Once-weekly insulin icodec better than once-daily insulin glargine for patients with type 2 diabetes: ONWARDS 4 trial

Insulin icodec (icodec) is a basal insulin analogue appropriate for once-weekly dosing. Prof Chantal Mathieu, Catholic University of Leuven, Leuven, Belgium, and colleagues aimed to evaluate the safety and efficacy of once-weekly icodec versus once-daily insulin glargine U100 (glargine U100) in patients with long-standing type 2 diabetes on a basal-bolus regimen in the ONWARDS 4 trial. ONWARDS 4 is a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial.

The trial, conducted for 26 weeks, involved adults from 80 sites across nine countries (the USA, Russia, Romania, the Netherlands, Mexico, Japan, Italy, India, and Belgium). Five hundred eighty-two participants were randomly assigned in a ratio of 1:1 to receive once-weekly icodec (n=291) or glargine U100 (n=291) combined with 2–4 daily bolus insulin aspart injections.

Safety outcomes were assessed in the safety analysis set that comprised all participants randomly allocated to receive at least one dose of the trial product. The study's primary outcome was a change in HbA1c from baseline to week 26 (non-inferiority margin of 0·3 percentage points), evaluated in the complete analysis set, i.e. all randomly assigned participants. The mean duration of the participants with type 2 diabetes of 17·1 year.

The study revealed the following findings:

• At week 26, the estimated mean change in HbA1c was −1·16 percentage points in the icodec group (baseline 8·29%) and −1·18 percentage points in the glargine U100 group (baseline 8·31%), showing non-inferiority for icodec versus glargine U100 (estimated treatment difference 0·02 percentage points).
• 59% of participants in the icodec group and 57% in the glargine U100 group had an adverse event.
• Thirty-five serious adverse events were reported in 8% of participants in the icodec group, and 33 serious adverse events were reported in 9% of participants receiving glargine U100.
• Combined level 2 and level 3 hypoglycaemia rates were similar between treatment groups. No new safety concerns were identified for icodec.

Key strengths of this trial were:

• The use of masked continuous glucose monitoring.
• The inclusion of a large, diverse, and multinational population.
• The high trial completion rate.

Limitations include the open-label design and relatively short trial duration.

Reference:

Mathieu C, Ásbjörnsdóttir B, Bajaj HS, Lane W, Matos ALSA, Murthy S, Stachlewska K, Rosenstock J. Switching to once-weekly insulin icodec versus once-daily insulin glargine U100 in individuals with basal-bolus insulin-treated type 2 diabetes (ONWARDS 4): a phase 3a, randomised, open-label, multicentre, treat-to-target, non-inferiority trial. Lancet. 2023 May 5:S0140-6736(23)00520-2. doi: 10.1016/S0140-6736(23)00520-2. Epub ahead of print. PMID: 37156252.