Novo Nordisk (PMID 29363040). It is authorised as a prescription medicine in the United States, the European Union and Canada. Drugs@FDA lists Ozempic and Wegovy as subcutaneous solutions and also lists separate oral tablet applications.

Also known as: Ozempic, Wegovy, Rybelsus, NN9535

Quick facts

Quick facts for Semaglutide
Also known as Ozempic, Wegovy, Rybelsus, NN9535
Category GLP-1 / incretin
Research status Approved drug
Overall evidence level Human RCT
Half-life Described as long in a systematic review of 17 clinical pharmacokinetic studies; no single value is stated here. [17]
Regulatory summary US: FDA-approved (prescription); EU: Authorised (EU centralised procedure); CA: Authorized (Health Canada)

Mechanism

Semaglutide is a modified analogue of human glucagon-like peptide-1 (GLP-1), developed with protein-acylation technology (PMID 29363040). In a human radiolabel study, intact semaglutide was the main circulating component, accounting for 69-83% of drug-related material in plasma. It was metabolised by proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty-acid side chain, and urine was the primary excretion route (PMID 28323117). A systematic review of 17 clinical pharmacokinetic studies described a long half-life. It reported that exposure increased with dose, and that food and dosing conditions affect exposure to the oral formulation (PMID 38952487).

Evidence summary

Each row is graded individually. Animal and in vitro findings do not establish effects in humans.

Evidence summary for Semaglutide
Finding as reportedLevelDesignnMain limitationSource
In SUSTAIN 2, a 56-week double-blind phase 3a trial in adults with type 2 diabetes, HbA1c was reported to fall by 1.3% and 1.6% with two semaglutide dose levels versus 0.5% with sitagliptin. Evidence level: Human RCT Randomized controlled trial1231Industry-sponsored. The comparator was a DPP-4 inhibitor. A 56-week duration does not address long-term clinical outcomes.PMID 28385659[7]
A pooled analysis of 16 phase IIIa SUSTAIN and PIONEER trials reported gastrointestinal disorders in 41.9% (subcutaneous) and 39.1% (oral) of semaglutide-treated patients versus 22.0% and 24.8% with comparators. Evidence level: Human RCT Pooled analysis of trials11159Post hoc pooled analysis across trials with different comparators and durations. Sponsor-authored.PMID 36700417[8]
In pooled STEP 1-3 data in adults with overweight or obesity, nausea was reported in 43.9% of semaglutide versus 16.1% of placebo participants. Authors reported that weight loss was largely independent of gastrointestinal adverse events. Evidence level: Human RCT Pooled analysis of trials3379Pooled post hoc analysis. Mediation analysis estimates contributions but does not establish causality.PMID 34514682[9]
In a prespecified pooled analysis of the STEP-HFpEF programme in obesity-related heart failure with preserved ejection fraction, authors reported similar weight reduction across frailty strata and the greatest improvement in the KCCQ-CSS symptom score in the most frail group. Evidence level: Human RCT Pooled analysis of trials1145Subgroup analysis. The frailty index was derived from trial data. Follow-up was 52 weeks.PMID 40956259[10]
A systematic review of ten randomised controlled trials (14,550 participants) reported thyroid cancer incidence below 1% in semaglutide-treated patients. The authors concluded this suggested no significant risk. Evidence level: Human RCT Review14550Trial follow-up is short relative to cancer latency. The abstract does not report a pooled effect estimate against comparators.PMID 38673931[11]
A retrospective cohort study of 3,344,205 patients with diabetes in the TriNetX database reported an association between semaglutide use and nonarteritic anterior ischemic optic neuropathy (NAION) at 2-4 years (HR 2.05-2.44), but not at 1 year or earlier. Evidence level: Human observational Cohort study3344205Retrospective design based on diagnostic codes. The authors state it can only infer associations, not causality.PMID 40146102[12]
The phase 3 evoke and evoke+ trials in Alzheimer's disease were declared negative by the sponsor on the week-104 CDR-SB endpoint. An independent reanalysis of later time points reported limited differences on some secondary measures. Evidence level: Human RCT Secondary analysis—Single-author secondary analysis of summary statistics at time points that were not the primary endpoint.PMID 42261705[13]
In milk samples from eight lactating women collected up to 24 hours after subcutaneous administration, semaglutide was not detected. The projected worst-case relative infant dose was 1.26%. Evidence level: Human observational Case series8Very small sample. Sampling was limited to 24 hours. Infant outcomes were not assessed.PMID 39275201[14]

Regulatory snapshot

Regulatory status of Semaglutide by jurisdiction
Jurisdiction Status Basis Official source Retrieved
United States FDA-approved (prescription) Listed in Drugs@FDA as Ozempic (NDA 209637, subcutaneous solution) and Wegovy (NDA 215256, subcutaneous solution), applicant Novo Nordisk. Oral tablet applications are also listed (NDA 213051, NDA 218316). Approved indications are defined in the current FDA labels. Drugs@FDA: Ozempic (semaglutide), NDA 209637
European Union Authorised (EU centralised procedure) EMA lists Ozempic (semaglutide) as authorised, with the marketing authorisation issued on 8 February 2018 (therapeutic area: diabetes mellitus). EMA also lists Wegovy (semaglutide) as authorised; its EMA overview describes use for weight management in adults with obesity or overweight with weight-related health problems, and in adolescents from 12 years of age with obesity. EMA EPAR: Ozempic (semaglutide)
Canada Authorized (Health Canada) The Health Canada Drug Product Database lists OZEMPIC (semaglutide) with current status Marketed and original market date 2018-02-22. It also lists WEGOVY (semaglutide, single-dose prefilled pen) with current status Approved and current status date 2021-11-23. Health Canada Drug Product Database: OZEMPIC (semaglutide)

Full regulatory status by country, with sources and changelog →

Known adverse effects

Listed only where reported in a cited source.

  • Nausea, diarrhoea, vomiting and constipation (Most frequent gastrointestinal events in pooled STEP 1-3 data; mostly mild to moderate, transient, and most frequent during or shortly after dose escalation.) [9]
  • Cholelithiasis (gallstones) (Higher incidence than placebo with subcutaneous and oral semaglutide in pooled SUSTAIN and PIONEER analyses.) [8]
  • Diabetic retinopathy (Higher incidence with subcutaneous semaglutide versus placebo in SUSTAIN 6.) [8]
  • Small increases in pulse rate (Reported with both formulations; no increased rate of arrhythmias was reported.) [8]
  • Nonarteritic anterior ischemic optic neuropathy (association) (Association reported in a retrospective cohort of patients with diabetes; causality not established.) [12]

Clinical trials snapshot

Registered studies
710
Most advanced phase
Phase 4
Recruiting or not yet recruiting
228
Most recent start
2028-10
Most frequent lead sponsor
Novo Nordisk A/S (261)
Most common status
Completed

Source: ClinicalTrials.gov, retrieved . Registry searches by name may miss studies that use other identifiers.

All registered studies for Semaglutide →

Frequently asked questions

Is semaglutide an approved medicine?

Semaglutide is authorised as a prescription medicine in the United States, the European Union and Canada under the brand names Ozempic and Wegovy. Product names, application numbers and official source links are listed on the legal status page for this entry.

How is semaglutide related to GLP-1?

Semaglutide is a modified analogue of human glucagon-like peptide-1 (GLP-1), developed with protein-acylation technology (PMID 29363040). A systematic review of clinical pharmacokinetic studies described a long half-life (PMID 38952487).

Which adverse events were most often reported in clinical trials?

Gastrointestinal events were reported most often. In pooled STEP 1-3 data, nausea, diarrhoea, vomiting and constipation were more common with semaglutide than placebo and were mostly mild to moderate and transient (PMID 34514682). Pooled SUSTAIN and PIONEER data also reported higher cholelithiasis incidence versus placebo (PMID 36700417).

Has semaglutide been studied outside type 2 diabetes and obesity?

Yes. It was studied in obesity-related heart failure with preserved ejection fraction in the STEP-HFpEF programme (PMID 40956259). The phase 3 evoke and evoke+ trials in Alzheimer's disease were declared negative on their primary endpoint (PMID 42261705).

Has semaglutide transfer into breast milk been measured?

One study analysed milk from eight lactating women and did not detect semaglutide in any sample. The authors projected a worst-case relative infant dose of 1.26%, and noted that long-term infant outcomes were not assessed (PMID 39275201).

Related

Related entries

Comparisons

Tools

Sources

  1. Drugs@FDA: Ozempic (semaglutide), NDA 209637 · NDA 209637 · retrieved November 3, 2026
  2. Drugs@FDA: Wegovy (semaglutide), NDA 215256 · NDA 215256 · retrieved November 3, 2026
  3. EMA EPAR: Ozempic (semaglutide) · retrieved November 3, 2026
  4. EMA EPAR: Wegovy (semaglutide) · retrieved November 3, 2026
  5. Health Canada Drug Product Database: OZEMPIC (semaglutide) · retrieved November 3, 2026
  6. Health Canada Drug Product Database: WEGOVY (semaglutide) · retrieved November 3, 2026
  7. Efficacy and safety of once-weekly semaglutide versus once-daily sitagliptin as an add-on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56-week, double-blind, phase 3a, randomised trial. · PMID 28385659 · retrieved November 3, 2026
  8. Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes. · PMID 36700417 · retrieved November 3, 2026
  9. Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss. · PMID 34514682 · retrieved November 3, 2026
  10. Frailty and Effects of Semaglutide in Obesity-Related HFpEF: Findings From the STEP-HFpEF Program. · PMID 40956259 · retrieved November 3, 2026
  11. Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review. · PMID 38673931 · retrieved November 3, 2026
  12. Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy Risk Among Patients With Diabetes. · PMID 40146102 · retrieved November 3, 2026
  13. Semaglutide showed limited improvements in patients with Alzheimer's disease: Revisiting the evoke and evoke + clinical trials. · PMID 42261705 · retrieved November 3, 2026
  14. Subcutaneous Semaglutide during Breastfeeding: Infant Safety Regarding Drug Transfer into Human Milk. · PMID 39275201 · retrieved November 3, 2026
  15. Semaglutide: First Global Approval. · PMID 29363040 · retrieved November 3, 2026
  16. Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. · PMID 28323117 · retrieved November 3, 2026
  17. Clinical Pharmacokinetics of Semaglutide: A Systematic Review. · PMID 38952487 · retrieved November 3, 2026

Changelog

  • — Definition, mechanism, evidence table, adverse effects and FAQ drafted from fetched PubMed records; pending human review.
  • — Revised after second review: removed administration wording and unsourced statements, corrected study design labels.
  • — Attribution wording revised; quality score 19/20 after review; published.
  • — Entry skeleton created.

Last reviewed: Data retrieved: