Governance Note – Sublingual vs Oral Semaglutide Dosing

HAUS OF ÄSTHETIK

Governance Note – Sublingual vs Oral Semaglutide Dosing

DATE OF IMPLEMENTATION:

1ST APRIL 2025

REVIEW DATE: 1ST APRIL 2026

VERSION NUMBER: 1.0

 

Background

Semaglutide is a GLP-1 receptor agonist licensed in the UK in injectable form (Ozempic®, Wegovy®) and as an oral tablet (Rybelsus®). Unlicensed sublingual formulations are compounded under MHRA “specials” regulations by certain UK pharmacies (e.g. Roseway Pharmacy).

 

Difference in Absorption Routes

  • Injectable semaglutide delivers the drug subcutaneously with ~89% bioavailability.

  • Rybelsus® uses SNAC (sodium N-[8-(2-hydroxybenzoyl) amino] caprylate) to temporarily alter gastric pH and solubilise semaglutide. Despite this, oral bioavailability remains ~1%.

  • Sublingual semaglutide specials are compounded in permeation-enhancing bases (e.g. SubMagna™) and absorbed directly across the oral mucosa into systemic circulation. This bypasses gastric degradation and first-pass metabolism, leading to presumed higher relative bioavailability than oral tablets.

 

 

Dosing Implications

  • Rybelsus® dosing: 3 mg once daily (initiation), titrated to 7 mg and up to 14 mg once daily. These higher doses reflect the extremely low absorption (1%) through the stomach.

  • Injectable dosing: 0.25 mg weekly (initiation), titrated to 0.5–2.4 mg weekly, with far smaller doses required due to high systemic absorption.

  • Sublingual specials dosing: Typically 0.25 mg daily → 0.5 mg daily → ~1 mg daily maintenance. Lower doses are used because the route bypasses gastric degradation. However, there is no MHRA-approved bioequivalence data, and dosing is based on compounding practice and extrapolation, not large-scale RCTs.

 

 

Rationale for Lower Sublingual Doses

  1. Bypassing stomach and gut destruction: Unlike Rybelsus®, sublingual absorption avoids gastric acid and digestive enzymes, preserving more of the drug.

  2. Bypassing hepatic first-pass metabolism: Absorption into systemic circulation via oral mucosa may reduce loss in the liver.

  3. Permeation enhancers: Compounded formulations use carriers to improve mucosal penetration, though absorption varies by patient and formulation.

  4. Empirical compounding data: International compounding practice supports lower daily doses, though evidence is not peer-reviewed at the same standard as licensed medicines.

 

 

Clinical and Regulatory Considerations

  • Unlicensed status: Sublingual semaglutide has no MHRA licence. It must only be prescribed where a special clinical need exists that licensed products cannot meet (e.g. intolerance, needle phobia).

  • Uncertainty: Bioavailability of sublingual forms has not been established in controlled trials. Dosing equivalence to injectable or oral licensed formulations cannot be guaranteed.

  • Monitoring: Close patient monitoring is essential (weight, HbA1c if diabetic, tolerance, adverse effects).

  • Liability: Prescriber assumes responsibility for use of the unlicensed special. Explicit informed consent must be obtained.

 

 

Conclusion

Lower sublingual doses of semaglutide compared to Rybelsus® are explained by differences in absorption routes: Rybelsus® suffers extreme gastric degradation (necessitating higher doses), whereas sublingual administration bypasses the stomach, permitting clinically observed effects at lower daily doses.

However, this rationale is scientific but not trial-validated. Therefore, the use of sublingual semaglutide must always be supported by:

  • Documented justification for unlicensed use,

  • Explicit patient consent highlighting risks and alternatives,

  • Careful monitoring of efficacy and safety outcomes.