A single weekly injection combining insulin icodec with semaglutide lowered blood sugar significantly more than semaglutide alone in 683 type 2 diabetes patients, but with less weight loss.
-1.35% vs -0.90% HbA1cIcoSema combination vs semaglutide alone over 52 weeks in a 683-patient Phase IIIa trial (p<0.0001)
What the researchers found
Once-weekly IcoSema (combining insulin icodec and semaglutide in a single injection) demonstrated superior HbA1c reduction compared to semaglutide alone over 52 weeks: -1.35% vs -0.90% (treatment difference -0.44%, p<0.0001). IcoSema also produced significantly greater fasting glucose reduction (-2.48 vs -1.43 mmol/L). However, semaglutide alone was significantly better for weight: -3.70 kg vs +0.84 kg with IcoSema. Rates of clinically significant hypoglycemia and gastrointestinal side effects were similar between groups.
Why it matters
Many type 2 diabetes patients on GLP-1 receptor agonists still don't achieve adequate blood sugar control and need insulin added. IcoSema combines both peptide drugs into a single weekly injection, simplifying treatment while delivering superior glucose control. The trade-off — less weight loss than semaglutide alone — reflects the insulin component but the convenience of one injection could improve patient adherence.
The numbers in context
n=683 · 52 weeks · HbA1c: -1.35% vs -0.90% (p<0.0001) · fasting glucose: -2.48 vs -1.43 mmol/L · weight: +0.84 kg vs -3.70 kg · 121 sites · 13 countries · similar hypoglycemia rates
How the study worked
Phase IIIa, 52-week, randomized, open-label, parallel-group trial across 121 sites in 13 countries. 683 adults with type 2 diabetes (HbA1c 7.0-10.0%) inadequately managed on GLP-1 RA therapy were randomized 1:1 to once-weekly IcoSema or semaglutide 1.0 mg. Primary endpoint: change in HbA1c at week 52 with superiority testing. Secondary endpoints: fasting glucose, body weight, and hypoglycemia rates.
Who was studied
683 adults with type 2 diabetes (mean HbA1c 8.0%, BMI 31.1, diabetes duration 12.6 years) inadequately managed on GLP-1 RA therapy
What this study cannot tell us
Open-label design means participants and investigators knew which treatment they received, potentially introducing bias. Funded by Novo Nordisk (manufacturer). The weight gain with IcoSema vs weight loss with semaglutide alone may limit its appeal. Semaglutide 1.0 mg comparator is not the highest available dose (2.4 mg for weight management).
How to read the evidence
This is a large Phase IIIa randomized clinical trial with 683 participants across 121 sites in 13 countries — high-quality clinical evidence. The open-label design is a minor limitation, but the objective primary endpoint (HbA1c) and large sample size provide strong confidence in the results.
When this study was published
Published in 2025 and registered on ClinicalTrials.gov (NCT05259033). This is part of the COMBINE clinical trial program that will determine whether IcoSema receives regulatory approval.
The bigger picture
The diabetes treatment landscape is rapidly evolving toward simplified, less frequent injections. IcoSema represents the convergence of two major peptide drug innovations — once-weekly basal insulin and GLP-1 receptor agonists — into a single product. If approved, it would give patients who need both therapies the convenience of one weekly injection instead of daily insulin plus separate GLP-1 treatment, though the weight trade-off will factor into prescribing decisions.
Questions still open
- Would combining insulin icodec with higher-dose semaglutide (2.0 or 2.4 mg) offset the weight gain while maintaining the glucose benefits?
- How does IcoSema compare to other fixed-ratio insulin/GLP-1 combinations like iDegLira (Xultophy) in real-world practice?
- Will the weight gain associated with IcoSema versus semaglutide alone limit its adoption given the current emphasis on weight management in diabetes care?
Common questions
What is IcoSema and how is it different from taking semaglutide and insulin separately?
Why did patients on IcoSema gain weight while those on semaglutide alone lost weight?
Read the original research
Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.
Diabetologia, 68(4), 739-751
Citation
Lingvay, Ildiko; Benamar, Malik; Chen, Liming; Fu, Ariel; Jódar, Esteban; Nishida, Tomoyuki; Riveline, Jean-Pierre; Yabe, Daisuke; Zueger, Thomas; Réa, Rosângela. (2025). Once-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.. Diabetologia, 68(4), 739-751. https://doi.org/10.1007/s00125-024-06348-5