Efficacy and Safety of Ultra-Rapid Lispro in Younger and Older Patients with Type 2 Diabetes: Randomized Double-Blind PRONTO-T2D Study

Abstract

Introduction: Ultra-rapid lispro (URLi) is a new prandial insulin lispro formulation. In the PRONTO-T2D study, URLi, in a basal-bolus regimen with glargine or degludec, was non-inferior to lispro (Humalog®) for HbA1c reduction and superior for postprandial glucose (PPG) control. We evaluated the efficacy and safety of URLi compared to lispro in younger versus older patients in PRONTO-T2D.

Methods: PRONTO-T2D was a phase 3, 26-week, double-blind, treat-to-target study in people with type 2 diabetes. In this sub-group analysis, we compared URLi to lispro on the change from baseline in HbA1c and rate of level 2 hypoglycemia (< 54 mg/dl) in patients aged < 65 (N = 406) and ≥ 65 years (N = 267).

Results: At baseline, patients < 65 versus ≥ 65 years had mean age of 54.9 versus 69.2 years and duration of diabetes 14.6 versus 19.4 years. Mean HbA1c at screening and randomization was 8.35 and 7.34%, respectively, in patients < 65 years, and 8.21 and 7.23%, respectively, in patients ≥ 65 years. At endpoint, mean HbA1c with URLi versus lispro was 6.92 versus 6.90%, respectively, in patients < 65 years and 6.89 versus 6.79%, respectively, in patients ≥ 65 years. URLi significantly reduced 1- and 2-h PPG excursions with a standardized meal test in both age groups: between-treatment differences at 1-h postmeal for younger and older patients was - 9.8 and - 15.1 mg/dl, respectively; and at 2-h postmeal, - 18.7 and - 15.1 mg/dl, respectively, all p < 0.05. Severe and nocturnal hypoglycemia were similar between groups. The relative rate (URLi/Humalog) of level 2 hypoglycemia was lower in older versus younger patients, with a significant treatment-by-age interaction observed. No differential treatment effects were noted for insulin dose, weight, and fasting and maximum glucose after the meal test.

Conclusions: URLi, in a basal-bolus regimen, resulted in endpoint HbA1c < 7% and significantly lower PPG excursions compared to lispro in both age groups, with reduced level 2 hypoglycemia in older versus younger patients.

Trial registration: ClinicalTrials.gov, NCT03214380.

Keywords: Efficacy; Elderly; Safety; Type 2 diabetes; URLi; Ultra rapid lispro.

© 2022. The Author(s).

Figures

Fig. 1

HbA1c time-course from screening to week 26. Data are mean at study entry and least squares mean ± standard error at all other time points. A mixed-effects model for repeated measures was used for post-baseline measures, which included treatment, visit, treatment-by-visit interaction, strata (pooled country, number of bolus injections at study entry, and type of basal insulin at lead-in) as fixed factors and baseline HbA1c as a covariate. The model used an unstructured covariance structure

Fig. 2

Post prandial glucose excursions following a standardized meal test at week 26. Data are least square means ± standard error. *p < 0.05; **p < 0.001. Note: the standardized liquid meal test consisted of ~ 700 cal, 100 g carbohydrate, 22 g fat, 26 g protein. Prandial insulin dose administered during the meal test was individualized for each patient. An analysis of covariance model was used in the analysis, which included treatment and strata (pooled country, HbA1c stratum at baseline, number of bolus injections at study entry, and type of basal insulin at lead-in) as fixed effects and baseline as a covariate

Fig. 3

Ten-point SMBG profiles at week 26. Data are least square means ± standard error. *p < 0.05. Note: Patients collected ten-point SMBG profiles on three non-consecutive days during the last 2 weeks of study treatment period. A mixed-effects model for repeated measures was used for post-baseline measures which included treatment, visit, treatment-by-visit interaction, and strata (pooled country, baseline HbA1c, number of bolus injections at study entry, and type of basal insulin at lead-in) as fixed factors and baseline as a covariate. The model used an unstructured covariance structure