Emergence of a New Glucoregulatory Mechanism for Glycemic Control With Dapagliflozin/Exenatide Therapy in Type 2 Diabetes

Context This study addresses the development of a new glucoregulatory mechanism in type 2 diabetes (T2D) patients treated with SGLT-2 inhibitors, which is independent of glucose, insulin and glucagon. The data suggest the presence of a potential trigger factor (s) arising in the kidney that stimulates endogenous glucose production (EGP) during sustained glycosuria.Objective To investigate effects of SGLT-2 inhibitor therapy together with GLP-1 receptor agonist on EGP and glucose kinetics in patients with T2D. 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 and glucagon suppression.Methods Seventy-five patients received a 5-hour dual-tracer oral glucose tolerance test (OGTT) (intravenous 3-(3H)-glucose oral (1-14C)-glucose): (1) before/after 1 of dapagliflozin (DAPA); exenatide (EXE), or both, DAPA/EXE (acute study), and (2) after 1 and 4 months of therapy with each drug.Results In the acute study, during the OGTT plasma glucose (PG) elevation was lower in EXE (Delta = 42 +/- 1 mg/dL) than DAPA (Delta = 72 +/- 3), and lower in DAPA/EXE (Delta = 11 +/- 3) than EXE and DAPA. EGP decrease was lower in DAPA (Delta = -0.65 +/- 0.03 mg/kg/min) than EXE (Delta = -0.96 +/- 0.07); in DAPA/EXE (Delta = -0.84 +/- 0.05) it was lower than EXE, higher than DAPA. At 1 month, similar PG elevations (EXE, Delta = 26 +/- 1 mg/dL; DAPA, Delta = 62 +/- 2, DAPA/EXE, Delta = 27 +/- 1) and EGP decreases (DAPA, Delta = -0.60 +/- 0.05 mg/kg/min; EXE, Delta = -0.77 +/- 0.04; DAPA/EXE, Delta = -0.72 +/- 0.03) were observed. At 4 months, PG elevations (EXE, Delta = 55 +/- 2 mg/dL; DAPA, Delta = 65 +/- 6; DAPA/EXE, Delta = 46 +/- 2) and lower EGP decrease in DAPA (Delta = -0.66 +/- 0.04 mg/kg/min) vs EXE (Delta = -0.84 +/- 0.05) were also comparable; in DAPA/EXE (Delta = -0.65 +/- 0.03) it was equal to DAPA and lower than EXE. Changes in plasma insulin/glucagon could not explain higher EGP in DAPA/EXE vs EXE mg/kg/min.Conclusion Our findings provide strong evidence for the emergence of a new long-lasting, glucose-independent, insulin/glucagon-independent, glucoregulatory mechanism via which SGLT2i-induced glycosuria stimulates EGP in patients with T2D. SGLT2i plus GLP-1 receptor agonist combination therapy is accompanied by superior glycemic control vs monotherapy.