Beta-cell function, incretin effect and glucose kinetics in response to a mixed meal in patients with type 2 diabetes treated with dapagliflozin plus saxagliptin

Objective - To explore complementary effects of DPP-4 and SGLT2 inhibitors combination as add on to metformin on hormonal and metabolic responses to meal ingestion. Research Design and Methods - Forty-five patients (58±8 y, HbA1c: 58±6 mmol/mol, BMI: 30.7±3.2 Kg/m2) uncontrolled with metformin were evaluated at baseline, 3- and 28-days after saxagliptin 5 mg (SAXA), dapagliflozin 10 mg (DAPA), and saxagliptin 5 mg plus dapagliflozin 10 mg (SAXA+DAPA) with a mixed meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion and sensitivity. Results - At day 3, fasting and mean MMTT glucose were lower with SAXA+DAPA (-31.1± 1.6 mg/dl; -91.5± 12.4 mg/dl) than SAXA (-7.1± 2.1 and -53±10.5 mg/dl) and DAPA (-17.0±1.1; -42.6±10.0 mg/dl; p<0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA 3%) and insulin sensitivity (+2.2±1.7, +0.4±0.7, +0.4±0.4 mg kg-1 min-1; respectively) improved with SAXA+DAPA (p<0.007). Mean GLP-1 was higher in SAXA+DAPA than SAXA and DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting EGP increased with SAXA+DAPA and DAPA. During MMTT EGP suppression was greater (48%) with SAXA+DAPA (SAXA 44%, p=0.02; DAPA 34%, p=0.2). Metabolic Clearance Rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, b cell glucose sensitivity, insulin sensitivity further increased in SAXA+DAPA (p=0.02) with no further changes in GLP-1, glucagon, fasting and MMTT EGP, and MCRglu. Conclusions SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA due to improved β cell function, insulin sensitivity, GLP-1 availability and glucose clearance.