Emergence of a New Gluco-Regulatory Mechanism for Glycemic Control with Dapagliflozin/Exenatide Therapy in Type 2 Diabetes

To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on endogenous glucose production [EGP], glucose kinetics in T2D patents. Our hypothesis was that increased EGP in response to SGLT2i-induced glycosuria persists for a long period and is not abolished by GLP-1 RA stimulation of insulin secretion, glucagon suppression.75 patients received 5-hour dual-tracer OGTT (IV 3-[3H]-glucose oral [1-14C]-glucose): i) before/after one dose of dapagliflozin [DAPA]; exenatide [EXE] or both, DAPA/EXE (ACUTE STUDY), and ii) after 1, 4 months therapy with each drug.In ACUTE STUDY, during OGTT plasma glucose [PG] elevation was lower in EXE [Δ=42 ± 1 mg/dl] than DAPA [Δ=72 ± 3]; lower in DAPA/EXE [Δ=11 ± 3] than EXE and DAPA. EGP decrease was lower in DAPA [Δ=-0.65 ± 0.03 mg/kg/min] than EXE [Δ=-0.96 ± 0.07]; in DAPA/EXE [Δ=-0.84 ± 0.05] it was lower than EXE, higher than DAPA. At 1-MONTH similar PG elevations [EXE, Δ=26 ± 1 mg/dl; DAPA, Δ=62 ± 2, DAPA/EXE, Δ=27 ± 1] and EGP decreases [DAPA, Δ=-0.60 ± 0.05 mg/kg/min, EXE, Δ=-0.77 ± 0.04, DAPA/EXE, Δ=-0.72 ± 0.03] were observed. At 4-MONTHS, PG elevations [EXE, Δ=55 ± 2 mg/dl; DAPA, Δ=65 ± 6, DAPA/EXE, Δ=46 ± 2] and lower EGP decrease in DAPA (Δ=-0.66 ± 0.04 mg/kg/min) vs. EXE (Δ=-0.84 ± 0.05) were also comparable; in DAPA/EXE (Δ=-0.65 ± 0.03) it was equal to DAPA, lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs. EXE mg/kg/min.Our findings provide strong evidence for the emergence of a new long-lasting, glucose-, insulin/glucagon-independent, gluco-regulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in T2D patients. SGLT2i plus GLP-1 RA combination therapy is accompanied by superior glycemic control versus monotherapy.