Modeling the Impact of Monthly Titration of Once-Weekly Insulin Icodec in Insulin-Naive Type 2 Diabetes: Analysis Based on ONWARDS 1 and 3

To explore whether monthly titration of once-weekly insulin icodec (icodec) could provide a feasible alternative to the weekly titration utilized in ONWARDS 1 and 3 for insulin-naive individuals with type 2 diabetes (T2D), supporting less-frequent dose adjustments tailored to individual needs. A validated pharmacokinetic/pharmacodynamic icodec model was adapted using pooled ONWARDS 1 and 3 data to simulate weekly and two different monthly titration scenarios, applying the same initiation dose and self-measured blood glucose (SMBG) target used in the trials. Scenarios 1 and 2 used ± 20 U and ± 50 U adjustments, respectively, informed by the last three fasting SMBG values. Simulations of fasting SMBG, glycated hemoglobin (HbA 1c ), icodec dose, and clinically significant (level 2) hypoglycemia were performed over 78 weeks. At week 78, model-predicted mean (95% range) HbA 1c was 7.3% (6.2–9.2%) for scenario 1 and 7.2% (6.0–8.9%) for scenario 2, versus 6.9% (5.9–8.4%) for the weekly titration reference. Model-predicted mean (95% range) prebreakfast SMBG was 7.3 mmol/L (6.0–9.8 mmol/L) and 7.1 mmol/L (5.6–9.3 mmol/L) versus 6.6 mmol/L (5.3–8.3 mmol/L), respectively. Predicted cumulative rates of clinically significant (level 2) hypoglycemia were 0.081 (scenario 1) and 0.15 (scenario 2) events per patient-year of exposure (PYE), both numerically lower than the already low rate predicted for the weekly titration (0.34 events per PYE). These lower predicted rates occurred alongside lower predicted icodec doses. Our findings support the feasibility of monthly titration of icodec as an alternative to weekly titration for individuals with T2D who require or prefer less-frequent dose adjustments. Prospective clinical evaluation is needed to confirm these model-based findings. ClinicalTrials.gov identifiers: NCT04460885 (ONWARDS 1), NCT04795531 (ONWARDS 3).