Ultra Rapid Lispro (URLi) Accelerates Insulin Lispro Absorption and Insulin Action vs Humalog® Consistently Across Study Populations: A Pooled Analysis of Pharmacokinetic and Glucodynamic Data

Abstract

Background and objective: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This pooled analysis compared the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with type 1 or type 2 diabetes mellitus.

Methods: The analysis included four randomized, double-blind, crossover, single-dose studies (healthy subjects [n = 74], patients with type 1 diabetes [n = 78], and type 2 diabetes [n = 38]) evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog during an 8- to 10-h euglycemic clamp procedure.

Results: The pooled analysis showed an ~ 5-min faster onset of appearance, an ~8-fold greater exposure in the first 15 min, a 43% reduction in exposure beyond 3 h, and a 68-min shorter exposure duration with URLi vs Humalog across all study populations and dose range. Compared with Humalog, URLi had a 10-min faster onset of action, a 3-fold greater insulin action in the first 30 min, a 35% reduction in insulin action beyond 4 h, and a 44-min shorter duration of action across all populations and dose range. Overall exposure and insulin action were similar between URLi and Humalog for each dose level and study population.

Conclusions: Across the studied populations and dose range, URLi consistently demonstrated a faster absorption, reduced late exposure, and overall shorter exposure duration compared with Humalog. Similarly, URLi demonstrated earlier insulin action while reducing late insulin action and shorter insulin action compared with Humalog across the study populations and dose range.

Clinical trial registration: NCT02942654 (registered: 21 October, 2016), NCT03286751 (registered: 15 September, 2017), NCT03166124 (registered: 23 May, 2017), and NCT03305822 (registered: 5 October, 2017).

Conflict of interest statement

Jennifer Leohr, Mary Anne Dellva, Kallin Carter, Elizabeth LaBell, and Helle Linnebjerg are employees and shareholders of Eli Lilly and Company.

© 2021. The Author(s).

Figures

Fig. 1

Mean (± standard error) serum insulin lispro concentration–time profile (top panels) and mean glucose infusion rates vs time profiles (bottom panels) for ultra rapid lispro (URLi) and Humalog in healthy subjects (left panels), patients with type 1 diabetes (younger adults; middle panels), and patients with type 2 diabetes (right panels). Data from [–23]. U units

Fig. 2

Forest plots of the difference and ratio of geometric least-squares means and 95% confidence interval (CI) between ultra rapid lispro (URLi) and Humalog for early insulin lispro pharmacokinetic parameters in adults in individual studies and in the pooled analysis. AUC area under the concentration–time curve, AUC0–15min AUC from 0 to 15 min, AUC0–30min AUC from 0 to 30 min, AUC0–1h AUC from 0 to 1 h, early 50% tmax time to early half-maximal drug concentration, T1D type 1 diabetes, T2D type 2 diabetes, U units

Fig. 3

Forest plots of the difference and ratio of geometric least-squares means and 95% confidence interval (CI) between ultra rapid lispro (URLi) and Humalog for late insulin lispro pharmacokinetic parameters in adults in individual studies and in the pooled analysis. AUC area under the concentration–time curve, AUC2–Xh AUC from 2 to X h, AUC3–Xh AUC from 3 to X h, late 50% tmax time to late half-maximal drug concentration, T1D type 1 diabetes, T2D type 2 diabetes, U units, X 8 h for trial 1 and 10 h for all other trials

Fig. 4

Forest plots of the difference and ratio of geometric least-squares means and 95% confidence interval (CI) between ultra rapid lispro (URLi) and Humalog for overall insulin lispro pharmacokinetic parameters in adults in individual studies and in the pooled analysis. AUC area under the concentration–time curve, AUC0–∞ AUC from time 0 to infinity, Cmax maximum observed drug concentration, T1D type 1 diabetes, T2D type 2 diabetes, tmax time to maximum observed drug concentration, U units

Fig. 5

Forest plots of the difference and ratio of geometric least-squares means and 95% confidence interval (CI) between ultra rapid lispro (URLi) and Humalog for early insulin action in adults in individual studies and in the pooled analysis. Note: For glucodynamic parameters with at least one patient with a value of 0, treatment ratios of least-squares means and their 95% CIs were estimated using Fieller’s method. early 50% tRmax time to half-maximal glucose infusion rate before maximum glucose infusion rate, Gtot total amount of glucose infused over the duration of the clamp procedure, Gtot,0–30min total amount of glucose infused over 30 min, Gtot,0–1h total amount of glucose infused over 1 h, T1D type 1 diabetes, T2D type 2 diabetes, Tonset time to onset of insulin action, U units

Fig. 6

Forest plots of the difference and ratio of geometric least-squares means and 95% confidence interval (CI) between ultra rapid lispro (URLi) and Humalog for late insulin action in adults in individual studies and in the pooled analysis. Note: For glucodynamic parameters with at least one patient with a value of 0, treatment ratios of least-squares means and their 95% CIs were estimated using Fieller’s method. Gtot total amount of glucose infused over the duration of the clamp procedure, Gtot,2h–End total amount of glucose infused from 2 h post-dose until the end of the clamp, Gtot,3h–End total amount of glucose infused from 3 h post-dose until the end of the clamp, Gtot,4h–End total amount of glucose infused from 4 h post-dose until the end of the clamp, late 50% tRmax time to half-maximal glucose infusion rate after maximum glucose infusion rate, T1D type 1 diabetes, T2D type 2 diabetes, U units

Fig. 7

Forest plots of the ratio of geometric least-squares means and 95% confidence interval (CI) between ultra rapid lispro (URLi) and Humalog for overall insulin action in adults in individual studies and in the pooled analysis. Gtot total amount of glucose infused over the duration of the clamp procedure, Rmax maximum glucose infusion rate, T1D type 1 diabetes, T2D type 2 diabetes, U units