Ultra rapid lispro improves postprandial glucose control compared with lispro in patients with type 1 diabetes: Results from the 26-week PRONTO-T1D study

Abstract

Aims: To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes in a 26-week, treat-to-target, phase 3 trial.

Materials and methods: After an 8-week lead-in to optimize basal insulin glargine or degludec, patients were randomized to double-blind mealtime URLi (n = 451) or lispro (n = 442), or open-label post-meal URLi (n = 329). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) to 26 weeks (non-inferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions after a meal test.

Results: Both mealtime and post-meal URLi demonstrated non-inferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi -0.08% [95% confidence interval (CI) -0.16, 0.00] and for post-meal URLi +0.13% (95% CI 0.04, 0.22), with a significantly higher endpoint HbA1c for post-meal URLi versus lispro (P = 0.003). Mealtime URLi was superior to lispro in reducing 1- and 2-hour PPG excursions during the meal test: ETD -1.55 mmol/L (95% CI -1.96, -1.14) at 1 hour and - 1.73 mmol/L (95% CI -2.28, -1.18) at 2 hours (both P < 0.001). The rate and incidence of severe, documented and postprandial hypoglycaemia (<3.0 mmol/L) was similar between treatments, but mealtime URLi demonstrated a 37% lower rate in the period >4 hours after meals (P = 0.013). Injection site reactions were reported by 2.9% of patients on mealtime URLi, 2.4% on post-meal URLi, and 0.2% on lispro. Overall, the incidence of treatment-emergent adverse events was similar between treatments.

Conclusions: The results showed that URLi provided good glycaemic control, with non-inferiority to lispro confirmed for both mealtime and post-meal URLi, while superior PPG control was demonstrated with mealtime dosing.

FIGURE 1

Mean glycated haemoglobin (HbA1c) from study entry to week 26. Data are mean at study entry and least squares mean ± SE at all other time points and based on the mixed‐effects model for repeated measures analysis. *P <0.05 for pairwise comparison of post‐meal ultra rapid lispro (URLi) versus lispro; ^ P <0.05 for pairwise comparison of post‐meal URLi versus mealtime URLi. Estimated treatment difference (ETD) between URLi and lispro (URLi−lispro) was −0.8 mmol/mol (−0.08%) with a two‐sided 95% confidence interval (CI) of −1.7 to 0.0 mmol/mol (−0.16 to 0.00%) for mealtime URLi, and +1.4 mmol/mol (+ 0.13%) with 95% CI 0.5 to 2.4 mmol/mol (0.04 to 0.22%) for post‐meal URLi, demonstrating non‐inferiority of both mealtime and post‐meal URLi to lispro in the change from baseline to week 26 in HbA1c

FIGURE 2

Postprandial glucose (PPG) excursions during a meal test at week 26. Data are least squares mean ± SE. *P <0.05 for pairwise comparison of ultra rapid lispro (URLi) versus lispro; **P <0.001 for pairwise comparison of URLi versus lispro. Prandial insulin dose for the mixed‐meal tolerance test (MMTT) was individualized for each patient based on their prandial insulin dosing plan. For patients using carbohydrate counting, the morning meal insulin‐to‐carbohydrate ratio was used to calculate the prandial insulin dose for the MMTT. For patients not using carbohydrate counting, the prandial insulin dose for MMTT was calculated based on the average total daily insulin dose for the 3 days prior to the MMTT. CI, confidence interval; ETD, estimated treatment difference (mealtime URLi−lispro)

FIGURE 3

Ten‐point self‐monitored blood glucose profile at week 26. Data are least squares mean ± SE. *P <0.05 for pairwise comparison of mealtime URLi versus lispro; ^ P <0.05 for pairwise comparison of post‐meal URLi versus lispro; #P <0.05 for pairwise comparison of post‐meal URLi versus mealtime URLi

FIGURE 4

Rate and incidence of hypoglycaemia (with or without symptoms) from randomization to week 26 [blood glucose <3.0 mmol/L (54 mg/dL)]. A, Rate and incidence of documented and nocturnal hypoglycaemia. B, Rate and incidence of post‐meal hypoglycaemia. Data are least squares mean (LSM) + SE for event rate and LSM for incidence. Note: Nocturnal hypoglycaemia was defined as documented hypoglycaemia occurring between bedtime and waking