Once-weekly insulin icodec versus once-daily insulin degludec as part of a basal-bolus regimen in individuals with type 1 diabetes (ONWARDS 6): a phase 3a, randomised, open-label, treat-to-target trial

Background ONWARDS 6 compared the efficacy and safety of once-weekly subcutaneous insulin icodec (icodec) and once-daily insulin degludec (degludec) in adults with type 1 diabetes. Methods This 52-week (26-week main phase plus a 26-week safety extension), randomised, open-label, treat-to-target, phase 3a trial was done at 99 sites across 12 countries. Adults with type 1 diabetes (glycated haemoglobin [HbA(1c)] <100% [86 mmol/mol]) were randomly assigned (1:1) to once-weekly icodec or once-daily degludec, both in combination with insulin aspart (two or more daily injections). The primary endpoint was change in HbA(1c) from baseline to week 26, tested for non-inferiority (03 percentage point margin) in all randomly assigned participants. This trial is registered with ClinicalTrials.gov, NCT04848480, and is now complete. Findings Between April 30 and Oct 15, 2021, of 655 participants screened, 582 participants were randomly assigned to icodec (n=290) or degludec (n=292). At week 26, from baseline values of 759% (icodec) and 763% (degludec), estimated mean changes in HbA(1c) were -047 percentage points and -051 percentage points, respectively (estimated treatment difference 005 percentage points [95% CI -013 to 023]), confirming non-inferiority of icodec to degludec (p=00065). Overall rate of combined clinically significant or severe hypoglycaemia (baseline to week 26) was statistically significantly higher with icodec than degludec (199 vs 104 events per patient-year of exposure; estimated rate ratio 19 [95% CI 15 to 23]; p<00001). The rate was also statistically significantly higher with icodec than degludec when evaluated over 57 weeks (52 weeks plus a 5-week follow-up period). 39 serious adverse events were reported in 24 (8%) participants receiving icodec, and 25 serious adverse events were reported in 20 (7%) participants receiving degludec. One participant in the icodec group died; this was judged unlikely to be due to the trial product. Interpretation In adults with type 1 diabetes, once-weekly icodec showed non-inferiority to once-daily degludec in HbA(1c) reduction at week 26, with statistically significantly higher rates of combined clinically significant or severe hypoglycaemia. For icodec, time below 30 mmol/L (<54 mg/dL) was at the threshold of the internationally recommended target (<1%) during weeks 22-26 and below target during weeks 48-52.