Abstract
ABSTRACTBackground: Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide.Research design and methods: A single-center, randomized, open-label, parallel-group trial investigated pharmacokinetic interactions of oral semaglutide with omeprazole (40 mg once-daily) in 54 healthy subjects. Primary endpoints were area under the plasma concentration-time curve over 24 h for semaglutide (AUC0−24h,semaglutide,Day10) and maximum concentration of semaglutide (Cmax,semaglutide,Day10) at day 10.Results: Exposure of semaglutide appeared to be slightly increased, although not statistically significantly, with oral semaglutide plus omeprazole versus oral semaglutide alone (AUC0−24h,semaglutide,Day10 [estimated treatment ratio 1.13; 90%CI 0.88, 1.45] and Cmax,semaglutide,Day10 [estimated treatment ratio 1.16; 90%CI 0.90, 1.49]). Gastric pH was higher with oral semaglutide and omeprazole versus oral semaglutide alone. Adverse events were mild or moderate and, most commonly, gastrointestinal disorders.Conclusions: There was a slight non-statistically significant increase in semaglutide exposure when oral semaglutide was administered with omeprazole, but this is not considered clinically relevant and no dose adjustment is likely to be required.
Highlights
The glucagon-like peptide-1 (GLP-1) receptor represents a valuable target for the management of type 2 diabetes, based on its abilities to stimulate insulin, inhibit glucagon secretion in a glucose-depending manner, delay gastric emptying, and reduce energy intake with a low risk of hypoglycemia [1,2], and the potential for cardiovascular protection [3,4]
The AUC0–24h,sodium N-(8-[2-hydroxylbenzoyl] amino) caprylate (SNAC),Day10 of SNAC appeared to be slightly higher in the oral semaglutide plus omeprazole group compared with oral semaglutide alone (Figure 4(b))
An increase in gastric pH was observed on day 9 in subjects in the oral semaglutide plus omeprazole group compared to the oral semaglutide alone group
Summary
The glucagon-like peptide-1 (GLP-1) receptor represents a valuable target for the management of type 2 diabetes, based on its abilities to stimulate insulin, inhibit glucagon secretion in a glucose-depending manner, delay gastric emptying, and reduce energy intake with a low risk of hypoglycemia [1,2], and the potential for cardiovascular protection [3,4]. The first orally delivered GLP-1 analog in clinical development for the treatment of type 2 diabetes is based on semaglutide, a GLP-1 analog shown to be effective at improving glycemic control, reducing body weight, and potentially providing cardiovascular protection in patients with type 2 diabetes when administered subcutaneously [3,5,6]. Since the first oral glucagon-like peptide-1 analog comprises semaglutide co-formulated with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which induces a transient, localized increase in gastric pH, we have investigated whether a proton pump inhibitor affects the pharmacokinetics of oral semaglutide. Primary endpoints were area under the plasma concentration-time curve over 24 h for semaglutide (AUC0−24h,semaglutide,Day10) and maximum concentration of semaglutide (Cmax,semaglutide,Day10) at day
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