Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine U100 (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and one or more oral glucose-lowering medications. RESEARCH DESIGN AND METHODSThis multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal insulin-treated (total daily dose 10-50 units) people with type 2 diabetes (HbA 1c 7.0-10.0% [53.0-85.8 mmol/mol]) to icodec with an initial 100% loading dose (in which only the first dose was doubled [icodec LD]), icodec with no loading dose (icodec NLD), or IGlar U100 for 16 weeks. Primary end point was percent time in range (TIR; 3.9-10.0 mmol/L [70-180 mg/dL]) during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary end points included HbA 1c , adverse events (AEs), and hypoglycemia. RESULTSEstimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; n 5 54), 66.0% (icodec NLD; n 5 50), and 65.0% (IGlar U100; n 5 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points [95% CI 1.8-13.9%]). Mean HbA 1c reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% (54.4 mmol/mol icodec LD) and 7.4% (57.6 mmol/mol icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable. CONCLUSIONSSwitching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to onceweekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.

Aim To describe the phase 3a ONWARDS clinical development programme investigating insulin icodec (icodec), a once‐weekly basal insulin, including the design and rationale for each of the ONWARDS 1–6 trials. Materials and Methods Six randomized controlled trials have been initiated in adults with type 2 diabetes (T2D) (insulin‐naive: ONWARDS 1, 3 and 5; previously insulin‐treated: ONWARDS 2 and 4) and type 1 diabetes (T1D) (ONWARDS 6). Each trial will investigate icodec use in a unique clinical scenario, with consideration of long‐term safety and varied comparator treatments (insulin glargine U100 or U300 or insulin degludec). ONWARDS 5 will incorporate real‐world elements and a digital dose titration solution to guide icodec dosing. The primary objective for each of the trials is to compare the change in HbA1c from baseline to week 26 or week 52 between icodec and comparator arms. Secondary objectives include investigating other glycaemic control and safety parameters, such as fasting glucose, time in glycaemic range and hypoglycaemia. Patient‐reported outcomes will assess treatment satisfaction. Conclusions The ONWARDS 1–6 trials will evaluate the efficacy and safety of once‐weekly icodec compared with currently available daily basal insulin analogues in T2D and T1D. These trials will generate comprehensive evidence of icodec use in diverse populations across the spectrum of diabetes progression and treatment experience.

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IntroductionHemoglobin glycation index (HGI) is the difference between observed and predicted glycated hemoglobin A1c (HbA1c), derived from mean or fasting plasma glucose (FPG). In this secondary, exploratory analysis of data from DEVOTE, we examined: whether insulin initiation/titration affected the HGI; the relationship between baseline HGI tertile and cardiovascular and hypoglycemia risk; and the relative strengths of HGI and HbA1c in predicting these risks.Research design and methodsIn DEVOTE, a randomized, double-blind, cardiovascular outcomes trial, people with type 2 diabetes received once per day insulin degludec or insulin glargine 100 units/mL. The primary outcome was time to first occurrence of a major adverse cardiovascular event (MACE), comprising cardiovascular death, myocardial infarction or stroke; severe hypoglycemia was a secondary outcome. In these analyses, predicted HbA1c was calculated using a linear regression equation based on DEVOTE data (HbA1c=0.01313 FPG (mg/dL) (single value)+6.17514), and the population data were grouped into HGI tertiles based on the calculated HGI values. The distributions of time to first event were compared using Kaplan–Meier curves; HRs and 95% CIs were determined by Cox regression models comparing risk of MACE and severe hypoglycemia between tertiles.ResultsChanges in HGI were observed at 12 months after insulin initiation and stabilized by 24 months for the whole cohort and insulin-naive patients. There were significant differences in MACE risk between baseline HGI tertiles; participants with high HGI were at highest risk (low vs high, HR: 0.73 (0.61 to 0.87)95% CI; moderate vs high, HR: 0.67 (0.56 to 0.81)95% CI; p<0.0001). No significant differences between HGI tertiles were observed in the risk of severe hypoglycemia (p=0.0911). With HbA1c included within the model, HGI no longer significantly predicted MACE.ConclusionsHigh HGI was associated with a higher risk of MACE; this finding is of uncertain significance given the association of HGI with insulin initiation and HbA1c.Trial registration numberNCT01959529.

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<b>OBJECTIVE</b><br><b></b><p><b> </b>Insulin icodec (icodec) is a novel once-weekly basal insulin analog. This trial investigated two approaches for switching to icodec versus once-daily insulin glargine U100 (IGlar U100) in people with type 2 diabetes receiving daily basal insulin and ≥1 oral glucose-lowering medication.</p> <p><b>RESEARCH DESIGN AND METHODS</b><br> This multicenter, open-label, treat-to-target phase 2 trial randomized (1:1:1) eligible basal-insulin-treated (total daily dose 10–50 U) people with type 2 diabetes (HbA_1c 7.0–10.0% [53.0–13.3 mmol/mo]) to icodec with an initial 100% loading dose (where only the first dose was doubled; icodec LD), icodec with no loading dose (icodec NLD) or IGlar U100 for 16 weeks. Primary endpoint was percent time in <a>range (TIR; 3.9–10.0 mmol/L [70–180 mg/dL]) </a>during weeks 15 and 16, measured using continuous glucose monitoring. Key secondary endpoints included HbA_1c,adverse events (AEs) and hypoglycemia. </p> <p><b>RESULTS</b><br> Estimated mean TIR during weeks 15 and 16 was 72.9% (icodec LD; <i>n</i> = 54), 66.0% (icodec NLD; <i>n</i> = 50) and 65.0% (IGlar U100; <i>n</i> = 50), with a statistically significant difference favoring icodec LD versus IGlar U100 (7.9%-points, 95% CI 1.8 to 13.9%). Mean HbA_1c reduced from 7.9% (62.8 mmol/mol) at baseline to 7.1% ([54.4 mmol/mol] icodec LD) and 7.4% ([57.6 mmol/mol] icodec NLD and IGlar U100); incidences and rates of AEs and hypoglycemic episodes were comparable.<br> <br> </p> <p><b>CONCLUSIONS</b><br> Switching from daily basal insulin to once-weekly icodec was well tolerated and provided effective glycemic control. Loading dose use when switching to once-weekly icodec significantly increased percent TIR during weeks 15 and 16 versus once-daily IGlar U100, without increasing hypoglycemia risk.</p>

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In the DEVOTE and SWITCH 2 trials, insulin degludec 100 units/mL (degludec) was superior to insulin glargine 100 units/mL (glargine U100) with respect to the rates of severe (DEVOTE; across trial) and overall symptomatic (SWITCH 2; during the maintenance period of the trial) hypoglycaemia in individuals with type 2 diabetes. In this post hoc analysis, data from 7635 individuals from DEVOTE and 720 individuals from SWITCH 2 were analysed by subgroups of diabetes duration at baseline (<10, ≥10-<15, ≥15-<20 and ≥20 years) using prespecified models from both trials. There was a trend towards lower rates of hypoglycaemia with degludec versus glargine U100 across all diabetes duration subgroups in both trials, with the difference being statistically significant in some subgroups in DEVOTE and SWITCH 2. Overall, however, no significant interaction was observed between diabetes duration and treatment (DEVOTE interaction, P = .496; SWITCH 2 interaction, P = .144). Therefore, in this post hoc analysis of DEVOTE and SWITCH 2, diabetes duration did not appear to affect the reduction in rates of hypoglycaemia observed with degludec compared with glargine U100.