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


BACKGROUND
Clinicaltrials.gov NCT01119846 Clinicaltrials.gov NCT01128621.
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America.
Derek J
DJ
Nunez
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America.
Mark A
MA
Bush
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America.
David A
DA
Collins
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America.
Susan L
SL
McMullen
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America.
Dawn
D
Gillmor
Ohio State University Clinical Pharmacology Unit, Columbus, Ohio, United States of America.
Glen
G
Apseloff
Worldwide Clinical Trials, San Antonio, Texas, United States of America.
George
G
Atiee
Duke University Medical Center, Durham, North Carolina, United States of America.
Leonor
L
Corsino
Profil Institute for Clinical Research, Chula Vista, California, United States of America.
Linda
L
Morrow
GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States of America.
Paul L
PL
Feldman
D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005768:Gastrointestinal Hormones / Q000378:metabolism*; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D008698:Mesylates / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D010069:Oxadiazoles / Q000494:pharmacology*; D019894:Peptide YY / Q000378:metabolism; D011379:Prognosis; D011719:Pyrazines / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*
C587902:(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)methyl methanesulfonate; D001786:Blood Glucose; D002096:C-Peptide; C519854:GPR119 protein, human; D005768:Gastrointestinal Hormones; D007004:Hypoglycemic Agents; D007328:Insulin; D008698:Mesylates; D010069:Oxadiazoles; D011719:Pyrazines; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; D019894:Peptide YY; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin; D000068900:Sitagliptin Phosphate