Switching to once-weekly insulin icodec versus once-daily insulin degludec in individuals with basal insulin-treated type 2 diabetes (ONWARDS 2): a phase 3a, randomised, open label, multicentre, treat-to-target trial

Background: Insulin icodec (icodec) is a once-weekly basal insulin currently under development. ONWARDS 2 aimed to assess the efficacy and safety of once-weekly icodec versus once-daily insulin degludec (degludec) in basal insulin-treated type 2 diabetes.

Methods: This 26-week, randomised, open-label, active-controlled, multicentre, treat-to-target phase 3a trial was conducted in 71 sites in nine countries. Eligible participants with type 2 diabetes inadequately controlled on once-daily or twice-daily basal insulin, with or without non-insulin glucose-lowering agents, were randomly assigned (1:1) to once-weekly icodec or once-daily degludec. The primary outcome was change from baseline to week 26 in HbA_1c; the margin used to establish non-inferiority of icodec compared with degludec was 0·3 percentage points. Safety outcomes (hypoglycaemic episodes and adverse events) and patient-reported outcomes were also assessed. The primary outcome was evaluated in all randomly assigned participants; safety outcomes were evaluated descriptively based on all randomly assigned participants who received at least one dose of trial product, with statistical analyses based on all randomly assigned participants. This trial is registered with ClinicalTrials.gov, NCT04770532, and is now complete.

Findings: Between March 5 and July 19, 2021, 635 participants were screened, of whom 109 were ineligible or withdrew, and 526 were randomly assigned to icodec (n=263) or degludec (n=263). From a mean baseline of 8·17% (icodec; 65·8 mmol/mol) and 8·10% (degludec; 65·0 mmol/mol), HbA_1c was reduced to a greater extent with icodec than degludec (7·20% vs 7·42% [55·2 vs 57·6 mmol/mol], respectively) at week 26. This translates to an estimated treatment difference (ETD) of -0·22 percentage points (95% CI -0·37 to -0·08) or -2·4 mmol/mol (95% CI -4·1 to -0·8), demonstrating non-inferiority (p<0·0001) and superiority (p=0·0028). The estimated mean change from baseline to week 26 in bodyweight was +1·40 kg for icodec and -0·30 kg for degludec (ETD 1·70 [95% CI 0·76 to 2·63]). Overall rates of combined level 2 or level 3 hypoglycaemia were less than one event per patient-year of exposure for both groups (0·73 [icodec] vs 0·27 [degludec]; estimated rate ratio 1·93 [95% CI 0·93 to 4·02]). Overall, 161 (61%) of 262 participants receiving icodec and 134 (51%) of 263 participants receiving degludec experienced an adverse event; 22 (8%) and 16 (6%), respectively, experienced a serious adverse event. One serious adverse event (degludec) was assessed as being possibly related to treatment. No new safety issues were identified in relation to icodec compared with degludec in this trial.

Interpretation: Among adults with basal insulin-treated type 2 diabetes, treatment with once-weekly icodec versus once-daily degludec demonstrated non-inferiority and statistical superiority in HbA_1c reduction after 26 weeks, associated with modest weight gain. Overall rates of hypoglycaemia were low, with numerically but not statistically significantly higher event rates of level 2 or level 3 hypoglycaemia with icodec versus degludec.

Funding: Novo Nordisk.