Summary: In this post hoc analysis of the randomised ONWARDS 1-5 trials (n=3765 adults with type 2 diabetes), once-weekly insulin icodec showed no statistically significant treatment interactions with baseline GLP-1 receptor agonist or SGLT2 inhibitor use across HbA1c change, body weight, basal insulin dose, or the composite of HbA1c below 7% without significant or severe hypoglycaemia (with minor ONWARDS 5 exceptions). The efficacy and hypoglycaemia profile of icodec versus once-daily basal insulin was generally consistent regardless of background therapy; this is a subgroup-consistency finding, not evidence of icodec superiority.
PICO Summary
| Element | Detail |
|---|---|
| Population | 3765 adults with type 2 diabetes pooled across the randomised ONWARDS 1-5 trials (post hoc analysis). At screening, 21.3% (801/3765) were on a GLP-1 receptor agonist and 36.9% (1388/3765) on an SGLT2 inhibitor. Multinational. |
| Intervention | Once-weekly insulin icodec, analysed within each trial by baseline GLP-1RA and/or SGLT2i subgroup. |
| Comparison | Once-daily basal insulin comparators (insulin glargine U100 or insulin degludec), per the originating ONWARDS trial. |
| Outcome | No statistically significant treatment-by-subgroup interactions for change in HbA1c, change in body weight, last-2-weeks weekly basal insulin dose, or achievement of HbA1c below 7% without clinically significant or severe hypoglycaemia, by GLP-1RA or SGLT2i use (exceptions: body weight change and basal insulin dose by SGLT2i use in ONWARDS 5). Rates of clinically significant or severe hypoglycaemia were below one episode per patient-year across all trials except ONWARDS 4 (the basal-bolus trial). The analysis reports interaction tests rather than between-drug effect estimates with 95% CIs or ARR/NNT, so no pooled superiority effect size is available. |
Expert Commentary
This is a reassuring but modest piece of evidence, and it should be read as such. The analysis was designed to ask whether the behaviour of once-weekly icodec relative to once-daily basal insulin is modified by whether a patient is already taking a GLP-1 receptor agonist or an SGLT2 inhibitor, and the answer is largely no. Across the ONWARDS 1-5 trials the treatment-by-subgroup interactions were not statistically significant for glycaemic control, body weight, insulin dose, or the hypoglycaemia-adjusted glycaemic target, apart from two body-weight and dose signals confined to ONWARDS 5. The verdict is that background incretin or SGLT2 therapy does not appear to materially change how icodec performs. It is important not to over-read this. A post hoc subgroup analysis cannot establish that icodec is superior to daily insulin, and the absence of an interaction is not the same as a demonstrated benefit; it simply means the effect was consistent. The single most important limitation is that this is an exploratory, underpowered subgroup exercise pooled across heterogeneous trial designs, so null interactions may reflect limited power rather than true uniformity. The study was funded by the manufacturer and several authors are employees, which warrants the usual caution. Can I use this with my patients? Yes, in a narrow sense: for an adult with type 2 diabetes already on a GLP-1RA or SGLT2 inhibitor for whom weekly basal insulin is being considered, this supports expecting similar performance to the parent trials. Clinicians should still anchor decisions to the primary ONWARDS results and individual hypoglycaemia risk.
References
Vilsbøll T, Fu A, Kellerer M, Kumar B, Søgaard SB, Goldenberg R. Efficacy and hypoglycaemia outcomes with once-weekly insulin icodec versus once-daily basal insulin in type 2 diabetes according to baseline glucagon-like peptide-1 receptor agonist and sodium-glucose co-transporter-2 inhibitor use: A post hoc analysis of ONWARDS 1-5. Diabetes Obes Metab. 2025;27(6):3165-3175. doi:10.1111/dom.16328
