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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
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 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.
Keywords: basal insulin, fixed-ratio combinations basal insulin GLP-1RAs, GLP-1RA, type 2 diabetes
College: Faculty of Medicine, Health and Life Sciences
Funders: 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.
Issue: S7
Start Page: 14
End Page: 25

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