Ultra rapid lispro improves postprandial glucose control versus lispro in combination with insulin glargine/degludec in adults with type 2 diabetes: a prospective, randomized, double-blind, phase 3 trial

Ultra rapid lispro (URLi) is a novel formulation of insulin lispro designed to more closely match the physiological insulin response to a meal, with the aim of improving postprandial glucose (PPG) control. We conducted a multinational, multicenter, randomized, double-blind, treat-to-target, 26-week, phase 3 trial to evaluate the efficacy and safety of URLi in adults with type 2 diabetes (T2D). After an 8-week lead-in period during which basal insulin glargine or degludec was optimized, adults with T2D were randomized (2:1) to prandial URLi (n = 395) or lispro (n = 200). The primary endpoint was non-inferiority of URLi versus lispro in glycated hemoglobin A1c (HbA1c) change from baseline to week 26. Multiplicity-adjusted analyses were performed to assess the superiority of URLi in 1- and 2-h PPG excursions during a mixed-meal tolerance test (MMTT) and HbA1c change at week 26. URLi showed non-inferiority for HbA1c change at week 26 versus lispro (least-squares mean [LSM] difference, 0.07%; 95% confidence interval: −0.07, 0.21). HbA1c was reduced by 0.56% and 0.63% with URLi and lispro, respectively, with no significant treatment difference (P = 0.321). URLi provided superior PPG excursion control versus lispro at 1 h (LSM difference: −14.6 mg/dL, P < 0.001) and 2 h (LSM difference: −21.8 mg/dL, P < 0.001) as well as other time points (30–240 min) during the MMTT. Incremental area under the glucose curve during the MMTT was also significantly lower with URLi versus lispro. The safety profiles were generally similar between treatment groups. In conclusion, URLi was superior to lispro for PPG control, with non-inferiority in HbA1c improvement, in adults with T2D.