TY - JOUR
T1 - Clinical parameters, fuel oxidation, and glucose kinetics in patients with type 2 diabetes treated with dapagliflozin plus saxagliptin
AU - Qin, Yuejuan
AU - Adams, John
AU - Solis-Herrera, Carolina
AU - Triplitt, Curtis
AU - Defronzo, Ralph
AU - Cersosimo, Eugenio
N1 - Funding Information:
Acknowledgments. The authors acknowledge the support of the staff and faculty of the CRC of TexasDiabetesInstitute–UniversityHealthSystem and nurse coordinator Khanh Horst for invaluable care of the study subjects. The authors are grateful to Lorrie Albarado, administrative assistant, Division of Diabetes, for help with the manuscript preparation. Funding and Duality of Interest. Funding for this study was provided in part by AstraZeneca and the Texas Diabetes Institute–University Health System and University of Texas Health Science Center at San Antonio and in part by National Institutes of Health grant DK-24091. C.T. has received honoraria from the speakers bureaus of Boehringer Ingelheim and AstraZe-neca. R.D. has received honoraria from the speakers bureaus of AstraZeneca and Novo Nordisk; is a member of the advisory boards of AstraZeneca, Novo Nordisk, Janssen Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, and Intarcia; and has received grant support from AstraZeneca, Janssen Pharmaceuticals, and Novo Nordisk. E.C. has received honoraria from the speakers bureaus of Sanofi, AstraZe-neca, and Boehringer Ingelheim-Eli Lilly Alliance and grants from AstraZeneca, Janssen Pharmaceuticals, and VeroScience. No other potential conflicts of interest relevant to this article were reported. Author Contributions. Y.Q., C.S.-H., C.T., and E.C. executed the research procedures and contributed to sample collection, laboratory analyses, and data interpretation. J.A. provided laboratory analyses and technical assistance. E.C. and R.D. designed the study; supervised the research procedures; provided clinical management and data interpretation; and wrote, reviewed, and edited the manuscript. E.C. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017.
Publisher Copyright:
© 2020 by the American Diabetes Association.
PY - 2020/10
Y1 - 2020/10
N2 - 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.
AB - 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.
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U2 - 10.2337/dc19-1993
DO - 10.2337/dc19-1993
M3 - Article
C2 - 32694214
AN - SCOPUS:85091470119
SN - 0149-5992
VL - 43
SP - 2519
EP - 2527
JO - Diabetes care
JF - Diabetes care
IS - 10
ER -