Once-Weekly Insulin Icodec vs Once-Daily Insulin Degludec in Adults With Insulin-Naive Type 2 Diabetes

Abstract

ImportanceOnce-weekly insulin icodec could provide a simpler dosing alternative to daily basal insulin in people with type 2 diabetes.ObjectiveTo 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 ParticipantsRandomized, 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).InterventionsParticipants 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 MeasuresThe 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.ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT04795531

Efficacy and safety of once‐weekly insulin icodec in type 2 diabetes: A meta‐analysis of ONWARDS phase 3 randomized controlled trials

“…The details of the study characteristics are depicted in Table 1. The trials included are named ONWARDS 1 to ONWARDS 5 10–14 . ONWARDS 1, 10 ONWARDS 2, 11 ONWARDS 4 13 and ONWARDS 5 14 were open‐label trials and only ONWARDS 3 12 was double‐masked and double‐dummy trial.…”

“…The trials included are named ONWARDS 1 to ONWARDS 5 10–14 . ONWARDS 1, 10 ONWARDS 2, 11 ONWARDS 4 13 and ONWARDS 5 14 were open‐label trials and only ONWARDS 3 12 was double‐masked and double‐dummy trial. ONWARDS 1, ONWARDS 3 and ONWARDS 5 were in insulin naïve and ONWARDS 2 and ONWARDS 4 were in individuals previously treated with basal insulin alone or basal‐bolus insulin respectively.…”

“…The comparator group was insulin glargine U100 in ONWARDS 1 10 and ONWARDS 4 13 and insulin degludec in ONWARDS 2 11 and ONWARDS 3, 12 whereas the comparator in ONWARDS 5 14 consisted of any of the following basal insulin analogues such as insulin glargine U100, insulin glargine U300 or insulin degludec. The pre‐trial non‐insulin antidiabetic background medication (except sulphonylureas and glinides) was maintained at the stable pre‐trial dose and at the same frequency during the entire treatment period.…”

“…The insulin dose during the last 3 weeks of the treatment period for the five trials inuslin dose, showed a significant difference in dose, which was lower in the comparator group when compared with insulin icodec [RR 1.09 (95% CI, 1.01‐1.18), p = .04] (Figure S2A). The insulin doses were calculated at 24‐26 weeks in ONWARDS 2, 11 ONWARDS 3 12 and ONWARDS 4, 13 and at 50‐52 weeks in ONWARDS 1 10 and ONWARDS 5 14 . The subgroup analysis comparing the insulin doses showed a higher dose ratio for insulin icodec when compared with degludec [RR 1.10 (95% CI, 1.03‐1.18), p = .007] and no difference in insulin dose ratio when compared with glargine U100 [RR 1.02 (95% CI, 0.90‐1.16), p = .72] (Figure S2B).…”

“…This meta‐analysis included phase 3 randomized controlled trials from ONWARDS 1 to ONWARDS 5 10–14 with a total of 3764 patients and looked at the efficacy and safety profile of once‐weekly insulin icodec in comparison with other basal insulin analogues to determine its potential clinical utility in the management of T2DM. The primary principle behind developing an ultra‐long acting insulin icodec is the assumption that diminishing the human insulin receptor's sensitivity along with a stronger human serum albumin (HSA)‐binding to additionally extend insulin's half‐life would make it longer acting 15 .…”