Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1.
The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.
Merck Research Laboratories, Rahway, New Jersey, USA.
E M
EM
Migoya
R
R
Bergeron
J L
JL
Miller
R N K
RN
Snyder
M
M
Tanen
D
D
Hilliard
B
B
Weiss
P
P
Larson
M
M
Gutierrez
G
G
Jiang
F
F
Liu
K A
KA
Pryor
J
J
Yao
L
L
Zhu
J J
JJ
Holst
C
C
Deacon
G
G
Herman
N
N
Thornberry
J
J
Amatruda
D
D
Williams-Herman
J A
JA
Wagner
R
R
SinhaRoy
D000293:Adolescent; D000328:Adult; D000818:Animals; D018592:Cross-Over Studies; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D006801:Humans; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000188:drug therapy / Q000201:enzymology; D055815:Young Adult
D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D008687:Metformin