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Clinical Trial
. 2023 Nov 4;402(10413):1636-1647.
doi: 10.1016/S0140-6736(23)02179-7. Epub 2023 Oct 17.

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

David Russell-Jones  1 , Tetsuya Babazono  2 , Roman Cailleteau  3 , Susanne Engberg  3 , Concetta Irace  4 , Maiken Ina Siegismund Kjaersgaard  5 , Chantal Mathieu  6 , Julio Rosenstock  7 , Vincent Woo  8 , David C Klonoff  9
Affiliations
Free article
Clinical Trial

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

David Russell-Jones et al. Lancet. .
Free article

Abstract

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 [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.

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 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.

Interpretation: In 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.

Funding: Novo Nordisk.

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Conflict of interest statement

Declaration of interests DR-J reports research income or advisory board honoraria from AstraZeneca, Dexcom, Lilly, Medtronic, Novartis, Novo Nordisk, and Sanofi. TB has received research grants from Abbott, Daiichi Sancho, Eli Lilly, Ono Pharmaceuticals, Terumo, Novartis, Sanwa Kagaku Kenkyusho, and Boehringer Ingelheim and has received honoraria or consulting fees from Tanabe-Mitsubishi, Sumitomo Farma, Eli Lilly, and Novo Nordisk. RC, SE, and MISK are employees of Novo Nordisk and hold stock in Novo Nordisk. CI provided advisory board services for Abbott, Ascensia, Menarini, Novo Nordisk, Roche Diabetes Care Italy, and Senseonics, and received speaker fees from Abbott, Ascensia, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk. CM serves or has served on the advisory panel for ActoBio Therapeutics, AstraZeneca, Avotres, Boehringer Ingelheim, Eli Lilly, Imcyse, Insulet, MannKind, Medtronic, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, Sandoz, Sanofi, Vertex, and Zealand Pharma; financial compensation for these activities has been received by KU Leuven (Leuven, Belgium). KU Leuven reports research support for CM from ActoBio Therapeutics, Imcyse, Medtronic, Novo Nordisk, and Sanofi. CM serves or has served on the speakers' bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, and Sanofi; financial compensation for these activities has been received by KU Leuven. JR has served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Hanmi, Intarcia, Novo Nordisk, Oramed, Sanofi, Scholar Rock, Structure Therapeutics, Terns Pharmaceuticals, and Zealand, and has received research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Novartis, Merck, Novo Nordisk, Oramed, Pfizer, and Sanofi. VW has acted as a consultant for Novo Nordisk and received speaker fees from Novo Nordisk. DCK has acted as a consultant for Better Therapeutics, EOFlow, Integrity, Lifecare, Nevro, Novo Nordisk, Sanofi, and Thirdwayv.

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