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

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.