Peptide fact-sheet · English

Semaglutide

GLP-1 receptor agonist

Once-weekly GLP-1 receptor agonist with phase 3 evidence in type 2 diabetes, obesity, and cardiovascular outcomes.

Translated and adapted from the canonical Portuguese version: /peptideos/semaglutida.

Quick answer

Semaglutide is a once-weekly GLP-1 receptor agonist with three regulatory indications: type 2 diabetes (Ozempic, FDA 2017; Rybelsus oral, FDA 2019), chronic weight management (Wegovy, FDA 2021), and cardiovascular risk reduction in adults with obesity and established cardiovascular disease without diabetes (SELECT label, FDA 2024). The pivotal weight-management trial STEP 1 (Wilding 2021, NEJM, PMID 33567185, n=1,961, 68 weeks) reported a mean weight loss of -14.9% versus -2.4% with placebo. SUSTAIN-6 (Marso 2016, NEJM, PMID 27633186, n=3,297) was the cardiovascular outcomes trial in type 2 diabetes (MACE HR 0.74). SELECT (Lincoff 2023, NEJM, PMID 37952131, n=17,604) extended the cardiovascular benefit to non-diabetic adults with obesity (MACE HR 0.80). Subcutaneous half-life is approximately 7 days, achieved by acylation with a C18 fatty diacid that prolongs albumin binding. The oral formulation (Rybelsus) co-formulates semaglutide with SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate) to enable gastric absorption. Gastrointestinal events (nausea, vomiting, diarrhea, constipation) are the most common adverse events and the leading cause of discontinuation across the program.

What it is

Semaglutide is a synthetic 31-amino-acid analog of human glucagon-like peptide-1 (GLP-1), engineered by Novo Nordisk for resistance to dipeptidyl peptidase-4 (DPP-4) degradation and for prolonged albumin binding. Two substitutions (Aib at position 8, Arg at position 34) and a C18 fatty diacid side chain at lysine 26 extend the plasma half-life from minutes (native GLP-1) to approximately 7 days, enabling once-weekly subcutaneous dosing.

Three registered products exist internationally:

Ozempic — subcutaneous, 0.25/0.5/1.0/2.0 mg weekly for type 2 diabetes. FDA approval 2017, EMA 2018.
Rybelsus — oral 3/7/14 mg tablets for type 2 diabetes, co-formulated with the absorption enhancer SNAC. FDA approval 2019. First oral GLP-1 receptor agonist.
Wegovy — subcutaneous, escalated to 2.4 mg weekly for chronic weight management (BMI ≥30, or ≥27 with at least one weight-related comorbidity). FDA approval 2021, EMA 2022. Label extended in 2024 to include cardiovascular risk reduction in adults with established cardiovascular disease and obesity without diabetes, based on the SELECT trial.

Mechanism of action

Semaglutide is a selective agonist at the GLP-1 receptor (GLP-1R), a class B G-protein-coupled receptor expressed on pancreatic beta cells, gastric smooth muscle, hypothalamic neurons (notably in the arcuate and paraventricular nuclei), and several peripheral tissues.

The pharmacologic effects relevant to clinical outcomes are:

Glucose-dependent insulin secretion from pancreatic beta cells — insulin release rises in proportion to ambient glucose, limiting the hypoglycemia risk seen with sulfonylureas or insulin in monotherapy.
Glucagon suppression in the postprandial state, reducing hepatic glucose output.
Delayed gastric emptying, which blunts the post-meal glucose excursion and contributes to satiety.
Central appetite regulation through hypothalamic and brainstem GLP-1R signaling, reducing energy intake. This is the dominant mechanism for the weight loss observed in STEP and SELECT.

The acylation strategy — covalent attachment of a C18 fatty diacid — is the structural basis for the long half-life and is shared (with variations) by liraglutide and tirzepatide.

What the trials show

STEP 1 — obesity without diabetes (Wilding 2021, NEJM, PMID 33567185, NCT03548935). Randomized double-blind placebo-controlled trial, 68 weeks, n=1,961 across 16 countries. Adults with BMI ≥30 or ≥27 with at least one weight-related comorbidity, without diabetes. Semaglutide 2.4 mg weekly subcutaneous produced a mean weight change of -14.9% versus -2.4% with placebo. 86.4% of semaglutide participants achieved ≥5% weight loss vs 31.5% with placebo. The trial established weekly semaglutide as the reference standard for pharmacologic weight management at the time of publication.

SUSTAIN-6 — cardiovascular outcomes in type 2 diabetes (Marso 2016, NEJM, PMID 27633186, NCT01720446). Randomized placebo-controlled trial, n=3,297 with type 2 diabetes and elevated cardiovascular risk, 104 weeks. First MACE occurred in 6.6% of semaglutide-treated participants vs 8.9% with placebo (HR 0.74, 95% CI 0.58-0.95). The driver was a significant reduction in non-fatal stroke. Pre-specified as a non-inferiority trial; nominal superiority observed.

SELECT — cardiovascular outcomes in obesity without diabetes (Lincoff 2023, NEJM, PMID 37952131, NCT03574597). Randomized placebo-controlled trial, n=17,604 with overweight or obesity (BMI ≥27) and established cardiovascular disease without type 2 diabetes. Mean follow-up ~40 months. Primary composite MACE 6.5% (semaglutide 2.4 mg) vs 8.0% (placebo), HR 0.80, 95% CI 0.72-0.90, p<0.001. The first RCT to demonstrate cardiovascular benefit from a GLP-1 receptor agonist in obesity without diabetes — the basis for the 2024 FDA label extension for Wegovy.

The SURMOUNT-5 head-to-head trial (Aronne 2025, NEJM, PMID 40353578, n=751, 72 weeks) compared maximum tolerated doses and reported tirzepatide -20.2% vs semaglutide -13.7% in obesity without diabetes, with gastrointestinal-related discontinuation 2.7% vs 5.6%. SURMOUNT-5 defines the current direct hierarchy between the two molecules for weight management without diabetes.

Pharmacokinetics

Subcutaneous half-life: approximately 7 days (~160 hours), enabling steady-state with weekly dosing in 4-5 weeks.
Oral (Rybelsus) half-life: ~24 hours; daily dosing required because of low and variable bioavailability (~1%) despite SNAC co-formulation. Tablet must be taken on an empty stomach with up to 120 mL of water, followed by a 30-minute fast.
Elimination: proteolytic degradation followed by renal and fecal excretion of fragments.
Dosing schedule (subcutaneous, obesity): escalation 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg weekly over 16 weeks, designed to mitigate gastrointestinal events.

Safety and adverse events

The most frequent adverse events across the STEP, SUSTAIN, and SELECT programs are gastrointestinal: nausea (43.9% on semaglutide 2.4 mg vs 16.1% placebo in STEP 1), diarrhea (~30%), vomiting (24%), constipation (24%), and abdominal pain. Most events are mild to moderate, occur during dose escalation, and resolve with continued treatment or with slower titration.

Boxed warning (FDA label, all semaglutide products): risk of thyroid C-cell tumors, based on rodent carcinogenicity studies. The class effect has not been characterized in human pharmacovigilance, but personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN-2) is a contraindication.

Other labeled risks include acute pancreatitis (uncommon but reported across the class), acute gallbladder disease (cholelithiasis observed at higher rates in weight-management trials), acute kidney injury (typically in the context of severe vomiting and dehydration), diabetic retinopathy complications (signal in SUSTAIN-6 among participants with pre-existing retinopathy and rapid HbA1c reduction), and hypoglycemia when combined with insulin or sulfonylureas.

Regulatory status (international)

FDA: Ozempic (T2D, 2017), Rybelsus (oral T2D, 2019), Wegovy (chronic weight management, 2021; cardiovascular risk reduction in obesity without diabetes added 2024).
EMA: Ozempic (2018), Rybelsus (2020), Wegovy (2022). Cardiovascular indication mirrored after SELECT publication.
INN (WHO): semaglutide (assigned and indexed).
WADA: not currently listed as a prohibited substance in the 2026 Prohibited List. Athletes should verify with their national anti-doping organization, as listings evolve.

What we still don't know

Long-term durability of weight loss beyond 4 years and outcomes following discontinuation. Observational extensions of STEP suggest substantial regain within 1 year of stopping treatment.
Mortality benefit in obesity without cardiovascular disease (SELECT enrolled established CVD).
Comparative effectiveness against tirzepatide and retatrutide in subgroups defined by baseline metabolic phenotype.
Long-term effects on lean mass, bone density, and physical function during sustained weight loss.
Cost-effectiveness frameworks suitable for low- and middle-income health systems.

Why it matters

Semaglutide reframed pharmacologic weight management when STEP 1 reported weight loss approaching that previously seen only after bariatric surgery in many participants. The SELECT extension into cardiovascular risk reduction in obesity without diabetes — the first such demonstration for a GLP-1 receptor agonist — broadened the clinical rationale beyond glycemic and weight endpoints. The molecule remains, in 2026, the most extensively studied GLP-1 receptor agonist by number of randomized participants across indications, though the SURMOUNT-5 head-to-head with tirzepatide and the phase 3 TRIUMPH program for retatrutide are reshaping the comparative landscape.