Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: A phase 1 randomized, crossover study

Abstract

Aims: To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D).

Materials and methods: This was a randomized, double-blind, four-period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal.

Results: URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half-maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post-meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post-meal with URLi were comparable to those in healthy subjects.

Conclusions: URLi demonstrated the fastest insulin absorption and the greatest numeric PPG-lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.

Keywords: glycaemic control; insulin analogues; pharmacodynamics; pharmacokinetics; randomized trial; type 1 diabetes.

FIGURE 1

Mean insulin lispro concentration (±SE) versus time post injection (A) and for the first hour post injection (C), mean insulin aspart concentration (±SE) versus time post injection (B) and for the first hour post injection (D) by treatment. LLOQ, lower limit of quantification

FIGURE 2

Mean insulin concentration (±SE) versus time for the first hour post injection by treatment (A). Mean normalized exposure absorbed (±SE) versus time (B) and for the first hour post‐injection (inset). Mean insulin concentration (±SE) by treatment compared to endogenous insulin (C). Mean normalized exposure remaining (±SE) versus time post‐meal (D) and from 3 to 7 hours post injection (inset)

FIGURE 3

Forest plots of insulin exposure. AUC, area under the concentration versus time curve; AUC(0‐15 min), AUC from time 0 to 15 minutes post‐dose; AUC(0–30 min), AUC from time 0 to 30 minutes post‐dose; AUC(0–1 h): AUC from time 0 to 1 hour post‐dose; AUC(0–2 h), AUC from time 0 to 2 hours post‐dose; AUC(2–7 h), AUC from time 2 to 7 hours post‐dose; AUC(3–7 h), AUC from time 3 to 7 hours post‐dose; AUC(0–∞), AUC from time zero to infinity; CI, confidence interval; C_max, maximum observed drug concentration; early 50% t_max, time to early half‐maximal drug concentration; late 50% t_max, time to late half‐maximal drug concentration; LS, least squares; t_max, time of maximum observed drug concentration. LS mean; Model: PK = period + treatment + sequence + patient (sequence) + random error, where patient (sequence) is fitted as a random effect. The CIs for the ratio were calculated using the Fieller's theorem. P value is for the test of the mean difference. LS mean calculated as pmol h/L. 'Duration' refers to time from study drug administration until the serum insulin lispro concentrations reached the lower limit of quantification

FIGURE 4

Mean (+SE) change from baseline glucose concentration versus time post‐meal by treatment (A) and partial glucose excursions (iAUC) over the 5 hours by treatment (B). AUC, area under the concentration versus time curve; iAUC, incremental area under the concentration versus time curve

FIGURE 5

Mean insulin concentration versus time post‐meal (A) and change from baseline glucose concentration (+SE) versus time post‐meal (B) after URLi in patients with type 1 diabetes (T1D) and in healthy subjects and after Humalog or URLi in patients with T1D and in healthy subjects (C,D)