Monograph in Incretin & amylin agonists
Semaglutide
The GLP-1 receptor agonist behind Ozempic, Wegovy and Rybelsus, with the largest trial record of any peptide on this site — including a cardiovascular-outcomes trial in people without diabetes.
Also called NN9535 · Ozempic · Wegovy · Rybelsus
Best evidence: Approved / regulatory-grade
FDA-approved as injection and tablet for type 2 diabetes, weight management and cardiovascular risk reduction; supported by large outcomes trials.
FDA-approved — Ozempic (2017), Rybelsus (2019), Wegovy (2021)
Residue Editorial Team · updated
What is Semaglutide?
Semaglutide is a GLP-1 receptor agonist, injected weekly or taken daily by mouth. It is FDA-approved as Ozempic and Rybelsus (type 2 diabetes) and Wegovy (weight management, cardiovascular risk)1FDAOZEMPIC prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-07-30.,2FDAWEGOVY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2024-04-23.. In STEP 1, weight fell 14.9% versus 2.4% on placebo over 68 weeks3PubMedOnce-Weekly Semaglutide in Adults with Overweight or Obesity. Wilding JPH et al. N Engl J Med. 2021.; in SELECT, major cardiovascular events fell 20%4PubMedSemaglutide and Cardiovascular Outcomes in Obesity without Diabetes. Lincoff AM et al. N Engl J Med. 2023.. Half-life: about 7 days5PubMedPharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. Hall S et al. Clin Pharmacokinet. 2018..
Key findings
- STEP 1 (1,961 adults without diabetes, 2.4 mg weekly): weight change −14.9% versus −2.4% with placebo at 68 weeks; 50.5% lost 15% or more3.
- SELECT (17,604 adults with cardiovascular disease and overweight or obesity, no diabetes): major adverse cardiovascular events 6.5% versus 8.0% (hazard ratio 0.80) over a mean 39.8 months4.
- STEP 5 showed the effect persisting to two years: −15.2% versus −2.6% at 104 weeks6PubMedTwo-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Garvey WT et al. Nat Med. 2022..
- One year after stopping, STEP 1 extension participants had regained about two-thirds of the weight they had lost7PubMedWeight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Wilding JPH et al. Diabetes Obes Metab. 2022..
- Discontinuation for adverse events was 16.6% with semaglutide versus 8.2% with placebo in SELECT4.
What is Semaglutide, chemically?
| PubChem CID | 56843331 “Semaglutide” |
|---|---|
| Formula | C187H291N45O59 |
| Molecular weight | 4,114 g/mol |
| CAS (as listed) | 910463-68-2 |
| FDA UNII | 53AXN4NNHX |
| InChIKey | DLSWIYLPEUIQAV-CCUURXOWSA-N |
| Half-life (reported) | About 7 days; steady state in 4–5 weeks5 |
| Route in trials | Once-weekly subcutaneous injection; once-daily tablet |
| Originator | Novo Nordisk |
| Mechanism | GLP-1 receptor agonist (fatty-acid–modified GLP-1 analog) |
How does Semaglutide work?
Semaglutide is an analog of human glucagon-like peptide-1 (GLP-1) that carries a fatty-acid side chain8PubMedAbsorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. Jensen L et al. Eur J Pharm Sci. 2017.. Labels for both the injection and tablet describe it as a GLP-1 receptor agonist1,9FDAOZEMPIC, RYBELSUS prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-01-30.. A radiolabel study in healthy volunteers found intact semaglutide made up 69–83% of drug-related material in plasma; it is metabolized by proteolytic cleavage and beta-oxidation of the side chain, and urine is the main excretion route8.
How long does Semaglutide last in the body?
At 0.5 or 1 mg weekly, semaglutide's half-life is about seven days, so steady state takes four to five weeks. Like other GLP-1 receptor agonists it delays gastric emptying, which may affect absorption of oral medicines5. A 2024 systematic review found exposure rises with dose for both routes; oral exposure is sensitive to food, water volume and dosing conditions, and no dose adjustment was needed for renal or hepatic impairment10PubMedClinical Pharmacokinetics of Semaglutide: A Systematic Review. Yang XD & Yang YY Drug Des Devel Ther. 2024..
What did the clinical trials find?
Weight management (STEP). STEP 1 randomized adults with obesity, or overweight with a comorbidity, without diabetes to 2.4 mg weekly or placebo. At 68 weeks, weight had fallen 14.9% versus 2.4% (−15.3 kg versus −2.6 kg); 86.4% lost at least 5% and 50.5% at least 15%3. STEP 5 extended the comparison to 104 weeks: −15.2% versus −2.6%6.
Maintenance and withdrawal. STEP 4 enrolled 803 people who had lost a mean 10.6% during a 20-week run-in. Those continuing lost a further 7.9% by week 68; those switched to placebo gained 6.9%11PubMedEffect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. Rubino D et al. JAMA. 2021.. The STEP 1 extension followed 327 participants for a year after stopping: they regained 11.6 of the 17.3 percentage points lost, and most cardiometabolic improvements reverted towards baseline7.
Cardiovascular outcomes (SELECT). SELECT enrolled 17,604 adults aged 45 or older with established cardiovascular disease and a BMI of 27 or more, without diabetes. Over a mean 39.8 months, the primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% on semaglutide and 8.0% on placebo (hazard ratio 0.80; 95% CI 0.72–0.90)4. This result underpins Wegovy's cardiovascular indication2.
What adverse events were reported in trials?
Gastrointestinal effects dominate. In STEP 1, nausea and diarrhea were the most common and were usually transient; 4.5% discontinued for gastrointestinal events versus 0.8% on placebo3. Over two years in STEP 5, gastrointestinal events were reported by 82.2% versus 53.9%6. In the much larger and longer SELECT trial, 16.6% stopped the drug for an adverse event versus 8.2% with placebo4.
Is Semaglutide FDA-approved?
| Record | Status | Source |
|---|---|---|
| WEGOVY, WEGOVY HD, WEGOVY FLEXTOUCH NDA215256 · NOVO | FDA-approved original approval 2021-06-04 SOLUTION SUBCUTANEOUS | 15 |
| WEGOVY NDA218316 · NOVO | FDA-approved original approval 2025-12-22 TABLET ORAL | 16 |
| OZEMPIC, RYBELSUS NDA213051 · NOVO | FDA-approved original approval 2019-09-20 TABLET ORAL | 14 |
| OZEMPIC NDA209637 · NOVO | Discontinued original approval 2017-12-05 SOLUTION SUBCUTANEOUS | 12 |
| RYBELSUS NDA213182 · NOVO NORDISK INC | FDA-approved original approval 2020-01-16 TABLET ORAL | 13 |
| SEMAGLUTIDE ANDA220314 · APOTEX INC | FDA-approved original approval 2026-04-07 INJECTION SOLUTION | 17 |
| Shortage & compounding | FDA declared the national shortage of semaglutide injection products resolved; the temporary enforcement-discretion windows for compounded copies have since ended. | 18 |
Six semaglutide applications appear in Drugs@FDA at our fetch: the Ozempic injection12FDADrugs@FDA: OZEMPIC (NDA209637). NOVO; original approval 2017-12-05; Prescription, Discontinued., Rybelsus tablets13FDADrugs@FDA: RYBELSUS (NDA213182). NOVO NORDISK INC; original approval 2020-01-16; Prescription., a tablet application covering Rybelsus and Ozempic tablets14FDADrugs@FDA: OZEMPIC, RYBELSUS (NDA213051). NOVO; original approval 2019-09-20; Prescription., Wegovy injection15FDADrugs@FDA: WEGOVY, WEGOVY HD, WEGOVY FLEXTOUCH (NDA215256). NOVO; original approval 2021-06-04; Prescription., a Wegovy tablet approved in December 202516FDADrugs@FDA: WEGOVY (NDA218316). NOVO; original approval 2025-12-22; Prescription., and a generic application whose marketing status is listed as "None (Tentative Approval)"17FDADrugs@FDA: SEMAGLUTIDE (ANDA220314). APOTEX INC; original approval 2026-04-07; None (Tentative Approval)..
The shortage that allowed widespread compounding is over. FDA's April 2026 statement notes semaglutide is not on the 503B bulks list or the drug-shortage list, and gives examples — such as semaglutide combined with vitamin B12 — that it may treat as essentially copies of approved products18FDAFDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. U.S. FDA, content current as of 04/01/2026..
What is still unknown?
- Long-term maintenance. Weight and cardiometabolic gains reverse after stopping7; durable strategies remain under study.
- New indications. Hundreds of registered studies test semaglutide in other conditions19TrialClinicalTrials.gov registry search: semaglutide. 785 registered studies at fetch.; registration alone is not evidence.
What effects has Semaglutide shown, by body system?
Each row is graded separately using the Residue evidence scale: a compound can carry an A for one use and a D for another.
| System | What was observed | Grade |
|---|---|---|
| Body weight | Approved for long-term weight reduction in adults and adolescents 12+ with obesity2; −14.9% at 68 weeks in STEP 13. | A |
| Glycemic control | Approved as an adjunct to diet and exercise in type 2 diabetes, as injection and tablet1,9. | A |
| Cardiovascular | Wegovy is indicated to reduce major adverse cardiovascular events in adults with established cardiovascular disease and obesity or overweight2, based on SELECT4. | A |
| Kidney | Ozempic is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease and cardiovascular death in type 2 diabetes with chronic kidney disease1. | A |
| Weight maintenance | Continuing after a 20-week run-in: −7.9% versus +6.9% on switching to placebo11. | B |
| Gastrointestinal (adverse) | Nausea and diarrhea most common, typically transient3; GI events 82.2% versus 53.9% over two years in STEP 56. | A |
How much research is there on Semaglutide?
| Phase | Studies | Breakdown |
|---|---|---|
| Early phase 1 | 8 | 0 completed, 7 active or recruiting, 0 stopped, 1 other |
| Phase 1 | 116 | 88 completed, 23 active or recruiting, 3 stopped, 2 other |
| Phase 2 | 136 | 52 completed, 72 active or recruiting, 5 stopped, 7 other |
| Phase 3 | 184 | 96 completed, 75 active or recruiting, 7 stopped, 6 other |
| Phase 4 | 121 | 28 completed, 74 active or recruiting, 5 stopped, 14 other |
| Not applicable | 77 | 17 completed, 51 active or recruiting, 0 stopped, 9 other |
| Observational | 143 | 70 completed, 64 active or recruiting, 5 stopped, 4 other |
Compare and continue
- Cagrilintide vs semaglutideComparison
- Retatrutide vs semaglutideComparison
- Semaglutide vs tirzepatideComparison
- TirzepatideIncretin & amylin agonists
- RetatrutideIncretin & amylin agonists
- CagrilintideIncretin & amylin agonists
Questions readers ask
What is the difference between Ozempic, Wegovy and Rybelsus?
All contain semaglutide. Ozempic (injection) and Rybelsus (tablet) are labeled for type 2 diabetes and related cardiovascular and kidney indications1,9. Wegovy is labeled for cardiovascular risk reduction in people with established cardiovascular disease and obesity or overweight, and for long-term weight reduction2.
What are the side effects of semaglutide?
Gastrointestinal effects are the most common: in STEP 1, nausea and diarrhea were typically transient and mild to moderate, and 4.5% stopped because of gastrointestinal events versus 0.8% on placebo3. In SELECT, 16.6% discontinued for any adverse event versus 8.2% on placebo4. The FDA label lists all warnings2.
What is the half-life of semaglutide?
About 7 days at 0.5 or 1 mg, so steady state is reached in 4–5 weeks5. Intact semaglutide accounts for 69–83% of circulating drug-related material8.
Do people regain weight after stopping semaglutide?
In the STEP 1 extension, participants regained about two-thirds of their prior weight loss within a year of stopping7. In STEP 4, switching to placebo after 20 weeks led to a 6.9% gain11.
Does semaglutide reduce heart attacks and strokes?
In SELECT, in people with cardiovascular disease and overweight or obesity but no diabetes, the composite of cardiovascular death, non-fatal heart attack or non-fatal stroke occurred in 6.5% versus 8.0% on placebo (hazard ratio 0.80)4.
Is compounded semaglutide still available?
FDA declared the semaglutide shortage resolved in February 2025. Its April 2026 statement says semaglutide is not on the 503B bulks list or the shortage list, and restates the limits on 503A pharmacies compounding essentially-copies of approved products18.
References
Every source below was retrieved from its official API or page and cached on the data-edition date. Numbers match the margin notes.
- 1 FDA OZEMPIC prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-07-30.
- 2 FDA WEGOVY prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2024-04-23.
- 3 PubMed Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021. PMID 33567185; doi:10.1056/NEJMoa2032183.
- 4 PubMed Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023. PMID 37952131; doi:10.1056/NEJMoa2307563.
- 5 PubMed Hall S, Isaacs D, Clements JN. Pharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. Clin Pharmacokinet 2018. PMID 29915923; doi:10.1007/s40262-018-0668-z.
- 6 PubMed Garvey WT, Batterham RL, Bhatta M, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med 2022. PMID 36216945; doi:10.1038/s41591-022-02026-4.
- 7 PubMed Wilding JPH, Batterham RL, Davies M, et al. Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension. Diabetes Obes Metab 2022. PMID 35441470; doi:10.1111/dom.14725.
- 8 PubMed Jensen L, Helleberg H, Roffel A, et al. Absorption, metabolism and excretion of the GLP-1 analogue semaglutide in humans and nonclinical species. Eur J Pharm Sci 2017. PMID 28323117; doi:10.1016/j.ejps.2017.03.020.
- 9 FDA OZEMPIC, RYBELSUS prescribing information: Indications and Usage. FDA-approved labeling via openFDA/DailyMed, version effective 2026-01-30.
- 10 PubMed Yang XD, Yang YY. Clinical Pharmacokinetics of Semaglutide: A Systematic Review. Drug Des Devel Ther 2024. PMID 38952487; doi:10.2147/DDDT.S470826.
- 11 PubMed Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA 2021. PMID 33755728; doi:10.1001/jama.2021.3224.
- 12 FDA Drugs@FDA: OZEMPIC (NDA209637). NOVO; original approval 2017-12-05; Prescription, Discontinued.
- 13 FDA Drugs@FDA: RYBELSUS (NDA213182). NOVO NORDISK INC; original approval 2020-01-16; Prescription.
- 14 FDA Drugs@FDA: OZEMPIC, RYBELSUS (NDA213051). NOVO; original approval 2019-09-20; Prescription.
- 15 FDA Drugs@FDA: WEGOVY, WEGOVY HD, WEGOVY FLEXTOUCH (NDA215256). NOVO; original approval 2021-06-04; Prescription.
- 16 FDA Drugs@FDA: WEGOVY (NDA218316). NOVO; original approval 2025-12-22; Prescription.
- 17 FDA Drugs@FDA: SEMAGLUTIDE (ANDA220314). APOTEX INC; original approval 2026-04-07; None (Tentative Approval).
- 18 FDA FDA clarifies policies for compounders as national GLP-1 supply begins to stabilize. U.S. FDA, content current as of 04/01/2026.
- 19 ClinicalTrials.gov ClinicalTrials.gov registry search: semaglutide. 785 registered studies at fetch.