The lancet. Diabetes & endocrinologyJun 7, 2025

Weekly IcoSema compared to weekly insulin icodec for managing type 2 diabetes: results from a large, open trial

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

In a study involving 1291 participants, IcoSema resulted in a 1.55 percentage point reduction in HbA1c compared to a 0.89 percentage point reduction with icodec after 52 weeks.

IcoSema, a combination of basal insulin icodec and semaglutide, may provide greater efficacy in reducing HbA1c levels than icodec alone.
The estimated treatment difference for HbA1c change was -0.66 percentage points, indicating IcoSema's superiority (p<0.0001).
Participants receiving IcoSema experienced a significantly lower rate of combined clinically significant or severe hypoglycaemia compared to those on icodec (0.14 vs 0.63 episodes per person-year).
Gastrointestinal disorders were the most common adverse events reported in the IcoSema group, while infections were more prevalent in the icodec group.
Serious adverse events occurred in 9% of participants in the IcoSema group and 11% in the icodec group, with no treatment-related deaths reported.

Simplified

BACKGROUND: IcoSema is a once‑weekly combination therapy of basal insulin icodec (icodec) and semaglutide (a GLP‑1 analogue) currently in development. COMBINE 1 compared the efficacy and safety of IcoSema with once‑weekly icodec alone in adults with inadequately controlled type 2 diabetes on daily basal insulin therapy.

METHODS: COMBINE 1, a 52‑week, open‑label, treat‑to‑target, randomised, phase 3a trial, was done at 192 outpatient clinics and hospital departments across 20 countries and regions. Individuals aged 18 years or older with a BMI of 40 kg/mor less and type 2 diabetes (HbA7·0-10·0% [53·0-85·8 mmol/mol]) treated with daily basal insulin with or without oral glucose‑lowering medications were randomly assigned (1:1) via a randomisation and trial supply management system to IcoSema (700 U/mL plus 2 mg/mL) or icodec (700 U/mL), both administered as subcutaneous injections on the same day each week, at any time of the day. There was no stratification based on participants' baseline characteristics. The primary endpoint was change in HbAfrom baseline to week 52, evaluated in the full analysis set (all randomly assigned participants). The trial is registered with ClinicalTrials.gov, NCT05352815, and has been completed. 2 1c1c

FINDINGS: Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60·6 years [SD 10·3]; 799 [62%] males and 492 [38%] females) were randomly assigned to IcoSema (n=646) or icodec (n=645). At week 52, from a baseline value of 8·22% (SD 0·83; 66·3 mmol/mol [9·1]), estimated mean change in HbAwas -1·55 percentage points (SE 0·03; -16·9 mmol/mol [0·4]) with IcoSema and -0·89 percentage points (SE 0·03]; -9·7 mmol/mol [0·4]) with icodec (estimated treatment difference [ETD] -0·66 percentages points [95% CI -0·76 to -0·57]; -7·3 mmol/mol [-8·3 to -6·2]; p<0·0001; superiority confirmed). The rate of combined clinically significant or severe hypoglycaemia from baseline to week 57 was significantly lower with IcoSema than with icodec (0·14 vs 0·63 episodes per person‑year of exposure; estimated rate ratio 0·22 [95% CI 0·14 to 0·36]; p<0·0001; superiority confirmed). The most frequently reported adverse events were within the system organ class of gastrointestinal disorders in the IcoSema group (303 [47%] of 644 participants had 1033 events during the trial) and infections and infestations in the icodec group (275 [43%] of 644 participants had 466 events. 59 (9%) participants in the IcoSema group and 69 (11%) participants in the icodec group had a serious adverse event. No treatment-related deaths occurred. 1c

INTERPRETATION: In adults with inadequately controlled type 2 diabetes on daily basal insulin therapy, once‑weekly IcoSema showed superiority to once-weekly icodec alone in changes in HbAand in overall lower rate of combined clinically significant or severe hypoglycaemia. IcoSema might provide an option for insulin therapy intensification in adults with type 2 diabetes. 1c

FUNDING: Novo Nordisk.

TRANSLATIONS: For the Chinese and Japanese translations of the abstract see Supplementary Materials section.

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Declaration of interests CM serves or has served on advisory panels for Abbott, Bayer, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Insulet, Medtronic, Novartis, Novo Nordisk, Roche, SAB Bio, Sanofi, and Vertex (financial compensation paid to institution); has received research support to institution from ActoBio Therapeutics, Medtronic, Novo Nordisk, and Sanofi; serves or has served on speaker bureaus for Abbott, Dexcom, Eli Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Vertex (financial compensation paid to institution); and is President of the European Association for the Study of Diabetes (EASD; all external support from EASD is to be found on www.easd.org) and Vice-President of the European Diabetes Forum. FG has received grants from Eli Lilly and Roche Diabetes Care; consulting fees from Eli Lilly and Novo Nordisk; support for attending meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, LifeScan, Merck Sharp & Dohme, Medtronic, Novo Nordisk, Roche Diabetes Care, and Sanofi Aventis; serves or has served on advisory panels for AstraZeneca, Biomea, Boehringer Ingelheim, Eli Lilly, LifeScan, Merck Sharp & Dohme, MedImmune, Medtronic, Novo Nordisk, Roche Diabetes Care, and Sanofi Aventis; has had unpaid leadership roles at EASD/EFSD, Società Italiana di Endocrinologia (SIE), and FO.Ri.SIE; and has received support for medical writing and statistical analysis from AstraZeneca, Biomea, Eli Lilly, Novo Nordisk, and Sanofi Aventis. SGK has received consulting fees and honoraria from AstraZeneca, Boehringer Ingelheim, Celltrion, Eli Lilly, Novo Nordisk, and Sanofi; and grants for medical research from Abbott, AstraZeneca, Boehringer Ingelheim, Celltrion, and Viatris. JHL, TMPR, and VBS are employees of Novo Nordisk and hold stock options in Novo Nordisk. AP-T provides consultation and advisory services on behalf of her employer Scripps Health for Dexcom, Eli Lilly, Medtronic, and Novo Nordisk; has received honoraria and support for presentations and travel or attendance to meetings from Corcept, Dexcom, Eli Lilly, and Novo Nordisk; and participated on behalf of her employer Scripps Health on an advisory board for Medtronic. YT has received consulting or lecture fees from Astellas Pharma, AstraZeneca, Eli Lilly Japan, Kowa Company, Mitsubishi Tanabe Pharma, MSD, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Sanofi, and Sumitomo Pharma; and grants from Nippon, Boehringer Ingelheim, and Sumitomo Pharma. LJ has received consulting fees or honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Fosun Pharma, Gan & Lee Pharmaceuticals, Innovent Biologics, MSD, Novo Nordisk, and Sanofi-Aventis; and has served on advisory panels for Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Fosun Pharma, Haisco Pharmaceutical, Innovent Biologics, Merck, MSD, Novo Nordisk, Sanofi Aventis, Sibionics, and Sinocare. AR declares no competing interests.

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Weekly IcoSema compared to weekly insulin icodec for managing type 2 diabetes: results from a large, open trial

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