Continuous glucose monitoring-based metrics and the duration of hypoglycaemia events with once-weekly insulin icodec versus once-daily insulin glargine U100 in insulin-naive type 2 diabetes: an exploratory analysis of ONWARDS 1.

Background: Continuous glucose monitoring (CGM) can provide a comprehensive assessment of glycaemic control. This exploratory analysis of the ONWARDS 1 trial assessed CGM-based metrics and CGM-derived hypoglycaemia duration in insulin-naive individuals with type 2 diabetes treated with subcutaneous once-weekly insulin icodec (icodec) versus once-daily insulin glargine U100 (glargine U100).
Methods: ONWARDS 1 was a 78-week (52-week main treatment phase and a 26-week treatment extension phase plus a 5-week follow-up), randomised, open-label, treat-to-target, phase 3a trial done at 143 sites (outpatient clinics and hospital departments) across 12 countries. Adults (aged ≥18 years) with type 2 diabetes (HbA _1c : 7·0-11·0%) who had not previously received insulin were randomly assigned (1:1) via an interactive web-response system to once-weekly icodec or once-daily glargine U100. Double-masked CGM data were collected during treatment initiation (weeks 0-4), midtrial (weeks 22-26), end of main phase (weeks 48-52), end of extension phase (weeks 74-78), and follow-up (weeks 78-83). Secondary and exploratory outcomes were CGM-based metrics, including the mean percentages of time in glycaemic range (TIR; sensor glucose 3·9-10·0 mmol/L [70-180 mg/dL]), time in tight range (TITR; 3·9-7·8 mmol/L [70-140 mg/dL]), time above range (TAR; >10·0 mmol/L [>180 mg/dL]), and time below range (TBR; <3·9 mmol/L [<70 mg/dL] and <3·0 mmol/L [<54 mg/dL]), and CGM-derived hypoglycaemic episode durations (episodes defined by sensor glucose <3·9 mmol/L [<70 mg/dL for ≥15 consecutive minutes]). Analyses were done in the full analysis set (all randomly assigned participants). The ONWARDS 1 trial is registered with ClinicalTrials.gov, NCT04460885, and is complete.
Findings: Participants were enrolled and randomly assigned in ONWARDS 1 between Nov 25, 2020, and Dec 1, 2022 (n=492 in each treatment group). During treatment initiation, we observed no statistically significant differences in the mean percentages of TIR, TITR, TAR, and TBR with icodec versus glargine U100. During the midtrial, end of main phase, and end of extension phase periods, the mean percentages of TIR and TITR were statistically significantly greater and the mean percentages of TAR statistically significantly lower with icodec versus glargine U100. The mean percentages of TIR met the internationally recommended CGM target (>70%) with icodec but not with glargine U100 during the three periods. TBR (<3·9 mmol/L [<70 mg/dL] and <3·0 mmol/L [<54 mg/dL]) was low and below recommended targets (<4% and <1%, respectively) across all study periods in both treatment groups, with no statistically significant differences between treatment groups for the lower threshold (<3·0 mmol/L [<54 mg/dL]). During the follow-up period, mean percentages of TIR, TITR, TAR, and TBR did not statistically significantly differ with icodec versus glargine U100. The duration of overall hypoglycaemic episodes was similar between treatment groups throughout the trial (median duration ≤35 min).
Interpretation: These CGM data support the long-term efficacy and safety of icodec versus glargine U100 during treatment and indicated no increase in the duration of individual hypoglycaemic episodes with icodec versus glargine U100 in insulin-naive individuals with type 2 diabetes.
Funding: Novo Nordisk.
Competing Interests: Declaration of interests RMB has received research support, consultant fees, or has served on advisory panels for Abbott Diabetes Care, Ascensia Diabetes Care, Bigfoot Biomedical, CeQur, Dexcom, Eli Lilly, Embecta, Hygieia, Insulet, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, Tandem Diabetes Care, United Healthcare, Vertex Pharmaceuticals, and Zealand Pharma. RMB's employer, the nonprofit organisation HealthPartners Institute, contracts for his services and he receives no personal income from these activities. BÁ and SKW are employees of Novo Nordisk; TN is both an employee and shareholder of Novo Nordisk. IL has received research funding (paid to their institution) from Boehringer Ingelheim, Merck, Mylan, Novo Nordisk, Pfizer, and Sanofi; and has received advisory or consulting fees, travel support, or manuscript editorial support from AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Intercept Pharmaceuticals, Johnson & Johnson, Merck, Novo Nordisk, Pfizer, Sanofi, Shionogi, Structure Therapeutics, Target Pharma, Translational Medical Academy, Valeritas, WebMD, and Zealand Pharma. JKM has received speaker fees from Abbott Diabetes Care, A Menarini Diagnostics, BD and Embecta, Dexcom, Eli Lilly, Medtronic, Medtrust, Novo Nordisk, Roche Diabetes Care, Sanofi, Servier, Viatris, and Ypsomed; is a member of advisory boards for Abbott Diabetes Care, BD and Embecta, Boehringer Ingelheim, Eli Lilly, Medtronic, Novo Nordisk, Prediktor, Roche Diabetes Care, Sanofi, and Viatris; is a board member of the Austrian Diabetes Society and of the European Association for the Study of Diabetes; is a chair for the Postgraduate Education Committee of the European Association for the Study of Diabetes; has received materials provided by Menarini Diagnostics and Dexcom; is a shareholder of Decide Clinical Software and Elyte Diagnostics; and serves as the Chief Medical Officer at Elyte Diagnostics. JR reports clinical research grants from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Carmot, Corcept, Eli Lilly, Hanmi, Merck, Novartis, Novo Nordisk, Oramed, Regeneron, Pfizer, and Sanofi; has served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Eli Lilly, Hanmi, Novo Nordisk, Oramed, Regeneron, Roche, Sanofi, Structure Therapeutics, and Zealand Pharma; and has received honoraria for lectures from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi.
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