Aim: G‐protein coupled receptor agonists are currently under investigation for their potential utility in patients with type 2 diabetes mellitus (T2DM). The objective was to determine the pharmacokinetics, pharmacodynamics, safety and tolerability of GPR119 agonist, JNJ‐38431055 in T2DM subjects.

Methods: This was a randomized, double‐blind, placebo‐ and positive‐controled, single‐dose cross‐over study and a randomized, double‐blind, placebo‐controled multiple‐dose parallel design study. The study was conducted at 4 US research centres. Two different experiments involving 25 and 32 different subjects were performed in male and female subjects, aged 25–60 years, mean body mass index between 22 and 39.9 kg/m2 who had T2DM diagnosed 6 months to 10 years before screening. JNJ‐38431055 (100 and 500 mg) or sitagliptin (100 mg) as a single‐dose or JNJ‐38431055 (500 mg) once daily for 14 consecutive days were tested. Effects on stimulated plasma glucose, insulin, C‐peptide and incretin concentrations were pre‐specified outcomes.

Results: JNJ‐38431055 was well tolerated and not associated with hypoglycaemia. Plasma systemic exposure of JNJ‐38431055 increased as the dose increased, was approximately two‐fold greater after multiple‐dose administration, and attained steady‐state after approximately 8 days. Compared with placebo, single‐dose administration of oral JNJ‐38431055 decreased glucose excursion during an oral glucose tolerance test, but multiple‐dose administration did not alter 24‐h weighted mean glucose. Multiple dosing of JNJ‐38431055 increased post‐meal total glucagon‐like peptide 1 and gastric insulinotropic peptide concentrations compared to baseline.

Conclusions: These studies provide evidence of limited glucose lowering and incretin activity for JNJ‐38431055 in subjects with T2DM.