Type 2 diabetes is characterized by impaired β-cell function associated with 
progressive reduction of insulin secretion and β-cell mass. Evidently, there is 
an unmet need for treatments with greater sustainability in β-cell protection 
and antidiabetic efficacy. Through an insulin and β cell-independent mechanism, 
empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) 
inhibitor, may potentially provide longer efficacy. This study compared the 
antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against 
glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient 
glucose homeostasis and β-cell function in Zucker diabetic fatty (ZDF) rats. 
Empagliflozin and liraglutide led to marked improvements in fed glucose and 
hemoglobin A1c levels, as well as impeding a progressive decline in insulin 
levels. In contrast, glibenclamide was ineffective. Whereas the effects of 
liraglutide were less pronounced at week 8 of treatment compared with week 4, 
those of empagliflozin remained stable throughout the study period. Similarly, 
empagliflozin improved glucose tolerance and preserved insulin secretion after 
both 4 and 8 weeks of treatment. These effects were reflected by less reduction 
in β-cell mass with empagliflozin or liraglutide at week 4, whereas only 
empagliflozin showed β-cell sparing effects also at week 8. Although this study 
cannot be used to dissociate the absolute antidiabetic efficacy among the 
different mechanisms of drug action, the study demonstrates that empagliflozin 
exerts a more sustained improvement of glucose homeostasis and β-cell protection 
in the ZDF rat. In comparison with other type 2 diabetic treatments, SGLT-2 
inhibitors may through insulin-independent pathways thus enhance durability of 
β-cell protection and antidiabetic efficacy.