What is the duration of action and elimination of semaglutide (glucagon-like peptide-1 receptor agonist) from the body?

Semaglutide Elimination Time from the Body

Semaglutide has an elimination half-life of approximately 1 week, which means it will remain in the circulation for about 5 weeks after the last dose. 1

Pharmacokinetic Properties of Semaglutide

• Semaglutide is a GLP-1 receptor agonist with an elimination half-life of approximately 1 week (7 days), which is significantly longer than endogenous GLP-1's half-life of only 2 minutes 2
• The drug reaches steady-state concentration in the body after 4-5 weeks of once-weekly administration 1, 3
• Semaglutide is extensively bound to plasma albumin (>99%), which contributes to its extended half-life 1
• The apparent clearance of semaglutide in patients with type 2 diabetes is approximately 0.05 L/h 1

Elimination Pathway

• The primary route of elimination for semaglutide is metabolism following proteolytic cleavage of the peptide backbone and sequential beta-oxidation of the fatty acid sidechain 1
• Only approximately 3% of the dose is excreted in the urine as intact semaglutide 1
• The extended half-life is due to molecular modifications that prevent cleavage and rapid inactivation by dipeptidyl peptidase-4 enzyme 2, 4
• Semaglutide's structure includes modifications at position 8 to provide stabilization against degradation by DPP-4 and at position 26 with a hydrophilic spacer and C18 fatty di-acid to facilitate albumin binding 1, 4

Clinical Implications of Semaglutide's Long Half-Life

• Due to its 1-week half-life, semaglutide will remain in the circulation for approximately 5 weeks after the last dose 1
• For perioperative considerations, it's recommended to hold semaglutide for at least three half-lives (approximately 3 weeks) before procedures to clear approximately 88% of the drug 2
• The prolonged presence in the body means that effects on gastric emptying may persist for several weeks after discontinuation 2
• This extended elimination time explains why weight regain is gradual rather than immediate after discontinuation 2

Factors Affecting Elimination

• Based on pharmacokinetic analyses, age, sex, race, ethnicity, and renal impairment do not have clinically meaningful effects on semaglutide pharmacokinetics 1
• Body weight affects semaglutide exposure (decreasing with increasing weight), but standard doses provide adequate systemic exposure across a wide weight range (40-198 kg) 1
• No dose adjustment is required for patients with renal impairment, including end-stage renal disease 1
• No dose adjustment is required for patients with hepatic impairment 1

Practical Considerations

• When discontinuing semaglutide, effects will gradually diminish over approximately 5 weeks 1
• For patients undergoing procedures, the American Society of Anesthesiologists suggests different approaches based on indication:
  • For weight loss: hold for at least three half-lives (3 weeks for semaglutide) 2
  • For diabetes: consult with the treating endocrinologist regarding risks and benefits of holding the medication 2
• The long elimination time contributes to both the benefits (weekly dosing convenience) and challenges (prolonged effects after discontinuation) of semaglutide therapy 3, 5