Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies

Abstract

GPR119 receptor agonists improve glucose metabolism and alter gut hormone profiles in animal models and healthy subjects. We therefore investigated the pharmacology of GSK1292263 (GSK263), a selective GPR119 agonist, in two randomized, placebo-controlled studies that enrolled subjects with type 2 diabetes. Study 1 had drug-naive subjects or subjects who had stopped their diabetic medications, and Study 2 had subjects taking metformin. GSK263 was administered as single (25-800 mg; n = 45) or multiple doses (100-600 mg/day for 14 days; n = 96). Placebo and sitagliptin 100 mg/day were administered as comparators. In Study 1, sitagliptin was co-administered with GSK263 or placebo on Day 14 of dosing. Oral glucose and meal challenges were used to assess the effects on plasma glucose, insulin, C-peptide, glucagon, peptide tyrosine-tyrosine (PYY), glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). After 13 days of dosing, GSK263 significantly increased plasma total PYY levels by ∼ five-fold compared with placebo, reaching peak concentrations of ∼ 50 pM after each of the three standardized meals with the 300 mg BID dose. Co-dosing of GSK263 and metformin augmented peak concentrations to ∼ 100 pM at lunchtime. GSK263 had no effect on active or total GLP-1 or GIP, but co-dosing with metformin increased post-prandial total GLP-1, with little effect on active GLP-1. Sitagliptin increased active GLP-1, but caused a profound suppression of total PYY, GLP-1, and GIP when dosed alone or with GSK263. This suppression of peptides was reduced when sitagliptin was co-dosed with metformin. GSK263 had no significant effect on circulating glucose, insulin, C-peptide or glucagon levels. We conclude that GSK263 did not improve glucose control in type 2 diabetics, but it had profound effects on circulating PYY. The gut hormone effects of this GPR119 agonist were modulated when co-dosed with metformin and sitagliptin. Metformin may modulate negative feedback loops controlling the secretion of enteroendocrine peptides.

Trial registration: Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.

Conflict of interest statement

Competing Interests: The authors declare the following completing interests: Derek Nunez is an employee of GlaxoSmithKline and was a stock/option holder at the time the studies were conducted. Mark Bush was an employee of GlaxoSmithKline and a stock/option holder at the time the studies were conducted. David Collins is an employee of GlaxoSmithKline and was a stock/option holder at the time the studies were conducted. Susan McMullen is an employee of GlaxoSmithKline and was a stock/option holder at the time the studies were conducted. Dawn Gillmor is an employee of GlaxoSmithKline and was a stock/option holder at the time the studies were conducted. Paul Feldman is an employee of GlaxoSmithKline and was a stock/option holder at the time the studies were conducted. Glen Apseloff is an employee of the Ohio State University and has consulted for GlaxoSmithKline. George Atiee was an employee of ICON Development Solutions at the time these studies were conducted. Leonor Corsino is an employee of the Duke University Medical Center. Linda Morrow is an employee of the Profil Institute for Clinical Research. The studies were sponsored by GlaxoSmithKline R&D. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Plasma concentrations of total PYY in Study 1 following 13 days of dosing GSK263, placebo or sitagliptin (A), and in Study 2 on Day 14 of co-dosing these study treatments with metformin (B).

The vertical black lines indicate the times of the meals. Values are Means (pmol/L) ± SEM.

Figure 2. Effects of GSK263 and sitagliptin on plasma total and active GLP-1.

Plasma concentrations of total GLP-1 in Study 1 following 13 days of dosing GSK263, placebo or sitagliptin (A), and in Study 2 following 14 days of co-administration of GSK263, placebo or sitagliptin with metformin (C). Plasma concentrations of active GLP-1 in Study 1 following 13 days of dosing (B), and in Study 2 after 14 days of dosing (D). The vertical black lines indicate the times of the meals. Values are Means (pmol/L) ± SEM.

Figure 3. Effects of GSK263 and sitagliptin on plasma total GIP.

Plasma concentrations of total GIP in Study 1 following 13 days of dosing GSK263, placebo or sitagliptin (A), and in Study 2 on Day 14 of co-dosing these study treatments with metformin (B). The vertical black lines indicate the times of the meals. Values are Means (pmol/L) ± SEM.

Figure 4. Plasma glucose and insulin.

Box plots of incremental plasma glucose AUC(0–3 h) (A; mmol*h/L) and insulin AUC(0–3 h) (B; pmol*h/L) after an OGTT. Single doses of GSK263, placebo and sitagliptin (Sit) were administered in a 5-way cross-over design. Boxplots of WM-AUC(0–24 h) for plasma glucose (C; mmol/L) and insulin (D; pmol/L) in Study 1 following 13 days of dosing GSK263, placebo or sitagliptin (Sit) after stopping prior diabetic medications. Boxplots of WM-AUC(0–24 h) for glucose (E; mmol/L) and insulin (F; pmol/L) following 14 days of co-administration of GSK263, placebo or sitagliptin (Sit) with metformin. Box plots show 25th, 50th, and 75th percentiles (horizontal bars), 1.5 interquartile ranges (error bars), and mean (+).

Figure 5. Steady-State plasma concentrations of GSK263 in Studies 1 and 2.

Mean (± SEM; ng/mL) concentration-time profiles of GSK263 on Day 13 of dosing in Study 1 (50 mg BID, 150 mg BID, 300 mg BID, and 600 mg QD) and on Day 14 in Study 2 (75 mg BID, 300 mg BID, and 600 mg QD). The concentration data for the 2 studies were combined for groups administered the same doses of GSK263 as there were no meaningful differences in the concentration-time profiles obtained when GSK263 was co-dosed with sitagliptin or metformin.