Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes: The ONWARDS 3 Randomized Clinical Trial

Abstract

Importance: Once-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes.

Objective: To evaluate the efficacy and safety of once-weekly icodec vs once-daily insulin degludec in people with insulin-naive type 2 diabetes.

Design, setting, and participants: Randomized, double-masked, noninferiority, treat-to-target, phase 3a trial conducted from March 2021 to June 2022 at 92 sites in 11 countries in adults with type 2 diabetes treated with any noninsulin glucose-lowering agents with hemoglobin A1c (HbA1c) of 7%-11% (53-97 mmol/mol).

Interventions: Participants were randomly assigned in a 1:1 ratio to receive either once-weekly icodec and once-daily placebo (icodec group; n = 294) or once-daily degludec and once-weekly placebo (degludec group; n = 294).

Main outcomes and measures: The primary end point was change in HbA1c from baseline to week 26 (noninferiority margin, 0.3% percentage points). Secondary end points included change in fasting plasma glucose from baseline to week 26, mean weekly insulin dose during the last 2 weeks of treatment, body weight change from baseline to week 26, and number of level 2 (clinically significant; glucose level <54 mg/dL) and level 3 (severe; requiring external assistance for recovery) hypoglycemic episodes.

Results: Among 588 randomized participants (mean [SD] age, 58 [10] years; 219 [37%] women), 564 (96%) completed the trial. Mean HbA1c level decreased from 8.6% (observed) to 7.0% (estimated) at 26 weeks in the icodec group and from 8.5% (observed) to 7.2% (estimated) in the degludec group (estimated treatment difference [ETD], -0.2 [95% CI, -0.3 to -0.1] percentage points), confirming noninferiority (P < .001) and superiority (P = .002). There were no significant differences between the icodec and degludec groups for fasting plasma glucose change from baseline to week 26 (ETD, 0 [95% CI, -6 to 5] mg/dL; P = .90), mean weekly insulin dose during the last 2 weeks of treatment, or body weight change from baseline to week 26 (2.8 kg vs 2.3 kg; ETD, 0.46 [95% CI, -0.19 to 1.10] kg; P = .17). Combined level 2 or 3 hypoglycemia rates were numerically higher in the icodec group than the degludec group from week 0 to 31 (0.31 vs 0.15 events per patient-year exposure; P = .11) and statistically higher in the icodec group from week 0 to 26 (0.35 vs 0.12 events per patient-year exposure; P = .01).

Conclusions and relevance: Among people with insulin-naive type 2 diabetes, once-weekly icodec demonstrated superior HbA1c reduction to once-daily degludec after 26 weeks of treatment, with no difference in weight change and a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups.

Trial registration: ClinicalTrials.gov Identifier: NCT04795531.

Figure 1.. Flow of Participants in a Trial of Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec for Type 2 Diabetes

There were no study- or country-level important protocol deviations during the trial. There were 26 important site-level protocol deviations, 68 at the participant level in the icodec group, 70 in the degludec group (164 in total.) ^aParticipants could not meet more than 1 inclusion criterion and/or meet more than 1 exclusion criterion. ^bAdditional reasons for screening failure in less than 5 participants: 2 met exclusion criteria for estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m² at screening, 2 met exclusion criteria for anticipated change in lifestyle affecting glucose control, 1 met exclusion criteria of treatment for obesity or diabetes with any drug not listed in the inclusion criteria within 90 days of screening, and 1 met exclusion criterion of anticipated change in concomitant medication known to affect weight or glucose metabolism. ^cDefined as alanine transaminase ≥2.5 times the upper normal limit or bilirubin >1.5 times the upper normal limit. ^dTwo participants withdrew based on investigator decision and 2 were lost to follow-up. ^eRandomization was stratified according to region (Asia, North America, South America, Europe) and treatment with sulfonylureas or glinides (yes, no). ^fOther reasons for discontinuation in the icodec group were participant unable to attend hospital/other appointments (n = 2), reluctance of the participant’s family because the product is not on the market (n = 1), and personal problems (n = 1). Other reasons for discontinuation in the degludec group were voluntary (n = 2), investigator decision (n = 1), and lack of adherence (n = 1).

Figure 2.. Key Efficacy and Safety Outcomes

A, Observed median HbA_1c from baseline over time among the full analysis set. B, Observed median fasting plasma glucose over time among the full analysis set. C, Observed median total weekly insulin dose over time among the safety analysis set, in which values are back-transformed from log-scale. D, Change in observed median body weight over time among the safety analysis set. Boxes indicate median and 1st and 3rd quartiles. Whiskers indicate minimum and maximum values within range (Q1 − 1.5 × IQR and Q3 + 1.5 × IQR). Open circles indicate outside values.