Semaglutide

CLASS

• Glucagon-like peptide-1 (GLP-1) receptor agonist
• Incretin mimetic
• Antidiabetic agent

PHYSICOCHEMICAL PROPERTIES

• Formulations: subcutaneous injection (Ozempic, Wegovny) or tablets (Rybelsus)
• Solubility: Soluble in water
• Physiological implications: Semaglutide is a synthetic analog of human GLP-1, designed to resist degradation by DPP-4 enzyme, enhancing its half-life and efficacy.

MECHANISM OF ACTION

• GLP-1 receptor agonist: Binds to GLP-1 receptors in pancreatic beta cells, enhancing glucose-dependent insulin secretion.
• Anatomic locations: Primarily affects pancreatic beta cells, gastric mucosa, and the central nervous system.
• Second messenger pathways: Activation of GLP-1 receptors increases cyclic AMP (cAMP) levels, leading to insulin release.
• Pharmacodynamic effects:
  • Increases insulin secretion in a glucose-dependent manner
  • Decreases glucagon secretion
  • Slows gastric emptying
  • Reduces appetite and food intake
• Duration of effect: Long-acting, with a half-life of approximately 7 days. Semaglutide is resistant to degradation by Dipeptidyl Peptidase-4 (DPP-4), the enzyme responsible for incretin metabolism.

PHARMACEUTICS

Ozempic

• Subcutaneous injection: single-dose disposable pre-filled pen (1.5 mL pens being phased out in 2025 in favour of 3 mL pens)
• Dosage forms: 0.25 mg or 0.5 mg dose pens.
• Adminstered weekly

Rybelsus

• oral tablets
• Dosage forms: 1.5 mg, 4 mg, 9 mg, 25 mg, 50 mg
• Adminstered daily
• Semaglutide coformulated with sodium N­[8(2­hydroxybenzoyl) amino] caprylate (SNAC) results in a complex that can be given orally as it is lipophilic and resistant to proteolysis.

Wegovny

• Subcutaneous injection: single-dose disposable pre-filled pen
• Dosage forms: 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, or 2.4 mg in each pen
• Adminstered weekly

DOSE

• Type 2 diabetes (Ozempic): Start with 0.25 mg once weekly for 4 weeks, then increase to 0.5 mg once weekly. If needed, further increase to 1 mg or 2 mg once weekly.
• Type 2 diabetes (Rybelsus): Start with 1.5 mg once daily for one month, then increase to a maintenance dose of 4 mg once daily. If needed, the dose can be escalated to the next higher dose after a minimum of one month on the current dose (4 mg, then 9 mg, then 25 mg, then 50 mg maximum)
• Weight management (Wegovny): 2.4 mg once weekly

INDICATIONS

• Type 2 diabetes mellitus: improve glycemic control and improved cardiovascular events (Ozempic, Rybelsus)
• Weight management: chronic weight management in adults with obesity or overweight with at least one weight-related condition (Wegovny)

CONTRA-INDICATIONS

Absolute:

• hypersensitivity
• Personal or Family History of Medullary Thyroid Carcinoma (increased risk in rodent studies)
• Multiple Endocrine Neoplasia Syndrome Type 2 (MEN 2)

Relative:

• History pancreatitis
• Severe GI disease (e.g gastroparesis) (due to delayed gastric emptying)
• Type 1 diabetes mellitus
• Pregnancy and breast feeding

ADVERSE EFFECTS

• Common:
  • GI: Nausea, vomiting, diarrhea, constipation.
  • CNS: Headache, fatigue.
• Life-threatening:
  • Pancreatitis.
  • Bowel obstruction
  • Gastroparesis (risk of aspiration under anaesthesia)
  • Hypoglycemia (when used with insulin or sulfonylureas).
  • Thyroid C-cell tumors (observed in rodents).

DRUG-DRUG INTERACTIONS

• Insulin and Sulfonylureas: increased risk of hypoglycemia when used together 
• Warfarin: May alter INR levels
• Beta-blockers (e.g., metoprolol): may mask symptoms of hypoglycemia
• Diuretics (e.g., furosemide): risk of dehydration and electrolyte imbalance
• SSRIs (e.g., fluoxetine, sertraline): potential for GI side effects and altered glycemic control

PHARMACOKINETICS

• Absorption: peak plasma concentration in 1-3 days. Bioavailability of oral tablets is <1%.
• Distribution: widely distributed, protein binding ~99% (albumin).
• Metabolism: metabolized by proteolytic cleavage (by DPP-4) and beta-oxidation.
• Excretion: primarily renal; half-life ~1 week.

PREGNANCY AND LACTATION

• Pregnancy: Category C; use only if potential benefit justifies the potential risk to the fetus.
• Lactation: Excreted in breast milk; use with caution.

DOSE ADJUSTMENTS IN ORGAN FAILURES

• Renal impairment: No dose adjustment required, but monitor renal function.
• Hepatic impairment: No dose adjustment required, but use with caution.

EVIDENCE

STEP-1 (Wilding et al, 2021)

• Design: Randomised, double-blind, placebo-controlled trial; N = 1,961 (1,306 semaglutide; 655 placebo)
• Intervention: Semaglutide 2.4 mg SC weekly + lifestyle intervention vs placebo + lifestyle intervention
• Primary Outcome: % change in body weight from baseline at 68 weeks
• Results:
  • Mean weight change: Semaglutide −14.9% vs Placebo −2.4%
  • Mean difference: −12.5 percentage points (95% CI: −13.4 to −11.6, p < 0.001)
  • ≥5% weight loss: Semaglutide 86.4% vs Placebo 31.5%
• Conclusion: Semaglutide 2.4 mg weekly produced clinically meaningful weight loss compared to placebo, with significant improvements in cardiometabolic risk factors.

SUSTAIN-7 (Pratley et al, 2018)

• Design: Randomised, open-label, phase 3b trial; N = 1,201 (semaglutide 0.5 mg or 1.0 mg; dulaglutide 0.75 mg or 1.5 mg)
• Intervention: Semaglutide SC weekly vs Dulaglutide SC weekly
• Primary Outcomes: Change in HbA1c and body weight at 40 weeks
• Results:
  • HbA1c reduction: Semaglutide 1.0 mg −1.8% vs Dulaglutide 1.5 mg −1.4%
  • Mean difference: −0.4% (95% CI: −0.55 to −0.25, p < 0.0001)
  • Weight loss: Semaglutide 1.0 mg −5.6 kg vs Dulaglutide 1.5 mg −3.0 kg
  • Mean difference: −2.6 kg (95% CI: −3.3 to −1.8, p < 0.0001)
• Conclusion: Semaglutide was superior to dulaglutide in reducing HbA1c and body weight, with a comparable safety profile.

SUSTAIN-6 (Marso et al, 2016)

• Design: Randomised, double-blind, placebo-controlled trial; N = 3,297 (1,648 semaglutide; 1,649 placebo)
• Intervention: semaglutide (0.5 mg or 1.0 mg SC weekly) vs placebo
• Primary Outcome: Major Adverse Cardiovascular Events (MACE): composite of CV death, nonfatal MI, or nonfatal stroke
• Results: Semaglutide: 6.6% vs Placebo 8.9% (ARR: 2.3%, RRR: 25.8%, Hazard Ratio (HR): 0.74, 95% CI: 0.58–0.95, p-value: 0.02)
• Conclusion: Semaglutide significantly reduced the risk of MACE compared to placebo, confirming cardiovascular safety and suggesting benefit.

CONTROVERSIES

• Off-label use: Increasing use for weight loss has led to supply shortages for diabetic patients.
• Compounded formulations: Safety concerns with off-brand compounded semaglutide leading to adverse events.
• GLP-1 agonists stimulate thyroidal C­ cell (parafollicular) tumors in rodents. However, thyroidal C cells in humans express very few GLP­1 receptors, so the relevance to use in humans is unclear.

PRACTICAL TIPS

• Administration: Inject once weekly on the same day each week, with or without food. Oral tablets are taken with water, then no other intake for 30 minutes due to poor bioavailability.
• Monitoring: Regularly monitor blood glucose levels, renal function, and signs of pancreatitis.
• Patient education: Counsel patients on potential side effects and the importance of adherence to dosing schedule.

Recommendations prior to anaesthesia and sedation (ANZCA et al, 2025):

• Do not routinely cease semaglutide preoperatively:
  • Elective cessation is not recommended due to risks of hyperglycaemia in diabetic patients and potential compromise of weight control in those using it for obesity.
• Assess aspiration risk:
  • Patients should be screened for GLP-1RA use and involved in discussions about aspiration risk, especially if they have conditions that delay gastric emptying (e.g., gastroparesis, Parkinson’s disease).
• Preprocedural dietary modification:
  • Recommend a 24-hour clear fluid diet followed by the standard 6-hour fasting period before anaesthesia or sedation.
• Risk mitigation strategies if the 24-hour clear fluid diet hasn’t been followed or was not possible, consider:
  • Ultrasound assessment for residual gastric contents.
  • Use of prokinetic agents.
  • Modification of anaesthetic technique.
  • Deferral of procedure, if necessary.

OTHER GLP-1 AGONISTS

Other drugs of the same class as semaglutide include:

• Exenatide (Byetta, Bydureon)
• Liraglutide (Victoza, Saxenda)
• Dulaglutide (Trulicity)
• Tirzepatide (Mounjaro, Zepbound) – dual GLP-1 and GIP agonist

REFERENCES

Journal articles

• Knudsen LB, Lau J. The Discovery and Development of Liraglutide and Semaglutide. Front Endocrinol (Lausanne). 2019 Apr 12;10:155. doi: 10.3389/fendo.2019.00155. PMID: 31031702; PMCID: PMC6474072.
• Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844. doi: 10.1056/NEJMoa1607141. Epub 2016 Sep 15. PMID: 27633186.
• Pratley RE, Aroda VR, Lingvay I, Lüdemann J, Andreassen C, Navarria A, Viljoen A; SUSTAIN 7 investigators. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018 Apr;6(4):275-286. doi: 10.1016/S2213-8587(18)30024-X. Epub 2018 Feb 1. PMID: 29397376.
• Ruder K. As Semaglutide’s Popularity Soars, Rare but Serious Adverse Effects Are Emerging. JAMA. 2023 Dec;330(22):2140-2142. DOI: 10.1001/jama.2023.16620. PMID: 37966850.
• 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. PMID: 33567185
• Xie Y, Choi T, Al-Aly Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med. 2025 Jan 20. doi: 10.1038/s41591-024-03412-w. Epub ahead of print. Erratum in: Nat Med. 2025 Jan 31. doi: 10.1038/s41591-025-03542-9. PMID: 39833406.

Textbooks

• Brunton LL, Knollmann BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 14th ed. New York, NY: McGraw Hill; 2023.
• Vanderah TW. Katzung’s Basic and Clinical Pharmacology. 16th ed. New York, NY: McGraw Hill; 2023.

FOAM and web resources

• ANZCA et al (2025). Clinical Practice Recommendations regarding patients taking GLP-1 receptor agonists and dual GLP-1/GIP receptor co-agonists prior to anaesthesia or sedation for surgical and endoscopic procedures. [pdf]
• TGA – Australian product information documents (pdf):
  • Ozempic
  • Rybelsus
  • Wegovny