Clinical Parameters, Fuel Oxidation, and Glucose Kinetics in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin

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 (-2.0 ± 0.3%) vs. DAPA (-1.4 ± 0.2%) and greater than PCB (0.2 ± 0.2%). Day 1 of drug administration, EGP (∼2.40 mg/kg/min) decreased by -0.44 ± 0.09 mg/kg/min in PCB (P < 0.05) but only by -0.21 ± 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 µmol/L with DAPA but declined by -110 with PCB and -90 µmol/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.

Trial registration: ClinicalTrials.gov NCT02613897.

© 2020 by the American Diabetes Association.

Figures

Figure 1

A: Baseline plasma glucose concentration (mg/dL) and changes during 300 min following acute exposure (day 1). B: Baseline EGP (mg/kg/min) and changes during 300 min following acute exposure (day 1). C: Plasma glucose concentration (mg/dL) 16 weeks Post-Tx before and during 300 min following the last dose of the drug(s). D: EGP (mg/kg/min) 16 weeks Post-Tx before and during 300 min following the last dose of the drug(s).

Figure 2

A: Plasma insulin concentration (μU/mL) at baseline and mean values during the 300 min following acute drug exposure (Pre-Tx) and following drug exposure after 16 weeks of treatment (Post-Tx) with PCB, DAPA, and DAPA/SAXA. *P < 0.05 vs. PCB and DAPA/SAXA, **P < 0.05. B: Plasma C-peptide concentration (ng/mL) at baseline and mean values during the 300 min following acute drug exposure (Pre-Tx) and following drug exposure after 16 weeks of treatment (Post-Tx) with PCB, DAPA, and DAPA/SAXA. C: Plasma glucagon concentration (pg/mL) at baseline and mean values during the 300 min following acute drug exposure (Pre-Tx) and following drug exposure after 16 weeks of treatment (Post-Tx) with PCB, DAPA, and DAPA/SAXA. **P < 0.01 vs. DAPA and PCB.

Figure 3

Changes in basal rates of carbohydrate and lipid oxidation before drug administration (day 1) compared with week 16 following PCB, DAPA, and DAPA/SAXA. DAPA monotherapy significantly reduced carbohydrate and increased lipid oxidation rates compared with PCB. Combination therapy of DAPA/SAXA attenuated the reduction in carbohydrate oxidation and prevented elevation in lipid oxidation rates after 16 weeks. *P < 0.001 DAPA vs. DAPA/SAXA and PCB.