Pharmacokinetic Properties of Liraglutide as Adjunct to Insulin in Subjects with Type 1 Diabetes Mellitus

Abstract

Background: The pharmacokinetic properties of liraglutide, a glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus (T2D), have been established in healthy individuals and subjects with T2D. Liraglutide has been under investigation as adjunct treatment to insulin in type 1 diabetes mellitus (T1D). This single-center, double-blind, placebo-controlled, crossover, clinical pharmacology trial is the first to analyze the pharmacokinetic properties of liraglutide as add-on to insulin in T1D.

Methods: Subjects (18-64 years; body mass index 20.0-28.0 kg/m2; glycated hemoglobin ≤9.5 %) were randomized 1:1:1 to 0.6, 1.2, or 1.8 mg liraglutide/placebo. Each group underwent two 4-week treatment periods (liraglutide then placebo or placebo then liraglutide) separated by a 2- to 3-week washout. Both trial drugs were administered subcutaneously, once daily, as adjunct to insulin. A stepwise hypoglycemic clamp was performed at the end of each treatment period (data reported previously). Pharmacokinetic endpoints were derived from liraglutide concentration-time curves after the final dose and exposure was compared with data from previous trials in healthy volunteers and subjects with T2D.

Results: The pharmacokinetic properties of liraglutide in T1D were comparable with those observed in healthy volunteers and subjects with T2D. Area under the steady-state concentration-time curve (AUC) and maximum plasma concentration data were consistent with dose proportionality of liraglutide. Comparison of dose-normalized liraglutide AUC suggested that exposure in T1D, when administered with insulin, is comparable with that observed in T2D.

Conclusions: Liraglutide, administered as adjunct to insulin in subjects with T1D, shows comparable pharmacokinetics to those in subjects with T2D. ClinicalTrials.gov Identifier: NCT01536665.

Conflict of interest statement

Compliance with Ethical Standards Funding This study was funded by Novo Nordisk A/S, Søborg, Denmark. Conflict of interest Julia Mader has received speaker honoraria from Novo Nordisk, Roche Diabetes Care, Nintamed, and Takeda, and has served on the advisory boards of Sanofi, Boehringer–Ingelheim and Eli Lilly. Erik Christiansen, Lene Jensen, and Steen Ingerwersen are employees and shareholders of Novo Nordisk A/S. Simon Heller has served as a consultant to Novo Nordisk, Eli Lilly, Sanofi, Boehringer–Ingelheim and Takeda, served on the speaker panel of Novo Nordisk, Eli Lilly, Sanofi, MSD, and Takeda, and received research support from Medtronic. Thomas Pieber has received research support from Novo Nordisk and has served on the advisory board or speakers’ bureau of Novo Nordisk, AstraZeneca, and Eli Lilly.

Figures

Fig. 1

Liraglutide concentration profiles in patients with type 1 diabetes. Greencurve represents liraglutide 0.6 mg; blue curve represents liraglutide 1.2 mg; orange curve represents liraglutide 1.8 mg. Data are geometric mean with 95 % confidence intervals

Fig. 2

Liraglutide a AUC and bCmax according to dose in patients with type 1 diabetes. Solid lines represent the estimated curves based on a linear model with logarithmic transformed dose as covariate fitted to the logarithmic transformed endpoint under the assumption of dose proportionality (i.e. an exponent of 1 in the regression model). Symbols represent observed values. AUC area under the curve, Cmax maximum concentration

Fig. 3

Scatter plot of dose-normalized liraglutide AUC for patients with type 1 diabetes taking insulin compared with patients with type 2 diabetes. Horizontal lines represent the geometric mean of the group. Data from the three trials in type 2 diabetes are also dose-normalized. Differences in baselines demographics, particularly sex and body weight, as described in the text, may have influenced outcomes. AUC steady-state area under the curve, PK pharmacokinetics