Characterization and comparison of sodium-glucose cotransporter 2 inhibitors: Part 2. Antidiabetic effects in type 2 diabetic mice

Abstract

Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin) or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin). In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day.

SGLT2 inhibitor ipragliflozin alone and combined with pioglitazone prevents progression of nonalcoholic steatohepatitis in a type 2 diabetes rodent model

“…Repeated administration of ipragliflozin lowered HbA 1c levels by increasing urinary glucose excretion. Further, ipragliflozin improved glucose tolerance, hyperinsulinemia, and insulin resistance, similar to findings reported in previous studies in type 2 diabetes models (Tahara et al, , ; Tahara, Takasu, Yokono, Imamura, & Kurosaki, ). Additionally, no hypoglycemic symptoms such as excessive weight loss or decreased locomotor activity were noted throughout the present study period.…”

Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease

“…liraglutide) as well as dipeptidyl dipeptidase 4 (DPP4) inhibitors, which act by increasing the bioavailability of incretins, have variably displayed the ability to elevate circulating adiponectin levels (Kim Chung le et al , ; Li et al , ; Sahebkar et al , ). Similarly, empagliflozin, a sodium‐glucose cotransporter 2 inhibitor used in the treatment of T2DM, reportedly increases adiponectin levels (Tahara et al , ). It is unclear whether such effects can be attributed to the improvement of systemic insulin sensitivity or are due to unidentified direct effects on AT.…”

Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin

“…Pharmacokinetic parameters, such as the area under plasma concentration-time curve from zero to infinity (AUC), were calculated from plasma concentration vs time curves using non-compartment analysis with WinNonlin (version 5.1; Pharsights, Cary, NC, USA). The AUC ratios (i.e., ratios of kidney AUC to plasma AUC) were calculated by dividing the AUC of the three Recently, Tahara et al [5] compared the pharmacokinetics, pharmacodynamics, and pharmacological characteristics of six SGLT2 inhibitors, such as ipragliflozin, dapagliflozin, tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. The study showed that all the SGLT2 inhibitors induced urinary glucose excretion in a dose-dependent manner but the duration of action differed among the six drugs.…”