Objectives and Methods: To examine changes in endogenous glucose production (EGP). Tissue glucose disappearance (Rd) and urinary glucose excretion (UGE) after SGLT2i alone and combined with DPP-4i. We randomized (2:2:1) 56 T2D patients (A1c=8.9±0.2, FPG=178±10, BMI=34±1.3) to receive dapagliflozin 10 mg [n=22, D], dapagliflozin/saxagliptin 10/5 mg [n=22, D/S], placebo [n=12, P]. Subjects received 75 g OGTT (240 min) with [3H-glu] IV and [14C-glu ] orally pre and post treatment (Tx) for 4 months.
Results: Post-Tx, A1c increased by 0.1±0.4% in P and decreased (p<001) by 1.4±0.2% in (D) and 1.9±0.3% in (D/S) (p<0.001). FPG decreased by 44 (D) and 56 (D/S) mg/dl (p <0.001) and was unchanged with (P). During OGTT, increment in PG was reduced by 21 (D) and 29 (D/S) (p<0.001) and increased by 12 mg/dl in (P).Pre-Tx, basal EGP was similar in 3 groups (~2.4 mg/kg.min) and decreased by ~50% during OGTT. Post-Tx, despite the marked decrease in FPG, basal EGP increased in both D and D/S; EGP suppression ~50% during OGTT was unchanged in D and D/S. Pre-Tx, UGE (mg/kg.min) during OGTT was negligible in 3 groups: Post-Tx, UGE increased to 1.0±0.1 (D) and 1.1±0.1 (D/S) (p<0.01) but not in P. Pre-Tx, Tissue Rd (mg/kg.min) increased similarly during OGTT in all 3 groups by ~ 40%; Post-Tx, the increase in Tissue Rd was greater (p<0.05) in D (∆1.7±0.3) and D/P (∆3.8±0.3) vs. P (∆1.4±0.2). Pre-Tx, basal glucose clearance (GC) was similar in all 3 groups (~1.4 ml/kg.min) and did not change during OGTT. Post-Tx, both basal GC and GC during OGTT increased (p<0.05-0.01) in D and D/S, without change in plasma insulin/C-peptide conc.
Conclusions: D and D/S treatment improved glycemic control by (i) increasing UGE and (ii) augmenting Tissue glucose clearance by ameliorating glucotoxicity, Saxa addition to dapa produced only modest further A1c reduction because it failed to block dapagliflozin-induced stimulation of EGP, even though it increased insulin and decreased glucagon secretion.
Y. Qin: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Abdul-Ghani: None. J.M. Adams: None. A.M. Ali: None. M.M. Eletrebi: None. R.A. Martinez: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker&s Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None.