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

Synergistic Effects of a GPR119 Agonist with Metformin on Weight Loss in Diet-Induced Obese Mice

“…The G protein-coupled receptor (GPCR) 119 (GPR119) has recently attracted attention because of preclinical and clinical evidence that its modulation may produce favorable effects on glucose homoeostasis, food intake and body weight gain, dyslipidemia, and possible b-cell preservation (Overton et al, 2008;Jones et al, 2009;Goodman et al, 2011;Nunez et al, 2014). GPR119 is a class A (rhodopsin-like) GPCR, with no close primary sequence relative in the human genome (Fredriksson et al, 2003), and its sequence is highly conserved in a human, mouse, and rat (Bonini et al, 2001).…”

“…GSK1292263, a clinical GPR119 agonist, increased plasma glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine (PYY) in diabetic subjects, and codosing of GSK1292263 with metformin augmented plasma GLP-1 and PYY peak concentration (Nunez et al, 2014)…”

Therapeutic application of GPR119 ligands in metabolic disorders

“…GSK1292263 was developed by GlaxoSmithKline and entered phase II clinical trials . Administration of GSK1292263 to ZDF rats for 7 weeks reduced HbA1c levels and glucose excursion .…”

“…Unlike PSN821, which inhibited gastric emptying and weight gain, GSK1292263 did not affect either of these parameters . According to 2 randomized phase II studies in type 2 diabetic subjects, GSK192263 did not significantly affect circulating glucose, insulin, glucagon, GLP‐1 or GIP levels, demonstrating that this compound does not improve glucose control in type 2 diabetes mellitus (T2DM) …”

“…Nevertheless, none of the GPR119 agonists that have entered clinical trials has gone beyond phase II . For instance, GSK1292263 alone did not increase GLP‐1 levels and had little effect on blood glucose and insulin levels in T2DM patients (http://clinicaltrials.gov Identifiers: NCT01119846, NCT01128621) . Although peak postprandial PYY values reached ~50 p M after repeated administration of GSK1292263, plasma fasting glucose and glucose weighted mean AUC were not reduced in subjects with T2DM .…”