- Design
- Phase 3b, randomised, open-label, treat-to-target, 40 weeks
- Population
- 485 insulin-naive adults with type 2 diabetes, HbA1c ≥8% on oral drugs
- Primary outcome
- HbA1c change at week 40
- Effect
- −3.32 vs −2.44 points; difference −0.88 (95% CI −1.12 to −0.63)
COMBINE 4, published in August, was a 40-week open-label, treat-to-target phase 3b trial at 97 sites in nine countries. It randomised 485 insulin-naive adults with type 2 diabetes and HbA1c of 8% or more on oral drugs to once-weekly IcoSema — a fixed combination of insulin icodec and semaglutide — or once-daily insulin glargine U100.
From a baseline HbA1c of about 9.5%, IcoSema lowered it by 3.32 points against 2.44 with glargine, a difference of 0.88 points. Weight fell by 0.8 kg with IcoSema and rose by 3.8 kg with glargine, a 4.6 kg difference. Clinically significant or severe hypoglycaemia was lower (0.29 vs 0.59 episodes per person-year). Gastrointestinal effects were the commonest adverse events. The trial was industry funded.
For a patient who would otherwise start basal insulin and gain weight, one weekly injection that does better on glucose, weight and hypoglycaemia is a real change in what insulin initiation can look like. Its licensing and availability vary; its status in India is not established here.
- Consider a basal insulin–GLP-1 combination rather than basal insulin alone when starting injectables.
- Expect gastrointestinal effects in the early weeks and warn patients about them.
- Check the product's local licensing and cost before discussing it with patients.
- Keep titration to fasting glucose as with any basal insulin.
Why it matters
Starting insulin no longer has to mean accepting weight gain and more hypoglycaemia.
Don't overread it
The trial was open-label and compared against glargine alone, not against glargine plus a separate GLP-1 receptor agonist.
The statistics, in plain English
A 0.88-point HbA1c difference is clinically meaningful, and its interval (−1.12 to −0.63) is well clear of zero. The hypoglycaemia rate ratio of 0.56 has an upper bound of 0.97, close to 1, so that benefit is less certain than the glucose and weight results.
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