• David Russell-Jones, Tetsuya Babazono, Roman Cailleteau, Susanne Engberg, Concetta Irace, KjaersgaardMaiken Ina SiegismundMISNovo Nordisk, Aalborg, Denmark., Chantal Mathieu, Julio Rosenstock, Vincent Woo, and David C Klonoff.
• The Cedar Centre, Royal Surrey Foundation Trust, Guildford, UK; Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK. Electronic address: davidrussell-jones@nhs.net.
• Lancet. 2023 Nov 4; 402 (10413): 163616471636-1647.

BackgroundONWARDS 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.MethodsThis 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 [HbA1c] <10·0% [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 HbA1c from baseline to week 26, tested for non-inferiority (0·3 percentage point margin) in all randomly assigned participants. This trial is registered with ClinicalTrials.gov, NCT04848480, and is now complete.FindingsBetween 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 7·59% (icodec) and 7·63% (degludec), estimated mean changes in HbA1c were -0·47 percentage points and -0·51 percentage points, respectively (estimated treatment difference 0·05 percentage points [95% CI -0·13 to 0·23]), confirming non-inferiority of icodec to degludec (p=0·0065). Overall rate of combined clinically significant or severe hypoglycaemia (baseline to week 26) was statistically significantly higher with icodec than degludec (19·9 vs 10·4 events per patient-year of exposure; estimated rate ratio 1·9 [95% CI 1·5 to 2·3]; p<0·0001). 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.InterpretationIn adults with type 1 diabetes, once-weekly icodec showed non-inferiority to once-daily degludec in HbA1c reduction at week 26, with statistically significantly higher rates of combined clinically significant or severe hypoglycaemia. For icodec, time below 3·0 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.FundingNovo Nordisk.Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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