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):

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at The Alfred ICU, where he is Deputy Director (Education). He is a Clinical Adjunct Associate Professor at Monash University, the Lead for the  Clinician Educator Incubator programme, and a CICM First Part Examiner.

He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives. He was one of the founders of the FOAM movement (Free Open-Access Medical education) has been recognised for his contributions to education with awards from ANZICS, ANZAHPE, and ACEM.

His one great achievement is being the father of three amazing children.

On Bluesky, he is @precordialthump.bsky.social and on the site that Elon has screwed up, he is @precordialthump.

| INTENSIVE | RAGE | Resuscitology | SMACC

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