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An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes

Geremia B. Bolli Orcid Logo, Francesca Porcellati, Paola Lucidi, Carmine G. Fanelli Orcid Logo, Gianluca Perseghin, Michael Horowitz, David Owens Orcid Logo

Diabetes, Obesity and Metabolism, Volume: 27, Issue: S7, Pages: 14 - 25

Swansea University Author: David Owens Orcid Logo

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DOI (Published version): 10.1111/dom.16616

Abstract

Advancing therapy in T2DM with injectables, i.e., basal insulin (BI) and GLP-1 receptor agonists (GLP-1RAs) is recommended after the failure of oral glucose lowering agents (OGLAs), BI alone, or BI in combination with OGLAs, especially in persons with, or at high risk of atherosclerotic cardiovascul...

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Published in: Diabetes, Obesity and Metabolism
ISSN: 1462-8902 1463-1326
Published: Wiley 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70950
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last_indexed 2025-11-22T05:32:24Z
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BI and GLP-1RAs can be administered separately or as fixed-ratio combinations (FRCs) for daily use (degludec+liraglutide, IDegLira, glargine-100&#x2009;+&#x2009;lixisenatide iGlarLixi) or weekly use (icodec+semaglutide, IcoSema). The currently available FRCs IDegLira and iGlarLixi differ in their respective BI as well as GLP-1RA components. Liraglutide predominantly stimulates glucose-dependent endogenous insulin secretion in response to nutrient challenges. In contrast, the rapid-acting lixisenatide primarily delays gastric emptying over a few hours post-dosing with little or no impact on insulin secretion. IDegLira in DUAL studies and iGlarLixi in LixiLan studies appear to have equivalent lowering effects on HbA1c, although IDegLira achieves a greater reduction in body weight. The weekly FRC IcoSema is superior to weekly insulin icodec (COMBINE 1), to semaglutide (COMBINE 2), and non-inferior to basal-bolus insulin therapy (COMBINE 3). Comparison of IcoSema with glargine-100 is ongoing (COMBINE 4). However, all FRCs are limited by the low GLP-1RA dose relative to the insulin delivered. 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spelling 2025-11-21T15:51:13.5726974 v2 70950 2025-11-20 An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes 2fd4b7c3f82c6d3bd546eff61ff944e9 0000-0003-1002-1238 David Owens David Owens true false 2025-11-20 MEDS Advancing therapy in T2DM with injectables, i.e., basal insulin (BI) and GLP-1 receptor agonists (GLP-1RAs) is recommended after the failure of oral glucose lowering agents (OGLAs), BI alone, or BI in combination with OGLAs, especially in persons with, or at high risk of atherosclerotic cardiovascular disease (ASCVD). BI and GLP-1RAs can be administered separately or as fixed-ratio combinations (FRCs) for daily use (degludec+liraglutide, IDegLira, glargine-100 + lixisenatide iGlarLixi) or weekly use (icodec+semaglutide, IcoSema). The currently available FRCs IDegLira and iGlarLixi differ in their respective BI as well as GLP-1RA components. Liraglutide predominantly stimulates glucose-dependent endogenous insulin secretion in response to nutrient challenges. In contrast, the rapid-acting lixisenatide primarily delays gastric emptying over a few hours post-dosing with little or no impact on insulin secretion. IDegLira in DUAL studies and iGlarLixi in LixiLan studies appear to have equivalent lowering effects on HbA1c, although IDegLira achieves a greater reduction in body weight. The weekly FRC IcoSema is superior to weekly insulin icodec (COMBINE 1), to semaglutide (COMBINE 2), and non-inferior to basal-bolus insulin therapy (COMBINE 3). Comparison of IcoSema with glargine-100 is ongoing (COMBINE 4). However, all FRCs are limited by the low GLP-1RA dose relative to the insulin delivered. Whenever higher GLP-1RA doses are required (i.e., in obese people), the option of separate dosing of BI and GLP-1RA with independent titration of each component should be considered. Journal Article Diabetes, Obesity and Metabolism 27 S7 14 25 Wiley 1462-8902 1463-1326 basal insulin, fixed-ratio combinations basal insulin GLP-1RAs, GLP-1RA, type 2 diabetes 1 8 2025 2025-08-01 10.1111/dom.16616 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This article was funded in part by the University of Perugia and a private donation (F.D.), and did not receive any additional funding from the public, commercial, or not-for-profit sectors. G.P. is supported by MUR -PRIN, 2022KZ4KMY. 2025-11-21T15:51:13.5726974 2025-11-20T11:32:11.5327861 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Geremia B. Bolli 0000-0003-4966-4003 1 Francesca Porcellati 2 Paola Lucidi 3 Carmine G. Fanelli 0000-0003-4063-158x 4 Gianluca Perseghin 5 Michael Horowitz 6 David Owens 0000-0003-1002-1238 7 70950__35686__a6d59212fa3e4d8288582bd216af90e2.pdf 70950.VOR.pdf 2025-11-21T15:46:42.9241272 Output 1253774 application/pdf Version of Record true © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License. true eng http://creativecommons.org/licenses/by/4.0/
title An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
spellingShingle An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
David Owens
title_short An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
title_full An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
title_fullStr An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
title_full_unstemmed An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
title_sort An overview of randomized clinical trials of fixed-ratio combinations of basal insulin plus GLP-1RA (injectable therapy): Lessons for advancing therapy in people with type 2 diabetes
author_id_str_mv 2fd4b7c3f82c6d3bd546eff61ff944e9
author_id_fullname_str_mv 2fd4b7c3f82c6d3bd546eff61ff944e9_***_David Owens
author David Owens
author2 Geremia B. Bolli
Francesca Porcellati
Paola Lucidi
Carmine G. Fanelli
Gianluca Perseghin
Michael Horowitz
David Owens
format Journal article
container_title Diabetes, Obesity and Metabolism
container_volume 27
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container_start_page 14
publishDate 2025
institution Swansea University
issn 1462-8902
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doi_str_mv 10.1111/dom.16616
publisher Wiley
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
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description Advancing therapy in T2DM with injectables, i.e., basal insulin (BI) and GLP-1 receptor agonists (GLP-1RAs) is recommended after the failure of oral glucose lowering agents (OGLAs), BI alone, or BI in combination with OGLAs, especially in persons with, or at high risk of atherosclerotic cardiovascular disease (ASCVD). BI and GLP-1RAs can be administered separately or as fixed-ratio combinations (FRCs) for daily use (degludec+liraglutide, IDegLira, glargine-100 + lixisenatide iGlarLixi) or weekly use (icodec+semaglutide, IcoSema). The currently available FRCs IDegLira and iGlarLixi differ in their respective BI as well as GLP-1RA components. Liraglutide predominantly stimulates glucose-dependent endogenous insulin secretion in response to nutrient challenges. In contrast, the rapid-acting lixisenatide primarily delays gastric emptying over a few hours post-dosing with little or no impact on insulin secretion. IDegLira in DUAL studies and iGlarLixi in LixiLan studies appear to have equivalent lowering effects on HbA1c, although IDegLira achieves a greater reduction in body weight. The weekly FRC IcoSema is superior to weekly insulin icodec (COMBINE 1), to semaglutide (COMBINE 2), and non-inferior to basal-bolus insulin therapy (COMBINE 3). Comparison of IcoSema with glargine-100 is ongoing (COMBINE 4). However, all FRCs are limited by the low GLP-1RA dose relative to the insulin delivered. Whenever higher GLP-1RA doses are required (i.e., in obese people), the option of separate dosing of BI and GLP-1RA with independent titration of each component should be considered.
published_date 2025-08-01T05:32:48Z
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