Semaglutide
NN9535, NNC0113-0217, GLP-1 receptor agonist (acylated), Wegovy, Ozempic, Rybelsus
Semaglutide is a chemically modified copy of the human gut hormone GLP-1, engineered to survive in the bloodstream for about a week instead of a few minutes. It lowers blood glucose and substantially reduces appetite and body weight. It is one of the very few peptides in this library with a large, replicated, regulator-scrutinised human evidence base.
Mechanism
Semaglutide is an analogue of glucagon-like peptide-1 (GLP-1), an incretin hormone released from intestinal L-cells after eating. It binds the GLP-1 receptor, a class B G-protein-coupled receptor, and signals principally through Gs-coupled adenylate cyclase, raising intracellular cAMP and activating protein kinase A and Epac2. In pancreatic beta cells this potentiates glucose-stimulated insulin secretion in a glucose-dependent manner, which is why GLP-1 agonists carry little intrinsic hypoglycaemia risk when used alone. It also suppresses glucagon release from alpha cells and slows gastric emptying.
The weight effect is largely central rather than gastrointestinal. GLP-1 receptors in the hypothalamic arcuate nucleus, the area postrema and the nucleus tractus solitarius mediate reduced energy intake, and semaglutide reaches these circumventricular and hypothalamic regions. Three structural modifications give it its duration of action: substitution of alanine 8 with alpha-aminoisobutyric acid, which blocks cleavage by dipeptidyl peptidase-4; substitution of lysine 34 with arginine, which directs acylation to a single site; and attachment of a C18 diacid fatty acid chain via a gamma-glutamyl and bis-AEEA spacer to lysine 26. That fatty acid drives strong, reversible binding to serum albumin, which both shields the peptide from renal clearance and creates a slow-release depot. The net result is a half-life of roughly a week, against about two minutes for native GLP-1.
What the research shows
The human evidence is unusually deep for a peptide. In SUSTAIN-6, 3,297 people with type 2 diabetes at high cardiovascular risk were randomised to semaglutide or placebo; major adverse cardiovascular events occurred in 6.6% versus 8.9%. That trial was designed and powered for non-inferiority, so the superiority result, driven mainly by non-fatal stroke, is best read as hypothesis-generating rather than as a definitive efficacy demonstration. In STEP 1, 1,961 adults with obesity and without diabetes lost a mean 14.9% of body weight on 2.4 mg weekly over 68 weeks against 2.4% on placebo. SELECT then tested the harder question of whether that weight loss translates into outcomes: in 17,604 people with established cardiovascular disease and overweight or obesity but without diabetes, cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% on semaglutide versus 8.0% on placebo over roughly 40 months. SELECT, unlike SUSTAIN-6, was a properly powered superiority test against placebo.
Benefit has since been shown in two further organ systems. FLOW randomised 3,533 people with type 2 diabetes and chronic kidney disease and found a 24% reduction in the composite of kidney disease progression and kidney or cardiovascular death. The ESSENCE phase 3 trial in metabolic dysfunction-associated steatohepatitis reported, in a planned interim analysis of the first 800 of 1,197 randomised participants, resolution of steatohepatitis without worsening fibrosis in 62.9% versus 34.3% on placebo, supporting an FDA accelerated approval in August 2025; the outcome phase of that trial does not report until 2029, so the histological benefit has not yet been shown to translate into fewer liver events. An oral 50 mg formulation produced 15.1% weight loss at 68 weeks in OASIS 1. The main honest caveats are that weight regain after discontinuation is substantial and well documented, that a meaningful fraction of the weight lost is lean mass, and that the long-term consequences of decades of use are simply not yet known.
Evidence assessment
High-quality evidence
Multiple large, replicated, placebo-controlled randomised outcome trials with hard endpoints across diabetes, obesity, cardiovascular disease, kidney disease and liver disease, all independently verified against PubMed and ClinicalTrials.gov, supported by approved regulatory labelling in the US, UK and EU.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes High-quality evidence
Major adverse cardiovascular events occurred in 6.6% on semaglutide versus 8.9% on placebo, meeting the prespecified non-inferiority margin, with a nominal superiority result driven largely by a reduction in non-fatal stroke.
Once-Weekly Semaglutide in Adults with Overweight or Obesity High-quality evidence
Mean body weight change was -14.9% with semaglutide 2.4 mg weekly versus -2.4% with placebo, with 86.4% versus 31.5% achieving at least 5% weight reduction.
Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes High-quality evidence
The composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% on semaglutide versus 8.0% on placebo (hazard ratio 0.80).
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes High-quality evidence
Semaglutide reduced the risk of the primary composite kidney outcome by 24% relative to placebo in people with type 2 diabetes and chronic kidney disease.
Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis High-quality evidence
Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% on semaglutide versus 34.3% on placebo, with fibrosis improvement without worsening steatohepatitis in 36.8% versus 22.4%.
Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial High-quality evidence
Oral semaglutide 50 mg daily produced a mean body weight change of -15.1% versus -2.4% with placebo.
Safety
Gastrointestinal adverse effects dominate: nausea, vomiting, diarrhoea, constipation and abdominal pain, usually dose-related, mostly mild to moderate, and generally worst during dose escalation. In SELECT, 16.6% of semaglutide recipients discontinued for adverse events against 8.2% on placebo, which is a real tolerability signal and not a trivial one. Recognised risks in approved labelling include acute pancreatitis, gallbladder disease including cholelithiasis (partly a consequence of rapid weight loss itself), acute kidney injury secondary to dehydration from vomiting, and diabetic retinopathy complications in people with pre-existing retinopathy and rapidly improving glycaemia, a signal first seen in SUSTAIN-6. Rodent carcinogenicity studies showed thyroid C-cell tumours, leading to a contraindication in people with a personal or family history of medullary thyroid carcinoma or MEN2; whether this translates to humans remains unresolved. Postmarketing attention has focused on gastroparesis, aspiration risk under general anaesthesia, and a debated and so far unconfirmed association with non-arteritic anterior ischaemic optic neuropathy. Loss of lean mass and bone density during rapid weight reduction is an active area of concern. Compounded and grey-market semaglutide is a distinct hazard: it bypasses the manufacturing controls that the trial evidence was generated under, and dosing errors with such products have caused documented harm.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Licensed by the MHRA for type 2 diabetes and, at the 2.4 mg weekly dose, for weight management alongside diet and physical activity. Prescription-only. NICE has issued technology appraisal guidance restricting NHS-funded use for weight management to defined BMI and comorbidity criteria, generally within specialist weight management services. Supply has been intermittently constrained. |
| United States | FDA approved. Injectable semaglutide was approved for type 2 diabetes in 2017, oral semaglutide in 2019, and 2.4 mg weekly for chronic weight management in 2021. Later approvals added cardiovascular risk reduction in people with obesity and established cardiovascular disease (2024), chronic kidney disease in type 2 diabetes (2025) and, by accelerated approval, metabolic dysfunction-associated steatohepatitis with moderate to advanced fibrosis (August 2025). A prescription-only medicine. |
| WADA (sport) | Not prohibited. GLP-1 receptor agonists do not appear on the WADA Prohibited List in or out of competition, though this reflects an absence of listing rather than an affirmative finding that they lack performance relevance, and the position is periodically reviewed. |
Questions
Semaglutide activates one receptor, the GLP-1 receptor. Tirzepatide activates two, GLP-1 and GIP. Two head-to-head randomised trials exist: SURPASS-2 in type 2 diabetes, where tirzepatide produced greater reductions in HbA1c and body weight than semaglutide 1 mg weekly, and SURMOUNT-5 in obesity, where tirzepatide produced greater weight loss than semaglutide 2.4 mg weekly. There is no head-to-head cardiovascular outcome trial between them. Semaglutide retains the broader set of placebo-controlled hard-endpoint benefits across heart, kidney and liver disease.
Yes, in most people. The STEP 1 extension found participants regained roughly two-thirds of the weight lost within a year of stopping, and cardiometabolic improvements reverted alongside it. This is consistent with the drug suppressing appetite while it is present rather than resetting a long-term set point. Obesity behaves like a chronic relapsing condition in these trials, which is why the licensed indications are framed around long-term use.
No. The trial evidence above was generated with a specific, tightly manufactured product at controlled concentrations. Compounded, grey-market and 'research use only' semaglutide is not held to those standards, and analyses of such products have found incorrect content, salt forms that are not the studied compound, and impurities. Dosing errors with concentrated multi-dose vials have caused documented overdoses. The phrase 'for research use only' on a vial sold to a consumer is a legal shield, not a quality claim.
SELECT, a 17,604-person randomised placebo-controlled trial in people with cardiovascular disease and obesity but no diabetes, found a 20% relative reduction in cardiovascular death, non-fatal myocardial infarction or non-fatal stroke over about 40 months. SUSTAIN-6 pointed the same way in type 2 diabetes, though it was powered for non-inferiority rather than superiority. These are hard clinical endpoints in large randomised trials, which is a far stronger form of evidence than the surrogate markers most peptides in this library rely on.