Clinical parameters, fuel oxidation, and glucose kinetics in patients with type 2 diabetes treated with dapagliflozin plus saxagliptin

Yuejuan Qin, John Adams, Carolina Solis-Herrera, Curtis Triplitt, Ralph Defronzo, Eugenio Cersosimo

Research output: Contribution to journalArticlepeer-review

Abstract

OBJECTIVE To examine the mechanisms responsible for improved glycemia with combined sodium–glucose cotransporter 2 inhibitor (SGLT2i) plus dipeptidyl peptidase 4 inhibitor therapy in type 2 diabetes. RESEARCH DESIGN AND METHODS Fifty-six patients (HbA1c 8.9 ± 0.2% [74 ± 2 mmol/mol]) were randomized to dapagliflozin (DAPA) 10 mg, DAPA/saxagliptin (SAXA) 10/5 mg, or placebo (PCB) for 16 weeks. Basal endogenous glucose production (EGP) (3-3H-glucose), urinary glucose excretion, glucose/lipid oxidation, HbA1c, and substrate/hormone levels were determined before treatment (Pre-Tx) and after treatment (Post-Tx). RESULTS At week 16, HbA1c decrease was greater (P < 0.05) in DAPA/SAXA (22.0 ± 0.3%) vs. DAPA (21.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (~2.40 mg/kg/min) decreased by 20.44 ± 0.09mg/kg/mininPCB(P < 0.05) but only by 20.21 ± 0.02 mg/kg/min in DAPA and DAPA/SAXA (P < 0.05 vs. PCB). At week 16, EGP increased to 2.67 ± 0.09 mg/kg/min (DAPA) and 2.61 ± 0.08 mg/kg/min (DAPA/SAXA), despite reductions in fasting plasma glucose by 47 and 77 mg/dL, respectively, and no changes in PCB. Baseline plasma free fatty acids rose by 40 mmol/L with DAPA but declined by 2110 with PCB and 290mmol/L with DAPA/SAXA (P< 0.05, Pre-Tx vs. Post-Tx). In DAPA, carbohydrate oxidation rates decreased from 1.1 ± 0.1 to 0.7 ± 0.1 mg/kg/min, whereas lipid oxidation rates increased from 0.6 ± 0.1 to 0.8 ± 0.1 mg/kg/min (P < 0.01). In DAPA/SAXA, the shift in carbohydrate (1.1 ± 0.1 to 0.9 ± 0.1 mg/kg/min) and lipid (0.6 ± 0.1 to 0.7 ± 0.1 mg/kg/min) oxidation was attenuated (P < 0.05). CONCLUSIONS The addition of SAXA to DAPA resulted in superior glycemic control compared with DAPA monotherapy partly because of increased glucose utilization and oxidation. Although the decrease in insulin/glucagon ratio was prevented by SAXA, EGP paradoxical elevation persisted, indicating that other factors mediate EGP changes in response to SGLT2i-induced glucosuria.

Original languageEnglish (US)
Pages (from-to)2519-2527
Number of pages9
JournalDiabetes care
Volume43
Issue number10
DOIs
StatePublished - Oct 2020

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

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