Semaglutide
Semaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. It is FDA-approved for type 2 diabetes (Ozempic, Rybelsus) and chronic weight management (Wegovy).
Overview
Semaglutide is a synthetic analogue of human glucagon-like peptide-1, an incretin hormone released from the gut after eating. Developed by Novo Nordisk, it was engineered with amino acid substitutions and a fatty acid side chain so that it binds albumin in the blood and resists enzymatic breakdown. These changes give it a much longer duration of action than native GLP-1, supporting once-weekly injectable dosing and, in a separate formulation, oral administration.
Semaglutide is FDA-approved as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for chronic weight management. Its clinical program is among the largest for any peptide drug, including the SUSTAIN trials in type 2 diabetes, the STEP trials in obesity and the SELECT cardiovascular outcomes trial. It is a reference compound for incretin pharmacology and peptide half-life extension.
Compare: Semaglutide vs Tirzepatide vs Retatrutide, Semaglutide vs liraglutide.
Structure
Semaglutide is based on human GLP-1(7-37), a 31-residue peptide. Alanine at position 8 is replaced with α-aminoisobutyric acid (Aib) to block cleavage by dipeptidyl peptidase-4, and lysine at position 34 is replaced with arginine. The lysine at position 26 carries a side chain made of a hydrophilic linker, a γ-glutamic acid spacer and a C18 fatty diacid, which promotes reversible albumin binding. The oral product combines the peptide with the absorption enhancer SNAC (sodium N-[8-(2-hydroxybenzoyl)amino]caprylate).
Mechanism
Semaglutide is an agonist of the GLP-1 receptor, a class B G protein-coupled receptor expressed on pancreatic beta cells, in the brain and in other tissues. In the pancreas, receptor activation enhances glucose-dependent insulin secretion and suppresses glucagon release, lowering blood glucose with limited intrinsic risk of hypoglycemia. It also slows gastric emptying.
Effects on body weight are attributed mainly to actions on appetite-regulating regions of the brain, including the hypothalamus and brainstem, which reduce hunger and food intake. Reversible albumin binding and resistance to dipeptidyl peptidase-4 extend its half-life to about a week. The mechanisms behind cardiovascular and kidney outcome effects are under study and likely involve multiple pathways.
Research
Type 2 diabetes: SUSTAIN and PIONEER
The SUSTAIN program evaluated once-weekly injectable semaglutide in type 2 diabetes, comparing it with placebo and active comparators, and showed improvements in glycemic control measured by HbA1c, along with weight reduction. The PIONEER program evaluated oral semaglutide. These trials supported the approvals of Ozempic and Rybelsus. SUSTAIN-6 also assessed cardiovascular safety in people with type 2 diabetes at high cardiovascular risk.
Obesity: the STEP trials
The STEP phase 3 program evaluated once-weekly semaglutide 2.4 mg in adults with overweight or obesity, with and without type 2 diabetes. In STEP 1, published in 2021, semaglutide produced substantially greater weight loss than placebo when combined with lifestyle intervention, meeting its primary endpoints. Other STEP trials examined weight maintenance after treatment withdrawal and use in adolescents. These results supported approval of Wegovy.
Cardiovascular outcomes: SELECT
SELECT was a large randomized trial of semaglutide 2.4 mg in adults with established cardiovascular disease and overweight or obesity, but without diabetes. Published in 2023, it met its primary endpoint, showing a reduction in major adverse cardiovascular events compared with placebo. This trial supported an expanded indication for Wegovy to reduce cardiovascular risk in this population. It was one of the first trials to show cardiovascular outcome effects for an obesity medicine in people without diabetes.
Other areas under investigation
Semaglutide has been studied in chronic kidney disease, heart failure with preserved ejection fraction, metabolic dysfunction-associated steatohepatitis and other conditions linked to obesity and diabetes. Results vary by indication, and approved uses are defined by the current labeling. Readers should consult the specific trial publications and current prescribing information rather than generalizing from one trial to another. Trial designs, populations and comparators differ substantially across programs.
Regulatory status
Semaglutide is FDA-approved as Ozempic (injectable, type 2 diabetes), Rybelsus (oral, type 2 diabetes) and Wegovy (injectable, chronic weight management and cardiovascular risk reduction in eligible adults), all from Novo Nordisk. It is also approved in many other countries. Compounding of semaglutide has been shaped by FDA drug shortage determinations, which change over time; check current FDA guidance. For its status in sport, check the current WADA Prohibited List.
Status changes often. See the regulatory tracker for dated updates.
Quality and identity testing
A COA should confirm identity by mass spectrometry, with the observed mass matching the expected mass for the acylated peptide shown on this page, and report purity by reverse-phase HPLC. The fatty diacid side chain must be present and correctly attached at Lys26; non-acylated peptide, incompletely built side chains and positional isomers are key impurities. Salt forms matter: material sold as semaglutide sodium or acetate is not the same as the approved drug substance, and FDA has warned that salt forms differ from the active ingredient in approved products. Aggregation, oxidation of tryptophan and deamidation should also be monitored. Endotoxin and net peptide content should be reported.
For a walkthrough of each section of a certificate, see how to read a COA.
Storage and stability
Research material should be stored lyophilized at -20 °C, sealed and protected from light. The acylated peptide is amphiphilic and can self-associate or aggregate in solution, so avoid vigorous shaking and use buffers appropriate to the specific application. Approved drug products are stored according to their labeling, which typically involves refrigeration before first use. Avoid repeated freeze-thaw cycles for laboratory solutions.
Download the Semaglutide data sheet (PDF): sequence, masses, expected MS ions and handling on one printable page.
Latest research
The newest PubMed-indexed papers that mention Semaglutide in their title or abstract, retrieved through Europe PMC and refreshed automatically. Inclusion is not an endorsement of a paper's findings.
Loading the latest papers…
Frequently asked questions
Is semaglutide FDA approved?
Yes. Semaglutide is FDA-approved as Ozempic and Rybelsus for type 2 diabetes and as Wegovy for chronic weight management and for reducing cardiovascular risk in certain adults with overweight or obesity and established cardiovascular disease. Each product has its own labeled indications. It is also approved in many other countries.
What is the difference between Ozempic and Wegovy?
Both contain semaglutide and are made by Novo Nordisk. Ozempic is approved for type 2 diabetes, while Wegovy is approved for chronic weight management and cardiovascular risk reduction in eligible adults. They differ in approved indications and dose strengths. Rybelsus is an oral tablet form for type 2 diabetes.
What is the difference between semaglutide and tirzepatide?
Semaglutide activates only the GLP-1 receptor. Tirzepatide is a single peptide that activates both the GIP and GLP-1 receptors. Both are long-acting, acylated peptides given once weekly, and both are FDA-approved for type 2 diabetes and weight management. They were developed by different companies and have separate clinical trial programs.
Is semaglutide a peptide?
Yes. Semaglutide is a 31-residue peptide based on human GLP-1, with two amino acid substitutions and a fatty acid side chain attached to a lysine. The side chain allows it to bind albumin reversibly, which extends its half-life to about a week. Its backbone is closely related to the native hormone.
Related compounds
- Tirzepatide
Tirzepatide is a once-weekly peptide that activates both the GIP and GLP-1 receptors. It is FDA-approved for type 2 diabetes (Mounjaro) and chronic weight management (Zepbound).
- Retatrutide
Retatrutide is an investigational once-weekly peptide that activates the GIP, GLP-1 and glucagon receptors. It is not FDA-approved; Eli Lilly plans a BLA submission in Q1 2027 after phase 3 results.
- Cagrilintide
Cagrilintide is an investigational long-acting acylated analogue of amylin, a pancreatic hormone involved in satiety. It has been studied alone and in combination with semaglutide (CagriSema) for weight management.
- AOD-9604
AOD-9604 is a synthetic peptide based on the C-terminal region of human growth hormone, with an added N-terminal tyrosine. It was studied as an anti-obesity agent, but clinical development was discontinued.
References
- Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021. Find on PubMed
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023. Find on PubMed
- PubMed: all indexed literature on Semaglutide
- ClinicalTrials.gov: registered studies mentioning Semaglutide
Cite this page