Summary: In the phase 3a COMBINE 1 trial in inadequately controlled type 2 diabetes on basal insulin, once-weekly IcoSema (insulin icodec plus semaglutide) lowered HbA1c significantly more than icodec alone and cut clinically significant or severe hypoglycemia by nearly 80%.
PICO Summary
| Element | Detail |
|---|---|
| Population | 1291 adults with type 2 diabetes (HbA1c 7.0–10.0%) on daily basal insulin; 192 sites across 20 countries. |
| Intervention | Once-weekly IcoSema (insulin icodec 700 U/mL plus semaglutide 2 mg/mL) for 52 weeks (n=646). |
| Comparison | Once-weekly insulin icodec alone (n=645); treat-to-target. |
| Outcome | HbA1c fell -1.55 vs -0.89 percentage points (ETD -0.66; 95% CI -0.76 to -0.57; p<0.0001, superiority). Clinically significant or severe hypoglycemia 0.14 vs 0.63 episodes/person-year (rate ratio 0.22; p<0.0001). Gastrointestinal events more common with IcoSema; no treatment-related deaths. |
COMBINE 1: IcoSema vs insulin icodec
RCT · type 2 diabetes · 52 weeks
Once-weekly IcoSema lowered HbA1c more than icodec alone and cut clinically significant or severe hypoglycemia by nearly 80%, at the cost of more gastrointestinal events.
Expert Commentary
This is a genuinely useful phase 3 result, and I read it positively. Combining a once-weekly basal insulin with semaglutide in a single weekly injection is an appealing way to intensify therapy, and the trial delivered on both axes that matter: meaningfully greater HbA1c reduction and, importantly, a large fall in clinically significant or severe hypoglycemia, the usual price of insulin intensification. That the GLP-1 component appears to offset insulin’s hypoglycemia risk while improving glucose is exactly the synergy one hopes for, and weekly dosing genuinely eases burden. My caveats are measured. The trial is open-label, which can influence titration behaviour, the active comparator was icodec alone rather than a GLP-1-plus-insulin regimen that many would already use, and gastrointestinal side effects were predictably more frequent with the combination. Can I use this with my patients? Yes, prospectively, once available and approved. For a patient on basal insulin who is above target and would benefit from a GLP-1 agonist’s weight and hypoglycemia advantages, a single weekly combination injection is an attractive intensification option, with the usual counselling on gastrointestinal tolerability during titration.
References
Mathieu C, Giorgino F, Kim SG, et al. Once-weekly IcoSema versus once-weekly insulin icodec in type 2 diabetes management (COMBINE 1): an open-label, multicentre, treat-to-target, randomised, phase 3a trial. Lancet Diabetes Endocrinol. 2025;13(7):568–579. doi:10.1016/S2213-8587(25)00096-8