Semaglutide
Semaglutide is an acylated analogue of the 31-residue human incretin hormone GLP-1(7-37). It carries two substitutions relative to the native peptide, α-aminoisobutyric acid at position 8 and arginine at position 34, and is derivatised at lysine 26 with a C18 diacid attached through a γ-glutamate and short polyethylene-glycol linker; the Aib8 substitution blocks dipeptidyl peptidase-4 cleavage while the fatty diacid confers reversible serum-albumin binding, extending the plasma half-life from minutes to roughly seven days at the 0.5–1.0 mg doses studied. It is a prescription medicine, approved by the US Food and Drug Administration for type 2 diabetes and subsequently for chronic weight management, and has been evaluated in large phase 3 programmes in diabetes, obesity, cardiovascular disease, chronic kidney disease, steatohepatitis and Alzheimer's disease. An orally absorbed tablet formulation using a permeation enhancer was developed alongside the injectable form and carried through its own cardiovascular outcomes trial.
Information on this page is provided for laboratory research reference. The compound is not a drug, supplement, or medical product, and is not for human or veterinary use, ingestion, or consumption.
No reviewed report has been published for this product family yet. The molecular values opposite are public reference data, not results measured on a CRX sample.
Browse published reports →- Aib
- α-Aminoisobutyric acid — Backbone-rigidifying methylated alanine; resists DPP-4 cleavage.
Semaglutide is an agonist at the GLP-1 receptor, a class B G-protein-coupled receptor that signals principally through Gs and cAMP. Its receptor affinity, 0.38 ± 0.06 nM, is threefold lower than that of liraglutide; the molecule trades receptor potency for much stronger albumin binding and full resistance to metabolic degradation, which is what makes weekly exposure possible. The established pharmacology is incretin pharmacology: glucose-dependent potentiation of insulin secretion, suppression of glucagon, and a central reduction in appetite and energy intake. Whole-brain imaging of fluorescently labelled semaglutide and c-Fos mapping in mice show that semaglutide does not cross the blood-brain barrier but reaches the brain through circumventricular organs and sites adjacent to the ventricles, engaging hindbrain, septal and hypothalamic GLP-1 receptor populations and secondarily activating regions such as the lateral parabrachial nucleus that it never touches directly. Whether the cardiovascular, renal and hepatic outcomes seen in the large trials follow entirely from weight and glycaemic change, or partly from direct receptor engagement in those tissues, remains proposed rather than settled.1,2,5,6
Primary and, as far as is known, sole molecular target. A Gs-coupled class B GPCR whose activation raises cAMP in pancreatic beta cells, driving glucose-dependent insulin release and suppressing glucagon. Semaglutide binds it at 0.38 nM affinity.1,5
Site of the appetite effect. In mice semaglutide reaches the brainstem, septal nucleus and hypothalamus via circumventricular organs without crossing the blood-brain barrier, and induces c-Fos activity in ten brain areas including regions with no direct drug access.6
Metabolic & weight
In a 68-week double-blind trial in 1961 adults with obesity or overweight without diabetes (STEP 1), mean body weight changed by −14.9% in the semaglutide 2.4 mg group versus −2.4% with placebo (−15.3 kg versus −2.6 kg), and 50.5% versus 4.9% of participants lost at least 15% of baseline weight.7
In an event-driven trial in 17,604 adults aged 45 or older with established cardiovascular disease and BMI 27 or greater but no diabetes (SELECT), the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% of the semaglutide 2.4 mg group versus 8.0% on placebo over a mean 39.8 months (hazard ratio 0.80, 95% CI 0.72–0.90).8
In the week-72 interim analysis of a phase 3 trial in 800 patients with biopsy-defined metabolic dysfunction-associated steatohepatitis and fibrosis stage 2 or 3 (ESSENCE), resolution of steatohepatitis without worsening fibrosis occurred in 62.9% of the semaglutide 2.4 mg group versus 34.3% on placebo, and fibrosis improved without worsening steatohepatitis in 36.8% versus 22.4%.9
In a randomised trial in 3533 patients with type 2 diabetes and chronic kidney disease (FLOW), major kidney disease events occurred in 331 patients assigned to semaglutide 1.0 mg versus 410 on placebo over a median 3.4 years (hazard ratio 0.76, 95% CI 0.66–0.88), and death from any cause was 20% lower (hazard ratio 0.80, 95% CI 0.67–0.95); the trial stopped early at a prespecified interim analysis.10
In 3297 patients with type 2 diabetes at high cardiovascular risk followed for 104 weeks (SUSTAIN-6), the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.6% of semaglutide-treated patients versus 8.9% on placebo (hazard ratio 0.74, 95% CI 0.58–0.95), with non-fatal stroke at 1.6% versus 2.7%.11
In 529 patients with heart failure with preserved ejection fraction and obesity treated for 52 weeks (STEP-HFpEF), the Kansas City Cardiomyopathy Questionnaire clinical summary score rose 16.6 points in the semaglutide 2.4 mg group versus 8.7 points on placebo, six-minute walk distance changed 21.5 m versus 1.2 m, and C-reactive protein fell a mean 43.5% versus 7.3%.12
In a 72-week open-label head-to-head trial in 751 adults with obesity but without type 2 diabetes (SURMOUNT-5), weight changed by −13.7% (95% CI −14.9 to −12.6) in the semaglutide arm titrated to its maximum tolerated dose versus −20.2% (95% CI −21.4 to −19.1) with tirzepatide, and waist circumference by −13.0 cm versus −18.4 cm.13
In a 68-week phase 3 trial in 407 adults with obesity and moderate knee osteoarthritis with at least moderate pain (STEP 9), the WOMAC pain score fell 41.7 points in the semaglutide 2.4 mg group versus 27.5 points on placebo, with body weight changing −13.7% versus −3.2% and SF-36 physical function improving 12.0 versus 6.5 points.14
In a 20-week double-blind parallel-group trial in 72 adults with obesity, ad libitum energy intake at a test lunch was 35% lower in the semaglutide 2.4 mg group than on placebo (1736 versus 2676 kJ), and the investigators found no evidence of delayed gastric emptying at week 20: the 5-hour paracetamol AUC was 8% above placebo (P = 0.005) but not after correction for body weight (P = 0.12).15
Cognition & neuroprotection
In two phase 3 trials in 3808 adults with amyloid-confirmed early symptomatic Alzheimer's disease (evoke and evoke+), oral semaglutide 14 mg did not slow progression: the change in Clinical Dementia Rating-Sum of Boxes at week 104 was 2.3 versus 2.3 with placebo in evoke (difference −0.08, 95% CI −0.35 to 0.20) and 2.2 versus 2.1 in evoke+ (0.10, 95% CI −0.17 to 0.38). Both were discontinued for negative clinical outcome.16
In a 9-week phase 2 trial in 48 non-treatment-seeking adults with alcohol use disorder, low-dose semaglutide reduced alcohol consumed in a post-treatment laboratory self-administration task relative to placebo (β −0.48, 95% CI −0.85 to −0.11 for grams) and reduced drinks per drinking day (β −0.41, 95% CI −0.73 to −0.09), with no effect on drinks per calendar day or number of drinking days.17
In 3xTg mice, a transgenic model of Alzheimer's disease, 30 days of alternate-day semaglutide improved learning and memory across a behavioural battery — the report does not break out which individual tests reached significance — and reduced hippocampal amyloid-β plaque and neurofibrillary tangle burden, with raised SIRT1 and GLUT4 expression; in cultured HT22 mouse hippocampal neurons the SIRT1 inhibitor EX527 abolished the effects on glycolysis and GLUT4 translocation.18
What investigators recorded alongside the results above, at the rates their papers state.
Gastrointestinal events — nausea, diarrhoea, vomiting and constipation — typically transient and mild to moderate, concentrated during dose escalation7,19
Risk ratio 1.49 (95% CI 1.38–1.60) versus placebo pooled across six randomised trials in 3962 adults with overweight or obesity; in STEP 1, 4.5% of the semaglutide group versus 0.8% of the placebo group discontinued treatment because of gastrointestinal events
Permanent discontinuation of trial product for adverse events8
16.6% (1461/8803) with semaglutide 2.4 mg versus 8.2% (718/8801) with placebo over a mean 34.2 months of exposure (P<0.001)
Diabetic retinopathy complications — vitreous haemorrhage, blindness, or conditions requiring intravitreal treatment or photocoagulation11
Significantly higher with semaglutide than placebo over 104 weeks: hazard ratio 1.76 (95% CI 1.11–2.78, P=0.02)
Gallbladder and biliary disease, including cholelithiasis and cholecystitis (class-level signal for GLP-1 receptor agonists, not semaglutide alone)20
Relative risk 1.37 (95% CI 1.23–1.52) across 76 randomised trials in 103,371 patients; the signal was larger in the 13 weight-loss trials (RR 2.29, 95% CI 1.64–3.18) than in the 63 diabetes and other trials (RR 1.27, 95% CI 1.14–1.43), and larger at higher doses (RR 1.56) than lower (RR 0.99)
Pancreatitis, bowel obstruction and gastroparesis (pooled across semaglutide and liraglutide users)21
In a cohort of 5411 US patients dispensed a weight-loss drug (613 semaglutide, 4144 liraglutide, 654 bupropion-naltrexone), GLP-1 agonist use versus bupropion-naltrexone carried adjusted hazard ratios of 9.09 (95% CI 1.25–66.00) for pancreatitis, 4.22 (95% CI 1.02–17.40) for bowel obstruction and 3.67 (95% CI 1.15–11.90) for gastroparesis; biliary disease was not significantly raised (1.50, 95% CI 0.89–2.53). Absolute rates were low, and the confidence intervals are very wide
Non-arteritic anterior ischaemic optic neuropathy (NAION)22
In a propensity-matched single-centre neuro-ophthalmology registry, 36-month cumulative incidence was 8.9% versus 1.8% among patients with type 2 diabetes (hazard ratio 4.28, 95% CI 1.62–11.29) and 6.7% versus 0.8% among patients who were overweight or obese (hazard ratio 7.64, 95% CI 2.21–26.36). The absolute event counts were small (17 and 20 events) and the cohort was drawn from patients already referred to neuro-ophthalmology, so the design cannot establish causality
Cancer, including thyroid and pancreatic — no excess detected, but the analysis is underpowered for rare events23
Versus placebo, odds ratios were 2.04 (95% CI 0.33–12.61) for thyroid cancer, 0.25 (95% CI 0.03–2.24) for pancreatic cancer and 0.95 (95% CI 0.62–1.45) for all neoplasms, pooled across 37 randomised trials and 19 real-world studies covering 16,839 placebo-controlled and 13,330 real-world patients
Overall treatment-emergent adverse events in an older neurological population16
91.2% (1729/1896) of participants receiving oral semaglutide versus 84.8% (1613/1902) receiving placebo across evoke and evoke+; five deaths were judged treatment-related by investigators, one in the semaglutide group and four in the placebo group
- 1.Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. · J Med Chem · 2015 · PMID 26308095
- 2.Pharmacokinetics and Clinical Implications of Semaglutide: A New Glucagon-Like Peptide (GLP)-1 Receptor Agonist. · Clin Pharmacokinet · 2018 · PMID 29915923
- 3.Wegovy (semaglutide): a new weight loss drug for chronic weight management. · J Investig Med · 2022 · PMID 34706925
- 4.Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. · N Engl J Med · 2019 · PMID 31185157
- 5.Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. · Cell Metab · 2018 · PMID 29617641
- 6.Semaglutide lowers body weight in rodents via distributed neural pathways. · JCI Insight · 2020 · PMID 32213703
- 7.Once-Weekly Semaglutide in Adults with Overweight or Obesity. · N Engl J Med · 2021 · PMID 33567185
- 8.Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. · N Engl J Med · 2023 · PMID 37952131
- 9.Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. · N Engl J Med · 2025 · PMID 40305708
- 10.Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. · N Engl J Med · 2024 · PMID 38785209
- 11.Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. · N Engl J Med · 2016 · PMID 27633186
- 12.Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. · N Engl J Med · 2023 · PMID 37622681
- 13.Tirzepatide as Compared with Semaglutide for the Treatment of Obesity. · N Engl J Med · 2025 · PMID 40353578
- 14.Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis. · N Engl J Med · 2024 · PMID 39476339
- 15.The effect of semaglutide 2.4 mg once weekly on energy intake, appetite, control of eating, and gastric emptying in adults with obesity. · Diabetes Obes Metab · 2021 · PMID 33269530
- 16.Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials. · Lancet · 2026 · PMID 41865758
- 17.Once-Weekly Semaglutide in Adults With Alcohol Use Disorder: A Randomized Clinical Trial. · JAMA Psychiatry · 2025 · PMID 39937469
- 18.Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer's disease via the GLP-1R/SIRT1/GLUT4 pathway. · Neuropharmacology · 2023 · PMID 37730113
- 19.Efficacy and safety of semaglutide 2.4 mg for weight loss in overweight or obese adults without diabetes: An updated systematic review and meta-analysis including the 2-year STEP 5 trial. · Diabetes Obes Metab · 2024 · PMID 38016699
- 20.Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. · JAMA Intern Med · 2022 · PMID 35344001
- 21.Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. · JAMA · 2023 · PMID 37796527
- 22.Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. · JAMA Ophthalmol · 2024 · PMID 38958939
- 23.Semaglutide and cancer: A systematic review and meta-analysis. · Diabetes Metab Syndr · 2023 · PMID 37531876
- 24.Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. · N Engl J Med · 2025 · PMID 40544433