Once-weekly IcoSema versus once-weekly insulin icodec in type 2 diabetes management (COMBINE 1): an open-label, multicentre, treat-to-target, randomised, phase 3a trial

초록

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/m(2) or less and type 2 diabetes (HbA(1c) 7<middle dot>0-10<middle dot>0% [53<middle dot>0-85<middle dot>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 HbA(1c) from 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. Findings Between June 1, 2022, and March 13, 2023, 1671 individuals were screened, of whom 1291 (mean age 60<middle dot>6 years [SD 10<middle dot>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<middle dot>22% (SD 0<middle dot>83; 66<middle dot>3 mmol/mol [9<middle dot>1]), estimated mean change in HbA(1c) was -1<middle dot>55 percentage points (SE 0<middle dot>03; -16<middle dot>9 mmol/mol [0<middle dot>4]) with IcoSema and -0<middle dot>89 percentage points (SE 0<middle dot>03]; -9<middle dot>7 mmol/mol [0<middle dot>4]) with icodec (estimated treatment difference [ETD] -0<middle dot>66 percentages points [95% CI -0<middle dot>76 to -0<middle dot>57]; -7<middle dot>3 mmol/mol [-8<middle dot>3 to -6<middle dot>2]; p<0<middle dot>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<middle dot>14 vs 0<middle dot>63 episodes per person-year of exposure; estimated rate ratio 0<middle dot>22 [95% CI 0<middle dot>14 to 0<middle dot>36]; p<0<middle dot>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. 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 HbA(1c) and 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. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

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