Icodec-Semaglutide Combo Outperforms Glargine in T2D

Combining a once-weekly basal insulin with a once-weekly GLP-1 receptor agonist is emerging as a strategy to simplify regimens while improving glycemic and weight outcomes in type 2 diabetes (T2D). New phase 3 data on insulin icodec co-formulated with semaglutide (icosema) suggest the approach may outperform traditional basal insulin titration, adding to a growing list of insulin-incretin combinations following degludec-liraglutide and glargine-lixisenatide.

On a recent episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, reviewed findings from COMBINE 4, a 40-week randomized, open-label, treat-to-target trial in adults with T2D and baseline A1C >8%. Participants received either icosema (n = 243) or once-daily insulin glargine U100 (n = 242), with both arms titrated to a fasting glucose target of 70-90 mg/dL.

Watch the full episode discussing IcoSema here.

A1C fell by 3.32 percentage points with icosema, from a baseline of 9.57%, compared with a 2.44-point reduction with glargine, a between-group difference of 0.88%. Body weight decreased by 0.79 kg in the icosema arm, while the glargine group gained 3.81 kg, a difference of 4.61 kg favoring the combination. Continuous glucose monitoring data also showed 79.8% time in range with icosema versus 64.5% with glargine, a gap the hosts noted is clinically meaningful given that even a 5% improvement in time in range has been associated with reduced complication risk.

The hosts attributed the advantage to the pairing's complementary mechanisms. Semaglutide slows gastric emptying and stimulates endogenous insulin secretion in response to rising glucose, blunting postprandial excursions that often require basal insulin over-titration, a pattern linked to hypoglycemia and weight gain with glargine monotherapy. Earlier trials in the COMBINE program reinforced this signal: COMBINE 1 and 3 showed icosema was superior or non-inferior to icodec alone or basal-bolus therapy for A1C, with superior weight reduction and significantly lower hypoglycemia, while COMBINE 2 demonstrated superior A1C reduction over semaglutide 1.0 mg alone in insulin-naive patients already on GLP-1 therapy.

Beyond efficacy, the hosts pointed to practical advantages of a fixed-ratio, once-weekly formulation, including simplified titration and the single-copay structure that has made similar combination products like glargine-lixisenatide and degludec-liraglutide more accessible. They cautioned that, as with any fixed-ratio product, clinicians lose the ability to titrate each component independently, a trade-off that will factor into patient selection.

Collectively, the COMBINE program data position icosema as a candidate to consolidate weekly GLP-1 and basal insulin therapy into a single injection, potentially improving both glycemic control and adherence compared with separately administered regimens.

Editors’ Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.

References

1. Ji L, Benamar M, Mohan V, et al. Once-weekly ICOSEMA versus once-daily insulin glargine U100 in type 2 diabetes management (Combine 4): An open-label, multicentre, treat-to-target, randomised, phase 3B trial. The Lancet Diabetes & Endocrinology. Published online August 13, 2026. doi:10.1016/s2213-8587(26)00136-1