Long-Acting GLP-1 Receptor Agonist

Semaglutide

Also Known As: NN9535, NNC0113-0217, Ozempic, Wegovy, Rybelsus

Semaglutide is a synthetic 31-amino-acid peptide analog of human glucagon-like peptide-1 (GLP-1) developed by Novo Nordisk and approved as Ozempic, Wegovy, and Rybelsus. An Aib substitution at position 8 confers DPP-4 resistance, and acylation at lysine 26 with a γGlu / 2× OEG / C18 fatty di-acid linker enables reversible albumin binding, giving an elimination half-life of approximately seven days. Pivotal trials (SUSTAIN-6, STEP-1, SELECT, FLOW, PIONEER 6) have demonstrated benefit across glycemic control, weight loss, cardiovascular endpoints, renal function, and MASH.

Identity & Chemistry

Two-dimensional skeletal structural formula of semaglutide showing the 31-residue GLP-1 peptide backbone with the Aib substitution at position 8, Arg at position 34, and the γGlu / 2× OEG / C18 fatty di-acid side chain conjugated to Lys26.
Image credit: Edgar181, via Wikimedia Commons · Public Domain
Amino Acid Sequence
H-Aib-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K(γGlu-2×OEG-C18 diacid)-E-F-I-A-W-L-V-R-G-R-G
Molecular Formula
C₁₈₇H₂₉₁N₄₅O₅₉
Molecular Weight
4113.64 Da
CAS Number
910463-68-2
PubChem CID
56843331
DrugBank ID
DB13928
IUPAC Name
[Aib⁸, Arg³⁴, Lys²⁶(Nε-(γ-Glu(Nα-hexadecanedioyl))-AEEAc-AEEAc)]-GLP-1(7-37)
Solubility
Qualitatively water-soluble; commercial formulations (Ozempic, Wegovy) are aqueous solutions buffered with disodium phosphate dihydrate at pH ~7.4. Quantitative solubility values are not publicly disclosed by Novo Nordisk. Lyophilized research-grade material is typically freely soluble in water (≥1 mg/mL) and dilute acetic acid; sparingly soluble in DMSO.
Storage
Lyophilized peptide: −20 °C, sealed and protected from light; reported integrity up to 24 months under those conditions. Reconstituted or commercial solutions: refrigerate at 2–8 °C; once in use, Ozempic / Wegovy pens may be kept up to 56 days at 2–8 °C or up to 30 °C per FDA prescribing information.

Mechanism of Action

Semaglutide is a long-acting agonist of the glucagon-like peptide-1 receptor (GLP-1R) that mimics endogenous incretin signaling — augmenting glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and reducing appetite via central GLP-1R-expressing neurons.

Semaglutide was engineered from native GLP-1(7-37) by Novo Nordisk (Lau et al. 2015) to overcome the rapid (~1–2 minute) plasma clearance of the endogenous hormone. Substitution of alanine at position 8 with α-aminoisobutyric acid (Aib) confers resistance to DPP-4 cleavage. Acylation of Lys²⁶ with a γ-glutamic acid spacer and two 8-amino-3,6-dioxaoctanoic acid (OEG/ADO) units terminating in a C18 fatty di-acid creates a high-affinity, reversible interaction with circulating albumin, shielding the peptide from renal filtration and neprilysin-mediated proteolysis. The Lys³⁴→Arg substitution prevents off-target acylation during synthesis. Together these modifications extend the elimination half-life to approximately 165–184 hours (~7 days), supporting once-weekly subcutaneous dosing. Rybelsus achieves oral delivery via co-formulation with the absorption enhancer SNAC (sodium N-(8-[2-hydroxybenzoyl]amino)caprylate), which transiently elevates local gastric pH and promotes transcellular uptake — albeit with absolute bioavailability of only ~1%.

Molecular Targets

  • Glucagon-like peptide-1 receptor (GLP-1R; UniProt P43220) — primary high-affinity target (Kᵢ ≈ 0.38 nM)
  • Human serum albumin — non-covalent binding via the C18 fatty di-acid side chain (>99% plasma protein binding)
  • No meaningful activity at GIP, glucagon, or other class B GPCRs at therapeutic concentrations

Signaling Pathways

  • Gαs-coupled adenylyl cyclase → ↑ intracellular cAMP → PKA and Epac2 activation in pancreatic β-cells
  • cAMP-mediated potentiation of glucose-stimulated insulin secretion (closure of K-ATP channels, Ca²⁺ influx)
  • Glucose-dependent suppression of glucagon secretion from pancreatic α-cells
  • CNS GLP-1R activation in the area postrema, hypothalamic arcuate nucleus, and brainstem — promotes satiety, reduces food intake, slows gastric emptying
  • Pleiotropic cardiovascular and renal effects (anti-inflammatory signaling, modulation of natriuresis, improved endothelial function); mechanisms incompletely characterized

Research Applications

Semaglutide has been evaluated in a comprehensive clinical program spanning type 2 diabetes, obesity, cardiovascular prevention, chronic kidney disease, and MASH; pivotal RCTs are published in NEJM with combined enrollments exceeding 30,000 participants.

Type 2 diabetes mellitus (SUSTAIN-6)

Phase III

Studies report once-weekly semaglutide reduced HbA1c by ~1.1–1.4 percentage points vs placebo and reduced the composite cardiovascular endpoint (CV death, non-fatal MI, non-fatal stroke) to 6.6% vs 8.9% (HR 0.74; 95% CI 0.58–0.95; n=3297, 104 weeks).

— Marso et al., NEJM 2016;375(19):1834–1844

Obesity / chronic weight management (STEP-1)

Phase III

Studies report mean change in body weight from baseline to week 68 of −14.9% with semaglutide 2.4 mg vs −2.4% on placebo (estimated treatment difference −12.4 percentage points); 86.4% achieved ≥5% and 50.5% ≥15% weight loss (n=1961, no diabetes).

— Wilding et al., NEJM 2021;384(11):989–1002

Cardiovascular outcomes in obesity without diabetes (SELECT)

Phase III

In SELECT (n=17,604, mean follow-up 39.8 months), semaglutide 2.4 mg reduced the primary MACE composite to 6.5% vs 8.0% on placebo (HR 0.80; 95% CI 0.72–0.90), a 20% relative risk reduction.

— Lincoff et al., NEJM 2023;389(24):2221–2232

Chronic kidney disease in T2DM (FLOW)

Phase III

Studies report semaglutide 1.0 mg reduced the composite primary kidney outcome (kidney failure, ≥50% sustained eGFR decline, kidney/CV death) to 18.7% vs 24.0% (HR 0.76; 95% CI 0.66–0.88; n=3533; trial stopped early for efficacy).

— Perkovic et al., NEJM 2024;391(2):109–121

Oral semaglutide and cardiovascular outcomes (PIONEER 6)

Phase III

Studies report non-inferiority for the MACE composite (HR 0.79; 95% CI 0.57–1.11), with reductions in all-cause mortality (1.4% vs 2.8%; HR 0.51) and CV death (HR 0.49) among 3183 T2DM patients at high CV risk.

— Husain et al., NEJM 2019;381(9):841–851

Metabolic dysfunction-associated steatohepatitis (ESSENCE)

Phase III

Studies report semaglutide 2.4 mg significantly improved both resolution of MASH without worsening of fibrosis and improvement in fibrosis without worsening of MASH at week 72 vs placebo in adults with biopsy-confirmed MASH (F2–F3); supported FDA approval of Wegovy for MASH (August 2025).

— Sanyal et al., ESSENCE readout 2024–2025

Clinical Status

Regulatory Status
Approved. FDA approvals: Ozempic (T2DM, 2017; CV risk reduction in T2DM with CVD, 2020; CKD/CV risk reduction in T2DM with CKD, 2025); Rybelsus (oral T2DM, 2019; CV risk reduction, 2025); Wegovy (chronic weight management, 2021; MACE reduction in adults with overweight/obesity and CVD without diabetes, March 2024; MASH, August 2025; oral 25 mg, December 2025). EMA approvals: Ozempic (February 2018), Rybelsus (April 2020), Wegovy (January 2022).
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Highest Trial Phase
Approved (Phase IV / post-marketing across multiple indications)
Sponsor
Novo Nordisk A/S

Key Clinical Trials

  • SUSTAIN-6: cardiovascular outcomes of semaglutide vs placebo in type 2 diabetes at high CV risk
    Phase 3
    NCT01720446
  • STEP-1: once-weekly semaglutide 2.4 mg vs placebo in adults with overweight or obesity
    Phase 3
    NCT03548935
  • SELECT: cardiovascular outcomes of semaglutide 2.4 mg in adults with overweight/obesity and established CVD
    Phase 3
    NCT03574597
  • FLOW: renal outcomes of semaglutide 1.0 mg in T2DM with chronic kidney disease
    Phase 3
    NCT03819153
  • PIONEER 6: oral semaglutide cardiovascular outcomes in T2DM at high CV risk
    Phase 3
    NCT02692716
  • ESSENCE: semaglutide 2.4 mg in non-cirrhotic MASH with fibrosis
    Phase 3
    NCT04822181

Safety Profile

Observed in research settings

Across the SUSTAIN, STEP, SELECT, FLOW, and PIONEER programs, the most frequent adverse events observed in research settings were dose-dependent and transient gastrointestinal symptoms (nausea, vomiting, diarrhea, constipation), generally arising during dose escalation. Serious findings include gallbladder disease, pancreatitis (low absolute incidence), worsening of pre-existing diabetic retinopathy in patients with rapid HbA1c lowering, and a rodent-only signal for thyroid C-cell tumors that triggered an FDA boxed warning.

Adverse Events Reported in Studies

  • Nausea (up to ~44% on Wegovy 2.4 mg; ~15–20% on Ozempic 0.5–1.0 mg)
  • Diarrhea (~30% Wegovy; ~9% Ozempic)
  • Vomiting (~24% Wegovy; ~5–9% Ozempic)
  • Constipation (~24% Wegovy; ~3–5% Ozempic)
  • Abdominal pain (~20% Wegovy; ~6–7% Ozempic)
  • Headache, fatigue, dyspepsia, eructation (>5%); injection-site reactions usually mild

Serious Adverse Events

  • Thyroid C-cell tumors / medullary thyroid carcinoma — FDA boxed warning based on rodent studies; human relevance unknown. Contraindicated in personal/family history of MTC or MEN-2
  • Acute pancreatitis — reported in trials; discontinue if suspected. Meta-analyses have not detected a significantly elevated risk
  • Gallbladder disease — cholelithiasis 1.6% vs 0.7% placebo; cholecystitis 0.6% vs 0.2% (Wegovy 2.4 mg dataset)
  • Diabetic retinopathy complications (SUSTAIN-6: 3.0% vs 1.8%; HR 1.76) — concentrated in patients with pre-existing retinopathy and rapid HbA1c lowering
  • Acute kidney injury reported in association with dehydration from severe GI symptoms
  • Hypersensitivity reactions including anaphylaxis and angioedema (rare)
  • Non-arteritic anterior ischemic optic neuropathy (NAION) — very rare pharmacovigilance signal (2024–2025)
  • Gastroparesis / delayed gastric emptying — elevated incidence reported in real-world cohorts

References

  1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375(19):1834–1844. 2016 .

    DOI: 10.1056/NEJMoa1607141 PMID: 27633186 View Source

  2. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021;384(11):989–1002. 2021 .

    DOI: 10.1056/NEJMoa2032183 PMID: 33567185 View Source

  3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023;389(24):2221–2232. 2023 .

    DOI: 10.1056/NEJMoa2307563 PMID: 37952131 View Source

  4. Perkovic V, Tuttle KR, Rossing P, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med 2024;391(2):109–121. 2024 .

    DOI: 10.1056/NEJMoa2403347 PMID: 38785209 View Source

  5. Husain M, Birkenfeld AL, Donsmark M, et al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381(9):841–851. 2019 .

    DOI: 10.1056/NEJMoa1901118 PMID: 31185157 View Source

  6. Lau J, Bloch P, Schäffer L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide. J Med Chem 2015;58(18):7370–7380. 2015 .

    DOI: 10.1021/acs.jmedchem.5b00726 PMID: 26308095 View Source

  7. Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne) 2019;10:155. 2019 .

    DOI: 10.3389/fendo.2019.00155 PMID: 31031702 View Source

  8. U.S. Food and Drug Administration Wegovy (semaglutide) Highlights of Prescribing Information (2025 revision). FDA Drug Label. 2025 .

    View Source

Frequently Asked Questions

What is semaglutide?
Semaglutide is a synthetic 31-amino-acid peptide analog of human glucagon-like peptide-1 (GLP-1) developed by Novo Nordisk and approved as Ozempic, Wegovy, and Rybelsus. It is engineered for resistance to DPP-4 cleavage and for high-affinity albumin binding, giving it an elimination half-life of approximately 7 days and supporting once-weekly dosing.
How does semaglutide differ from liraglutide?
Both are GLP-1 receptor agonists from Novo Nordisk and share an Aib substitution at position 8, but liraglutide carries a shorter C16 mono-acid via a single γ-Glu spacer (half-life ~13 h, daily dosing), whereas semaglutide adds a longer C18 di-acid linked via γ-Glu plus two OEG units, conferring stronger albumin binding and a ~7-day half-life. Semaglutide also includes a Lys³⁴→Arg substitution that liraglutide lacks. Head-to-head SUSTAIN-10 reported greater HbA1c lowering and weight loss for semaglutide.
Is semaglutide approved by regulators?
Yes. The subcutaneous form (Ozempic) has been FDA-approved for type 2 diabetes since December 2017 and EMA-approved since February 2018. Wegovy (semaglutide 2.4 mg) was FDA-approved for chronic weight management in June 2021 and added a cardiovascular-risk-reduction indication in March 2024 based on the SELECT trial. Rybelsus (oral) has been approved since September 2019.
What is the molecular structure of semaglutide?
It is a 31-residue peptide with the sequence H-Aib-EGTFTSDVSSYLEGQAAK*-EFIAWLVRGRG (where Aib is 2-aminoisobutyric acid and Lys26, marked with *, carries a γGlu / 2× OEG / C18 fatty di-acid side chain). Molecular formula C₁₈₇H₂₉₁N₄₅O₅₉; molecular weight ~4113.6 Da. CAS 910463-68-2; PubChem CID 56843331.
What weight loss has been observed in semaglutide trials?
In STEP-1 (Wilding et al., NEJM 2021), adults with overweight or obesity (no diabetes) lost a mean of 14.9% of body weight at 68 weeks on semaglutide 2.4 mg vs 2.4% on placebo, with 50.5% reaching ≥15% weight loss. In SELECT, similar weight reductions (~9% mean placebo-subtracted) accompanied a 20% reduction in major adverse cardiovascular events.
What are the main side effects observed with semaglutide?
The most common adverse events reported in clinical trials are dose-related gastrointestinal symptoms — nausea, diarrhea, vomiting, constipation, and abdominal pain — generally mild-to-moderate and most pronounced during dose escalation. Less common but important findings include gallbladder disease, acute pancreatitis, worsening of pre-existing diabetic retinopathy (notably in SUSTAIN-6), and a rodent-only signal for thyroid C-cell tumors that carries an FDA boxed warning.

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