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Introduction: Insulin icodec is a basal insulin designed for once-weekly administration. This study assessed the pharmacological properties of icodec in Japanese individuals with type 1 diabetes (T1D)., Materials and Methods: In a randomized, open-label, crossover study, 24 Japanese individuals with T1D (20-64 years; glycated hemoglobin ≤9.0%) received once-weekly icodec for 8 weeks and once-daily insulin glargine U100 for 14 days at individual constant equimolar doses per week together with bolus insulin aspart. Individual doses were determined during run-in with glargine U100 titrated to prebreakfast self-measured plasma glucose (SMPG) of 4.4-7.2 mmol/L. Blood samples for icodec pharmacokinetics were taken from the first icodec dose until 35 days after last dose. The steady-state glucose-lowering effect was measured in glucose clamps (target 6.7 mmol/L) during 24-48 h and 150-168 h after last icodec dose and 0-24 h after last glargine U100 dose. One-week glucose-lowering effect of icodec was simulated using a pharmacokinetic/pharmacodynamic model. Hypoglycemia was identified from SMPG during the treatment periods., Results: Icodec pharmacokinetic steady state was achieved on average after 2-3 weeks of treatment. Model-derived daily glucose-lowering effect during the weekly dosing interval averaged 14.6%, 18.0%, 16.6%, 14.9%, 13.3%, 11.9%, and 10.7%, respectively. Rates of level 2 hypoglycemia (PG <3.0 mmol/L) were 37.3 vs 30.6 episodes per patient-year of exposure for icodec vs glargine U100., Discussion: Icodec pharmacological properties in Japanese individuals with T1D in this study support the potential of icodec to provide basal insulin coverage with once-weekly dosing in Japanese individuals with diabetes., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Insulin icodec (icodec), a once-weekly basal insulin analog, has been investigated in the phase 3a ONWARDS clinical trial program. This pharmacokinetic (PK)/pharmacodynamic (PD) modeling analysis of data from the ONWARDS 2 and 4 trials investigated efficacy outcomes and hypoglycemia rate in insulin-experienced individuals with type 2 diabetes when switching from daily basal insulin to icodec without or with a 50% one-time additional dose for the first injection only., Methods: Data from 2 randomized, 26-week, phase 3a trials of insulin-experienced individuals with type 2 diabetes on a basal (ONWARDS 2) or basal-bolus (ONWARDS 4) insulin regimen were used for PK/PD model development and validation. The effect of switching to icodec without versus with a 50% one-time additional dose on prebreakfast self-measured blood glucose, glycated hemoglobin, weekly insulin dose, and clinically significant hypoglycemia was assessed., Results: Model predictions suggested that switching to icodec without versus with a 50% one-time additional dose would result in a mild, transient (1-2 weeks) increase in prebreakfast self-measured blood glucose after treatment initiation that would decrease to matching levels between groups by week 4 and remain similar between groups until end of treatment (week 26). There were no model-predicted differences between groups in glycated hemoglobin reduction or clinically significant hypoglycemia over the 26-week study period or in weekly icodec dose at week 26., Conclusions: This PK/PD model analysis suggests that omitting administration of a 50% one-time additional dose when switching to icodec from daily basal insulin would not be predicted to result in any sustained effects., Competing Interests: Disclosure I.L. has received research funding (paid to the institution they are affiliated with) from Boehringer Ingelheim, Merck, Mylan, Novo Nordisk, Pfizer, and Sanofi, and has received advisory/consulting fees and/or other support from AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GI Dynamics, Intarcia Therapeutics, Intercept Pharmaceuticals, Johnson & Johnson, MannKind, Merck, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Shionogi, Structure Therapeutics, Target Pharma, Valeritas, and Zealand Pharma. B.Á., N.R.K., C.L., and F.K.K. are employees and shareholders of Novo Nordisk. A.V. has received fees for activities as an advisory board member for Abbott Diabetes Care, AstraZeneca, Eli Lilly, Medtronic, and Novo Nordisk; has carried out speaker activities for Abbott Diabetes Care, AstraZeneca, Eli Lilly, Medtronic, Novo Nordisk, and Roche; and has research grants from Anji Pharmaceuticals, Eli Lilly, and Novo Nordisk. I.L., A.V., and F.K.K. have received consultancy fees from Novo Nordisk. I.L. and A.V. have received grants from Novo Nordisk during the conduct of the ONWARDS 3 trial., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)