Weekly Semaglutide-Insulin Icodec Combination Improves Glycemic Control and Weight in Diabetes Patients: Study
China: A 40-week Phase 3b trial published in The Lancet Diabetes & Endocrinology has revealed that once-weekly semaglutide combined with basal insulin icodec achieved greater reductions in HbA1c and body weight, with less hypoglycemia, compared with daily insulin glargine in patients with type 2 diabetes receiving oral glucose-lowering medications.
The COMBINE 4 trial, led by Prof Linong Ji, Department of Endocrinology and Metabolism, Peking University Diabetes Centre, Peking University People's Hospital, Beijing, China, and colleagues, evaluated the efficacy and safety of IcoSema, a once-weekly fixed-ratio combination of insulin icodec and the GLP-1 receptor agonist semaglutide, against once-daily insulin glargine U100.
Treatment intensification is commonly required when oral glucose-lowering medicines fail to adequately control type 2 diabetes. Combining a GLP-1 receptor agonist with basal insulin may improve glycaemic control while limiting weight gain and hypoglycemia. The trial assessed whether this approach delivered better outcomes than basal insulin alone.
COMBINE 4 was a multicentre, open-label, treat-to-target, randomised Phase 3b study conducted at 97 sites across nine countries. Adults with type 2 diabetes, HbA1c of at least 8.0%, and inadequate control despite oral glucose-lowering therapy were randomly assigned to once-weekly IcoSema or once-daily glargine U100. Both treatments were titrated toward a fasting glucose target of 70–90 mg/dL.
A total of 485 participants were randomised, including 243 assigned to IcoSema and 242 to glargine U100. The median participant age was 58 years, and 59% were men.
The results showed:
- HbA1c declined by 3.32 percentage points with IcoSema versus 2.44 percentage points with glargine U100 at week 40, producing a treatment difference of −0.88 percentage points.
- Body weight decreased by 0.79 kg with IcoSema but increased by 3.81 kg with glargine U100, with an estimated treatment difference of −4.61 kg.
- Clinically significant or severe hypoglycemia occurred at 0.29 versus 0.59 episodes per person-year, respectively, corresponding to a rate ratio of 0.56.
- Gastrointestinal disorders were the most commonly reported adverse events among participants receiving IcoSema.
The findings indicate that once-weekly IcoSema provided greater improvements in glycaemic control and body weight while reducing clinically significant or severe hypoglycemia compared with daily insulin glargine.
The researchers suggested that IcoSema could represent a useful once-weekly option for insulin-naive adults with type 2 diabetes inadequately controlled on oral glucose-lowering therapies, although longer-term evidence will be important to further assess its safety and clinical benefits.
Reference:
Ji, L., Benamar, M., Mohan, V., Pletsch-Borba, L., Porcellati, F., Wang, N., Watada, H., & Rea, R. R. (2026). 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, 14(10), 831-840. https://doi.org/10.1016/S2213-8587(26)00136-1
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