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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Article Source : The Lancet Diabetes & Endocrinology

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Medha Baranwal

Medha Baranwal holds a Bachelor’s degree in Biomedical Sciences from the University of Delhi and a Master’s degree in Biotechnology from Amity University. Since May 2018, she has been contributing to Medical Dialogues, writing and editing medical news articles that translate complex research into clear, accessible information for healthcare professionals.

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