Semaglutide, a once-weekly human GLP-1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel

J Clin Pharmacol. 2015 May;55(5):497-504. doi: 10.1002/jcph.443. Epub 2015 Jan 14.


The effect of semaglutide, a once-weekly human glucagon-like peptide-1 (GLP-1) analog in development for type 2 diabetes (T2D), on the bioavailability of a combined oral contraceptive was investigated. Postmenopausal women with T2D (n = 43) on diet/exercise ± metformin received ethinylestradiol (0.03 mg)/levonorgestrel (0.15 mg) once daily for 8 days before (semaglutide-free) and during (steady-state 1.0 mg) semaglutide treatment (subcutaneous once weekly; dose escalation: 0.25 mg 4 weeks; 0.5 mg 4 weeks; 1.0 mg 5 weeks). Bioequivalence of oral contraceptives was established if 90%CI for the ratio of pharmacokinetic parameters during semaglutide steady-state and semaglutide-free periods was within prespecified limits (0.80-1.25). The bioequivalence criterion was met for ethinylestradiol area under the curve (AUC0-24 h ) for semaglutide steady-state/semaglutide-free; 1.11 (1.06-1.15). AUC0-24 h was 20% higher for levonorgestrel at semaglutide steady-state vs. semaglutide-free (1.20 [1.15-1.26]). Cmax was within bioequivalence criterion for both contraceptives. Reductions (mean ± SD) in HbA1c (-1.1 ± 0.6%) and weight (-4.3 ± 3.1 kg) were observed. Semaglutide pharmacokinetics were compatible with once-weekly dosing; the semaglutide dose and dose-escalation regimen were well tolerated. Adverse events, mainly gastrointestinal, were mild to moderate in severity. Asymptomatic increases in mean amylase and lipase were observed. Three subjects had elevated alanine aminotransferase levels ≥3x the upper limit of normal during semaglutide/oral contraceptive coadministration, which were reported as adverse events, but resolved during follow-up. Semaglutide did not reduce the bioavailability of ethinylestradiol and levonorgestrel.

Keywords: GLP-1; ethinylestradiol; levonorgestrel; once weekly; semaglutide; type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Area Under Curve
  • Blood Glucose
  • Contraceptives, Oral, Combined / pharmacokinetics*
  • Drug Combinations
  • Drug Interactions
  • Ethinyl Estradiol / pharmacokinetics*
  • Female
  • Glucagon-Like Peptides / blood
  • Glucagon-Like Peptides / pharmacology*
  • Glycated Hemoglobin
  • Half-Life
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacology*
  • Levonorgestrel / pharmacokinetics*
  • Metabolic Clearance Rate
  • Middle Aged
  • Postmenopause


  • Blood Glucose
  • Contraceptives, Oral, Combined
  • Drug Combinations
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • ethinyl estradiol, levonorgestrel drug combination
  • Ethinyl Estradiol
  • semaglutide
  • Levonorgestrel
  • Glucagon-Like Peptides