Semaglutide
Human RCTOzempic · Wegovy · Rybelsus · NN9535 · Semaglutide sodium
Highest available evidence among curated papers: Human RCT (as of 2026-06-04).
Chemical & identity
- Molecular formula
- C187H291N45O59
- Molecular weight
- 4114 g/mol · PubChem
- PubChem CID
- 56843331 · PubChem
- SMILES
- CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)NCC(=O)O)NC(=O)[C@H](CC3=CC=CC=C3)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CC[C@H](C(=O)O)NC(=O)CCCCCCCCCCCCCCCCC(=O)O)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)N)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC4=CC=C(C=C4)O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC5=CC=CC=C5)NC(=O)[C@H]([C@@H](C)O)NC(=O)CNC(=O)[C@H](CCC(=O)O)NC(=O)C(C)(C)NC(=O)[C@H](CC6=CN=CN6)N
- InChIKey
- DLSWIYLPEUIQAV-CCUURXOWSA-N
- ChEMBL ID
- CHEMBL2108724 · ChEMBL
- Category
- Metabolic/GLP-1
Chemical/structural fields are auto-pulled and source-linked. ChEMBL data: ChEMBL_36, CC BY-SA 3.0.
Mechanism (curated)
Glucagon-like peptide-1 (GLP-1) receptor agonist.
Pharmacology & handling
- Half-life
- Approximately 1 week (~165 hours), enabling once-weekly subcutaneous dosing; the oral formulation is dosed daily.
Research
Ambika Gopalakrishnan U et al. · Diabetes, obesity & metabolism · 2026 · RCT
A Phase III randomized controlled trial in 314 Indian adults with Type 2 diabetes compared synthetic semaglutide injection (test) with reference semaglutide (Ozempic) administered subcutaneously once weekly for 24 weeks. Both treatments produced significant HbA1c reductions at Week 24 (test: -2.04%, reference: -1.95%), with the test formulation meeting non-inferiority criteria (least-squares mean difference -0.09%, 95% CI: -0.26 to 0.09). Secondary endpoints including fasting blood glucose, post-prandial glucose, bodyweight, and HbA1c target achievement were similar between groups. The most common adverse events were mild-to-moderate gastrointestinal events (test 43.3% vs. reference 46.5%), and no anti-drug or neutralizing antibodies were detected.
Perkovic V et al. · The New England journal of medicine · 2024 · RCT
This randomized controlled trial (FLOW trial) in 3533 patients with type 2 diabetes and chronic kidney disease compared subcutaneous semaglutide 1.0 mg weekly to placebo over a median 3.4 years. Semaglutide reduced the risk of major kidney disease events (composite of kidney failure, ≥50% eGFR reduction, or kidney/cardiovascular death) by 24% versus placebo (hazard ratio 0.76; P=0.0003). Secondary outcomes also favored semaglutide, including slower annual eGFR decline, 18% lower risk of major cardiovascular events, and 20% lower risk of death from any cause. Serious adverse events were less frequent in the semaglutide group (49.6% vs 53.8%).
Lincoff AM et al. · The New England journal of medicine · 2023 · RCT
This multicenter, double-blind, randomized controlled trial (SELECT) enrolled 17,604 patients aged ≥45 years with preexisting cardiovascular disease and BMI ≥27 but no diabetes history. Participants were assigned to receive weekly subcutaneous semaglutide 2.4 mg or placebo. Over a mean follow-up of 39.8 months, the primary cardiovascular endpoint (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in 6.5% of the semaglutide group versus 8.0% of the placebo group (hazard ratio 0.80, 95% CI 0.72–0.90, P<0.001). Adverse events leading to permanent discontinuation occurred in 16.6% of the semaglutide group versus 8.2% of the placebo group.
Kosiborod MN et al. · The New England journal of medicine · 2023 · RCT
A randomized controlled trial of 529 patients with heart failure with preserved ejection fraction and obesity compared once-weekly semaglutide (2.4 mg) to placebo over 52 weeks. Semaglutide produced greater improvements in symptom burden (KCCQ-CSS: 16.6 vs 8.7 points), body weight reduction (-13.3% vs -2.6%), 6-minute walk distance (21.5 vs 1.2 m), and inflammatory markers (CRP: -43.5% vs -7.3%) compared to placebo. The hierarchical composite end point favored semaglutide (win ratio 1.72), and serious adverse events were less frequent in the semaglutide group (13.3% vs 26.7%).
Sanyal AJ et al. · The New England journal of medicine · 2025 · RCT
This Phase 3 randomized controlled trial (part 1, interim analysis at week 72) evaluated semaglutide, a GLP-1 receptor agonist, versus placebo in 800 patients with biopsy-defined MASH and fibrosis stage 2–3. Semaglutide 2.4 mg once weekly (n=534) produced resolution of steatohepatitis without fibrosis worsening in 62.9% versus 34.3% with placebo, and reduction in fibrosis without steatohepatitis worsening in 36.8% versus 22.4%. Combined resolution of steatohepatitis and fibrosis reduction occurred in 32.7% of semaglutide patients versus 16.1% of placebo patients. Mean body weight decreased 10.5% with semaglutide versus 2.0% with placebo. Gastrointestinal adverse events were more frequent in the semaglutide group.
Kosiborod MN et al. · The New England journal of medicine · 2024 · RCT
This randomized controlled trial assigned 616 patients with heart failure with preserved ejection fraction, obesity (BMI ≥30), and type 2 diabetes to receive once-weekly semaglutide 2.4 mg or placebo for 52 weeks. Semaglutide produced greater improvements in heart failure symptoms (KCCQ-CSS difference of 7.3 points), greater weight loss (-9.8% vs -3.4%), and better performance on secondary endpoints including 6-minute walk distance and C-reactive protein reduction compared to placebo. Serious adverse events were less frequent in the semaglutide group (17.7%) than the placebo group (28.8%).
Hamarsheh S et al. · Endocrinology, diabetes & metabolism · 2026 · Meta-analysis
This network meta-analysis of 25 randomized controlled trials compared tirzepatide, semaglutide, cagrilintide, and their combination (CagriSema) for weight loss in adults with overweight or obesity. Tirzepatide 15 mg achieved the greatest percent weight reduction (−17.97%), followed by CagriSema (−17.84%) and semaglutide 7.2 mg (−14.66%). At the ≥20% weight-loss threshold, CagriSema showed the highest rate (RR 27.82), followed by tirzepatide 15 mg (RR 23.70). Gastrointestinal adverse events increased across all treatments (RR 1.33–1.91), and semaglutide 7.2 mg had the highest treatment discontinuation rate (RR 3.09), while serious adverse events remained comparable to placebo.
Trott M et al. · BJPsych open · 2026 · Meta-analysis
This systematic review and meta-analysis examined randomized controlled trials of semaglutide (and tirzepatide) in people with schizophrenia spectrum disorders. Three trials (n=258) met inclusion criteria, testing semaglutide at doses of 1.0–2.0 mg over 26–36 weeks. Semaglutide significantly reduced body weight (−11.32 kg), BMI (−3.58 kg/m²), hemoglobin A1c (−0.37%), and fasting glucose (−0.54 mmol/L) compared to placebo. Adverse events included increased risks of abdominal pain, vomiting, and constipation, with no increased risk of serious adverse events. The authors conclude semaglutide shows promise as an adjunctive metabolic intervention in this population, though larger and longer trials are needed.
Chrzanowski J et al. · PLoS medicine · 2026 · Meta-analysis
A systematic review and meta-analysis of five observational studies examined the association between semaglutide use and nonarteritic anterior ischemic optic neuropathy (NAION) in patients with type 2 diabetes. Semaglutide use was associated with a significantly increased hazard of NAION compared with other glucose-lowering regimens (hazard ratio 2.17), though the absolute risk remained low at approximately 1 additional case per 7,000 treated patients annually. The authors note that evidence certainty is low due to reliance on retrospective, registry-based observational studies with potential for outcome misclassification and confounding. They recommend that clinicians be aware of this potential adverse event and that further high-quality studies are needed to clarify the association.
Marzano F et al. · Cardiovascular diabetology · 2026 · Meta-analysis
This meta-analysis of 8 randomized controlled trials involving 39,204 patients examined semaglutide, a GLP-1 receptor agonist, versus placebo across multiple clinical outcomes. Semaglutide treatment was associated with significant reductions in all-cause mortality (HR 0.84), cardiovascular mortality (HR 0.83), major adverse cardiovascular events (HR 0.82), nonfatal myocardial infarction (HR 0.75), worsening heart failure (HR 0.84), and kidney outcomes (HR 0.83) compared to placebo. No significant effect was observed for nonfatal stroke. The authors concluded that semaglutide is associated with lower incidence of all-cause and cardiovascular mortality and major cardiovascular and kidney events across the cardio-kidney-metabolic continuum.
Seighali N et al. · BMC pharmacology & toxicology · 2026 · Meta-analysis
This systematic review and meta-analysis of 13 randomized controlled trials involving 26,284 participants examined the effects of oral semaglutide compared with placebo on cardiometabolic risk factors in overweight and obese adults with or without diabetes. Compared with placebo, semaglutide significantly reduced body weight (−2.85 kg), BMI (−0.66 kg/m²), waist circumference (−1.79 cm), HbA1c (−0.94%), fasting plasma glucose (−26.91 mg/dL), systolic blood pressure (−2.71 mmHg), and diastolic blood pressure (−0.77 mmHg) over 6 months, with benefits consistent across different follow-up durations and doses. Gastrointestinal symptoms were the most common adverse events, with nausea and vomiting showing the highest relative risks. Semaglutide also showed a protective effect on cardiovascular events (OR = 0.64).
Cai CX et al. · Ophthalmology · 2026 · Cohort
This retrospective observational study across 12 OHDSI network databases (2017–2024) examined the association between semaglutide use and neovascular age-related macular degeneration (NVAMD) in 227,971 adults with type 2 diabetes. Using active-comparator cohort design with propensity score adjustment and self-controlled case-series analysis, the study found that semaglutide risk of NVAMD was similar to other GLP-1 receptor agonists (dulaglutide) and non-GLP-1RA agents (empagliflozin, sitagliptin, glipizide), with hazard ratios and incidence rate ratios showing no statistically significant differences. The authors concluded there was no evidence of increased or decreased risk for NVAMD associated with semaglutide exposure.
Wilding JPH et al. · The New England journal of medicine · 2021 · RCT
This double-blind randomized controlled trial enrolled 1,961 adults with overweight or obesity (BMI ≥30, or ≥27 with weight-related comorbidities) without diabetes and assigned them 2:1 to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg or placebo, both with lifestyle intervention. Semaglutide produced a mean body weight reduction of 14.9% compared to 2.4% with placebo (treatment difference −12.4 percentage points), with 86.4% of semaglutide recipients achieving ≥5% weight loss versus 31.5% on placebo. Participants receiving semaglutide showed greater improvements in cardiometabolic risk factors and physical functioning; nausea and diarrhea were the most common adverse events, typically transient and mild-to-moderate, though 4.5% of semaglutide recipients discontinued due to gastrointestinal events versus 0.8% on placebo.
Newsome PN et al. · The New England journal of medicine · 2021 · RCT
This phase 2, double-blind, placebo-controlled trial involved 320 patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and liver fibrosis (stage F1–F3) who received once-daily subcutaneous semaglutide at doses of 0.1, 0.2, or 0.4 mg or placebo for 72 weeks. NASH resolution with no worsening of fibrosis was achieved in 59% of patients receiving 0.4 mg semaglutide versus 17% in the placebo group (P<0.001), and mean weight loss was 13% in the 0.4-mg group versus 1% in placebo. Fibrosis stage improvement occurred in 43% of the 0.4-mg group versus 33% of placebo (P=0.48, not statistically significant). Common adverse events at the highest dose included nausea (42% vs. 11%), constipation (22% vs. 12%), and vomiting (15% vs. 2%); neoplasms (benign, malignant, or unspecified) were reported in 15% of semaglutide groups versus 8% in placebo.
Frías JP et al. · The New England journal of medicine · 2021 · RCT
This phase 3 randomized controlled trial compared tirzepatide, a dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist, with semaglutide (a selective GLP-1 agonist) in 1,879 patients with type 2 diabetes over 40 weeks. Tirzepatide at doses of 10 mg and 15 mg achieved greater reductions in glycated hemoglobin (−2.24 and −2.30 percentage points) compared with semaglutide (−1.86 percentage points), and tirzepatide produced larger weight reductions across all doses. The most common adverse events were gastrointestinal (primarily mild to moderate), with nausea in 17–22% of tirzepatide recipients and 18% of semaglutide recipients; serious adverse events occurred in 5–7% of tirzepatide recipients and 3% of semaglutide recipients.
Wilding JPH et al. · Diabetes, obesity & metabolism · 2022 · RCT
This randomized controlled trial extension (STEP 1) examined weight and cardiometabolic changes after semaglutide withdrawal in 327 adults without diabetes. Participants who received semaglutide 2.4 mg weekly for 68 weeks achieved 17.3% mean weight loss versus 2.0% with placebo. After discontinuing all treatment (semaglutide, placebo, and lifestyle intervention) for one year, semaglutide-treated participants regained approximately two-thirds of their prior weight loss (11.6 percentage points), resulting in a net 5.6% loss from baseline, while cardiometabolic improvements largely reverted toward baseline values. The findings suggest that ongoing treatment is required to maintain weight loss and health improvements achieved with semaglutide.
Rubino D et al. · JAMA · 2021 · RCT
STEP 4 is a randomized, double-blind, phase 3a withdrawal trial comparing continued weekly subcutaneous semaglutide 2.4 mg with placebo for weight maintenance in 803 adults with overweight or obesity, following a 20-week run-in period. Participants randomized to continued semaglutide experienced mean weight loss of 7.9% from weeks 20–68, whereas those switched to placebo gained 6.9%, a difference of 14.8 percentage points (P<0.001). Secondary outcomes—waist circumference, systolic blood pressure, and physical functioning—also improved significantly with continued semaglutide versus placebo. Gastrointestinal adverse events were more frequent with semaglutide (49.1%) than placebo (26.1%), but discontinuation rates due to adverse events were similar (2.4% vs 2.2%).
Davies M et al. · Lancet (London, England) · 2021 · RCT
This phase 3 randomized controlled trial in 1,210 adults with overweight or obesity and type 2 diabetes compared semaglutide 2.4 mg once weekly, semaglutide 1.0 mg once weekly, and placebo over 68 weeks. Semaglutide 2.4 mg achieved a mean bodyweight reduction of 9.6% compared to 3.4% with placebo (treatment difference −6.2 percentage points, p<0.0001), with 68.8% of patients on the 2.4 mg dose achieving at least 5% weight loss versus 28.5% on placebo. Adverse events were more frequent with semaglutide doses than placebo, with gastrointestinal adverse events (mostly mild to moderate) reported in 63.5% on semaglutide 2.4 mg and 34.3% on placebo.
Rubino DM et al. · JAMA · 2022 · RCT
The STEP 8 randomized controlled trial compared once-weekly semaglutide 2.4 mg with once-daily liraglutide 3.0 mg in 338 adults with overweight or obesity without diabetes over 68 weeks. Semaglutide produced significantly greater mean weight loss (-15.8% vs -6.4%, difference -9.4 percentage points) and higher proportions achieving ≥10%, ≥15%, and ≥20% weight loss thresholds compared to liraglutide. Treatment discontinuation rates were lower with semaglutide (13.5% vs 27.6%), and gastrointestinal adverse events occurred in approximately 84% of both groups. The study concluded that semaglutide resulted in significantly greater weight loss than liraglutide when combined with diet and physical activity counseling.
Wadden TA et al. · JAMA · 2021 · RCT
The STEP 3 trial was a 68-week randomized controlled trial in 611 adults with overweight or obesity (without diabetes) comparing once-weekly subcutaneous semaglutide 2.4 mg versus placebo, both combined with intensive behavioral therapy and an initial low-calorie diet. At week 68, semaglutide produced a mean body weight reduction of 16.0% compared to 5.7% for placebo (difference -10.3 percentage points). Significantly higher proportions of semaglutide-treated participants achieved weight losses of ≥5%, ≥10%, and ≥15% of baseline weight compared to placebo. Gastrointestinal adverse events occurred more frequently with semaglutide (82.8%) than placebo (63.2%), and 3.4% of semaglutide participants discontinued treatment due to these events.
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Regulatory status
- FDA approved
- Yes
- WADA prohibited
- No
- Compounding status
- FDA-approved (Ozempic/Rybelsus for type 2 diabetes; Wegovy for chronic weight management).
- Notes
- FDA-approved semaglutide (Ozempic/Rybelsus for type 2 diabetes; Wegovy for chronic weight management) as of 2026-06-04. Not listed on the WADA prohibited list.
Legal/regulatory status varies by jurisdiction and changes over time — accurate as of last review (2026-06-04).
Data sources: Curated IDs (PubChem/UniProt/ChEMBL) + Europe PMC + ClinicalTrials.gov (2026-06-04).
Last reviewed 2026-06-04