To investigate mechanisms responsible for the clinical and metabolic benefits observed with SGLT2i plus DPP-4i therapy, we randomized 30 T2D patients (A1c=8.6±0.2%, BMI=33.1±1.9) to receive dapagliflozin 10 mg [DAPA], dapagliflozin/saxagliptin 10/5 mg [DAPA/SAXA] or placebo [PCB]. Baseline OGTT, glucose kinetics (3-3H-glucose), indirect calorimetry, HbA1c, FPG, FFA, insulin, and glucagon were repeated after 16 weeks of therapy.

Results: Insulin secretion (δI/δG)0-120 min during OGTT increased (p<0.05) in DAPA (+0.6±0.1) and DAPA/SAXA (+0.6±0.1), but not in PCB (-0.4±0.20). The Matsuda Index improved (p<0.01) in DAPA (+0.6±0.20) and DAPA/SAXA (+0.7±0.1), but not in PCB (-0.1±0.2). The Disposition Index [IS/IR] increased (p<0.05) in DAPA (δ0.23±0.03) and DAPA/SAXA (δ 0.2±0.02), but not in PCB (δ0.03±0.04). The increase in fasting plasma glucagon in PCB (+37±4) and DAPA (+20±2) was blunted (p<0.05) in combo (-7±4 pg/ml). There were no significant changes in fasting plasma FFA.

Conclusion: DAPA/SAXA combination therapy was associated with improved glycemic control vs. DAPA due to the attenuation of the rise in EGP. Further, the increase in glucose Ox in combination with inhibition of lipid Ox and glucagon secretion inhibit ketone production which may reduce the risk of DKA. Addition of SAXA improves insulin secretion and prevents the glucagon elevation induced by DAPA.

     
Characteristics PCB DAPA DAPA/SAXA p-value 
δ BMI (Kg/m2) +0.16±0.27 -0.58±0.42 -0.77±0.01 *<0.05 
δ HbA1c (%) +0.6±0.2 -1.4±0.1 -1.7±0.2 *<0.01 
δ FPG (mg/dl) +35±3 -59±6 -68±8 *<0.001 
Mean OGTT Glu (mg/dl) +41±6 -73±8 -86±7 *<0.001 
δ Basal EGP (mg/kg.min) +0.26±0.04 +0.19±0.04 -0.06±0.05 **<0.01 
δ Lipid Ox (%) -8±6 +16±3 +10±2 *<0.001 & ***<0.05 
δ Glucose Ox (%) +5±4 -31±3 -17±2 *<0.001 &***<0.001 
     
Characteristics PCB DAPA DAPA/SAXA p-value 
δ BMI (Kg/m2) +0.16±0.27 -0.58±0.42 -0.77±0.01 *<0.05 
δ HbA1c (%) +0.6±0.2 -1.4±0.1 -1.7±0.2 *<0.01 
δ FPG (mg/dl) +35±3 -59±6 -68±8 *<0.001 
Mean OGTT Glu (mg/dl) +41±6 -73±8 -86±7 *<0.001 
δ Basal EGP (mg/kg.min) +0.26±0.04 +0.19±0.04 -0.06±0.05 **<0.01 
δ Lipid Ox (%) -8±6 +16±3 +10±2 *<0.001 & ***<0.05 
δ Glucose Ox (%) +5±4 -31±3 -17±2 *<0.001 &***<0.001 

*= DAPA & DAPA/SAXA vs. PCB; **=DAPA/SAXA vs. DAPA & PCB; ***=DAPA vs. DAPA/SAXA EGP=Endogenous Glucose Production; Ox: Oxidation

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Disclosure

Y. Qin: None. J.M. Adams: None. R.A. Martinez: None. A. Di Pino: None. H. Al Jobori: None. A.M. Ali: None. C.L. Triplitt: Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Eli Lilly and Company. Consultant; Self; Sanofi, Novo Nordisk Inc. R.A. DeFronzo: Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc.. Advisory Panel; Self; AstraZeneca, Novo Nordisk Inc., Janssen Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc.. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc. E. Cersosimo: Research Support; Self; AstraZeneca, VeroScience, LLC.. Speaker's Bureau; Self; AstraZeneca, Sanofi, Janssen Pharmaceuticals, Inc., Eli Lilly and Company.

© 2018 by the American Diabetes Association.
2018
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