Evidence connecting old, new and neglected glucose‐lowering drugs to bile acid‐induced GLP‐1 secretion: A review

Abstract

Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G-protein-coupled receptor 5 and the nuclear farnesoid X receptor, in intestinal L cells. The present article critically reviews current evidence connecting established glucose-lowering drugs to bile acid-induced GLP-1 secretion, and discusses whether bile acid-induced GLP-1 secretion may constitute a new basis for understanding how metformin, inhibitors of the apical sodium-dependent bile acids transporter, and bile acid sequestrants - old, new and neglected glucose-lowering drugs - improve glucose metabolism.

Impact of metformin use on the cardiovascular effects of dipeptidyl peptidase‐4 inhibitors: An analysis of Medicare claims data from 2007 to 2015

“…Since metformin is the consensus first‐line medical treatment for type 2 diabetes, recognizing how its presence impacts the effectiveness of next‐line agents such as DPP‐4 inhibitors could inform clinical practice and guideline development. Because there exists a potential GLP‐1‐based mechanism by which metformin could enhance the effect of DPP‐4 inhibitors, DPP‐4 inhibitors provide a sensible opportunity to study interactions with metformin.…”

“…Currently, how different medication classes interact to determine CV outcomes in type 2 diabetes is poorly understood. Since metformin is the consensus first-line medical treatment for type 2 diabetes, 1 exists a potential GLP-1-based mechanism by which metformin could enhance the effect of DPP-4 inhibitors, 8,9 DPP-4 inhibitors provide a sensible opportunity to study interactions with metformin.…”

“…The difference in overall DPP‐4 inhibitor effect between metformin user and non‐user subgroups was statistically significant ( P = 0.036). Because there is a physiological mechanism by which metformin could potentiate the effect of DPP‐4 inhibitors (metformin raises levels of glucagon‐like peptide‐1 [GLP‐1], and DPP‐4 inhibitors inhibit GLP‐1 degradation), it is plausible that the two drugs could interact synergistically.…”

Bile acid signaling and bariatric surgery

“…65 Bile acid sequestrants regulate glucose homeostasis, at least in part by modulating FXR- and TGR5-mediated pathways. 66,67 …”

<p>Add-On Therapy with DPP-4 Inhibitors May Improve Renal Function Decline in α-Glucosidase Inhibitor and Metformin Users: A Retrospective Observational Study</p>

“…Recently, a meta-analysis of the three major DPP-4 inhibitor cardiovascular outcomes trials (CVOTs) suggested that baseline metformin use may have a moderating effect on cardiovascular outcomes in DPP-4 inhibitor use. 10 DPP-4 inhibitors prevent the degradation of active glucagon-like peptide-1 (GLP-1), 8 and metformin 11,12 or α-glucosidase inhibitors 13,14 increase circulating GLP-1 levels in clinical studies. Therefore, it is plausible that these drugs could interact synergistically.…”