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.

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