Semaglutide

Semaglutide is a 31-amino-acid peptide GLP-1 receptor agonist marketed as Ozempic (T2D, subcutaneous), Wegovy (chronic weight management, subcutaneous), and Rybelsus (T2D, oral) by Novo Nordisk. It was the first-in-class blockbuster GLP-1 therapy and the benchmark against which all newer incretin drugs (including Tirzepatide) are compared.

Overview

The semaglutide sequence is a 94%-homologous analog of native GLP-1 with two amino-acid substitutions (Aib at position 8, Arg at position 34) and a C18 fatty-acid linker that binds albumin in plasma. The albumin binding extends half-life from native GLP-1's ~2 minutes to approximately 7 days, enabling weekly dosing.

Mechanism

GLP-1 receptor agonism produces:

• Glucose-dependent insulin secretion from pancreatic β-cells
• Suppressed glucagon release from α-cells (above hypoglycemic threshold)
• Slowed gastric emptying · prolonged satiety
• Central appetite suppression via hypothalamic and brainstem GLP-1 receptors
• Reduced hepatic gluconeogenesis

See: GLP-1_receptor, Incretin_effect, Gastric_emptying.

Evidence

Clinical evidence base is enormous:

• SUSTAIN program (T2D): semaglutide 1 mg reduced HbA1c by ~1.5% across head-to-head trials
• STEP program (obesity): semaglutide 2.4 mg produced 14.9% body-weight loss vs placebo 2.4% at 68 weeks
• SELECT trial (cardiovascular): 20% reduction in MACE in overweight/obese patients with established cardiovascular disease

Dosing literature

Per FDA labels:

• Ozempic / T2D: titration 0.25 → 0.5 → 1.0 → 2.0 mg once weekly, subcutaneous.
• Wegovy / weight: titration 0.25 → 0.5 → 1.0 → 1.7 → 2.4 mg once weekly, subcutaneous.
• Rybelsus / oral T2D: 3 → 7 → 14 mg once daily, taken at least 30 minutes before first food or drink of the day.

These dose schedules come from the approved FDA labels and are reproduced for reference. Any human use should be under clinical supervision.

Storage

Ozempic pen (multi-dose, branded): refrigerated 2–8 °C; after first use, room-temperature storage at 15–30 °C permitted for up to 56 days per [FDA label](https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/209637s008lbl.pdf). Wegovy pen (single-dose, branded): refrigerated 2–8 °C; up to 28 days at 8–30 °C in original carton before use. Research-use lyophilized: 2–8 °C until reconstituted; reconstituted solution stable 28 days at 2–8 °C. See Reconstitution.

Regulatory status

• United States. FDA-approved 2017 (Ozempic), 2021 (Wegovy), 2019 (Rybelsus).
• Compounding. FDA declared semaglutide injection shortages resolved in February 2025, with [enforcement-discretion windows](https://www.fda.gov/drugs/drug-alerts-and-statements/fda-clarifies-policies-compounders-national-glp-1-supply-begins-stabilize) ending April 22 (503A) and May 22 (503B), 2025, restricting compounded versions.
• WADA. Not on the prohibited list.

Side effects

Nausea, vomiting, diarrhea, constipation (most common, dose-dependent and titration-mitigated). Pancreatitis, gallbladder disease, ileus, and rare cases of non-arteritic anterior ischemic optic neuropathy have been reported. Boxed warning for thyroid C-cell tumors.

See also

• Tirzepatide · dual GIP/GLP-1 successor
• Liraglutide · daily GLP-1 predecessor
• GLP-1_receptor

References

• Wilding JPH, et al. "Once-weekly semaglutide in adults with overweight or obesity." N Engl J Med. 2021;384(11):989-1002. PMID 33567185.
• Lincoff AM, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes." N Engl J Med. 2023;389(24):2221-32. PMID 37952131.
• Davies M, et al. "Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2)." Lancet. 2021;397(10278):971-84. PMID 33667417.
• Lau J, et al. "Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide." J Med Chem. 2015;58(18):7370-80. PMID 26308095.