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

Abstract

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.

Efficacy and Safety of Liraglutide Added to Capped Insulin Treatment in Subjects With Type 1 Diabetes: The ADJUNCT TWO Randomized Trial

“…The increases in mean amylase, lipase, and pulse and reductions in mean systolic blood pressure reported in the liraglutide groups are of unknown clinical significance. Furthermore, these observations are similar to those seen in type 2 diabetesfocused trials involving this drug class (36)(37)(38).…”

Semaglutide seems to be more effective the other GLP-1Ras

“…On the basis of the experience with liraglutide, semaglutide was developed from liraglutide by changing 3 things: (I) Ala in position 8 was substituted to Aib (alpha-amino-iso-butyric acid; a change known to result in complete DPP-4 resistance); (II) substitution of the palmitic acid with a C-20 di-acid; and (III) introduction of a longer and more flexible linker. This increased its half-life in humans to 165 hours without significantly changing its ability to activate the GLP-1 receptor (25,26). This was interpreted to support a once weekly scheme of administration.…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…These medicines include exenatide (Byetta; AstraZeneca, Cambridge, UK), lixisenatide (Lyxumia; Sanofi, Paris, France), liraglutide (Victoza; Novo Nordisk, Copenhagen, Denmark), dulaglutide (Trulicity; Eli Lilly & Co., Indianapolis, IN), and albiglutide (Tanzeum; GlaskoSmithKline, Middlesex, UK). Semaglutide (Novo Nordisk, Copenhagen, Denmark) is a late-stage, longacting structural refinement related to liraglutide that when coformulated with suitable absorption enhancers is reported to be active in oral application (Gotfredsen et al, 2014;Finan et al, 2015a;Kapitza et al, 2015;Ahren et al, 2017;Blundell et al, 2017).…”