Safety and Pharmacokinetics of Single and Multiple Ascending Doses of the Novel Oral Human GLP-1 Analogue, Oral Semaglutide, in Healthy Subjects and Subjects with Type 2 Diabetes

Clin Pharmacokinet. 2019 Jun;58(6):781-791. doi: 10.1007/s40262-018-0728-4.


Background: Oral semaglutide is a novel tablet containing the human glucagon-like peptide-1 (GLP‑1) analogue semaglutide, co-formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The safety and pharmacokinetics of oral semaglutide were investigated in two randomised, double-blind, placebo-controlled trials.

Methods: In a single-dose, first-in-human trial, 135 healthy males received oral semaglutide (2-20 mg semaglutide co-formulated with 150-600 mg SNAC) or placebo with SNAC. In a 10-week, once-daily, multiple-dose trial, 84 healthy males received 20 or 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC, and 23 males with type 2 diabetes (T2D) received 40 mg oral semaglutide (with 300 mg SNAC), placebo, or placebo with SNAC.

Results: Oral semaglutide was safe and well-tolerated in both trials. The majority of adverse events (AEs) were mild, with the most common AEs being gastrointestinal disorders. In the single-dose trial, semaglutide exposure was highest when co-formulated with 300 mg SNAC. In the multiple-dose trial, semaglutide exposure was approximately twofold higher with 40 versus 20 mg oral semaglutide in healthy males, in accordance with dose proportionality, and was similar between healthy males and males with T2D. The half-life of semaglutide was approximately 1 week in all groups.

Conclusion: The safety profile of oral semaglutide was as expected for the GLP-1 receptor agonist drug class. Oral semaglutide co-formulated with 300 mg SNAC was chosen for further clinical development. The pharmacokinetic results supported that oral semaglutide is suitable for once-daily dosing. CLINICALTRIALS.

Gov identifiers: NCT01037582, NCT01686945.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Area Under Curve
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptides* / administration & dosage
  • Glucagon-Like Peptides* / adverse effects
  • Glucagon-Like Peptides* / blood
  • Healthy Volunteers
  • Humans
  • Hypoglycemic Agents* / administration & dosage
  • Hypoglycemic Agents* / adverse effects
  • Hypoglycemic Agents* / blood
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Young Adult


  • Hypoglycemic Agents
  • semaglutide
  • Glucagon-Like Peptides
  • Glucagon-Like Peptide 1

Associated data