Effect of Oral Semaglutide on the Pharmacokinetics of Lisinopril, Warfarin, Digoxin, and Metformin in Healthy Subjects

Abstract

Background Oral semaglutide is a tablet co-formulation of the human glucagon-like peptide-1 (GLP-1) analog semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). The absorption of coadministered oral drugs may be altered due to enhancement by SNAC, potential gastric emptying delay by semaglutide, or other mechanisms. Two one-sequence crossover trials investigated the effect of oral semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin. Methods In trial 1, 52 healthy subjects received lisinopril (20 mg single dose) or warfarin (25 mg single dose) with subsequent coadministration with SNAC alone (300 mg single dose), followed by oral semaglutide 20 mg once daily (steady state). In trial 2, 32 healthy subjects received digoxin (500 μg single dose) or metformin (850 mg twice daily for 4 days), with subsequent coadministration with SNAC alone followed by oral semaglutide, as in trial 1. Results There were no apparent effects of oral semaglutide on area under the plasma concentration–time curve (AUC) and maximum plasma concentration ( C max ) for lisinopril, warfarin, and digoxin. The AUC of metformin was increased by 32% (90% confidence interval 1.23–1.43) by oral semaglutide coadministration versus metformin alone, whereas the C max was unaffected. SNAC alone did not affect exposure of lisinopril, warfarin, digoxin, or metformin. Adverse events were in line with those previously observed for GLP-1 receptor agonists. Conclusions Oral semaglutide or SNAC alone did not appear to affect the exposure of lisinopril, warfarin, or digoxin, and, based on its wide therapeutic index, the higher metformin exposure with oral semaglutide was not considered clinically relevant. Electronic supplementary material The online version of this article (10.1007/s40262-019-00756-2) contains supplementary material, which is available to authorized users.

Oral Semaglutide: First-in-Class Oral GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes Mellitus

“…Absorption of concomitantly administered oral medications may be decreased because oral semaglutide delays gastric emptying. 4,9 Drugs that have a narrow therapeutic index may require increased clinical or laboratory monitoring when used in combination with oral semaglutide. 4,9,10 In one study, levothyroxine exposure increased by 33% (90% CI: 125-142) when administered with oral semaglutide.…”

“…4,9 Drugs that have a narrow therapeutic index may require increased clinical or laboratory monitoring when used in combination with oral semaglutide. 4,9,10 In one study, levothyroxine exposure increased by 33% (90% CI: 125-142) when administered with oral semaglutide. 10 There is currently no guidance on recommendations for administering these medications in practice, and this may present a challenge for patients currently taking levothyroxine because it has similar administration considerations.…”

“…11 On the other hand, omeprazole, lisinopril, warfarin, metformin, digoxin, ethinyl estradiol/levonorgestrel, rosuvastatin, and furosemide were evaluated for drug-drug interactions, and none of these agents affected semaglutide concentrations. 9,[12][13][14]…”

A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus

“…Omeprazole, lisinopril, warfarin, metformin, digoxin, the combined oral contraceptive ethinyl estradiol/levonorgestrel, rosuvastatin and furosemide have all been evaluated for drug interactions with semaglutide. None of these agents significantly affected orally administered semaglutide concentrations [ 34 ].…”

Integrating oral semaglutide into clinical practice in primary care: for whom, when, and how?

“…taking oral semaglutide prior to other oral medications and waiting at least 30 minutes before taking any other oral medications) [9]. Pharmacokinetic drug-drug interaction studies suggest no clinically relevant interactions or need for dose adjustment for patients receiving commonly used medications including omeprazole, lisinopril, warfarin, digoxin, metformin, furosemide, rosuvastatin, or the combined oral contraceptive ethinylestradiol/levonorgestrel [73][74][75][76]. When oral semaglutide is administered concomitantly with medications that have narrow therapeutic windows or that require clinical monitoring, increased clinical/laboratory monitoring should be considered [9].…”