A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans

Abstract

Empagliflozin (formerly known as BI 10773) is a potent, competitive, and selective inhibitor of the sodium glucose transporter SGLT2, which mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. Accordingly, empagliflozin treatment increased urinary glucose excretion. This has been observed across multiple species including humans and was reported under euglycemic conditions, in obesity and, most importantly, in type 2 diabetic patients and multiple animal models of type 2 diabetes and of type 1 diabetes. This led to a reduction in blood glucose, smaller blood glucose excursions during oral glucose tolerance tests, and, upon chronic treatment, a reduction in HbA1c in animal models and patients. In rodents, such effects were observed in early and late phases of experimental diabetes and were associated with preservation of pancreatic β-cell function. Combination studies in animals demonstrated that beneficial metabolic effects of empagliflozin may also manifest when added to other types of anti-hyperglycemic treatments including linagliptin and pioglitazone. While some anti-hyperglycemic drugs lead to weight gain, empagliflozin treatment was associated with reduced body weight in normoglycemic obese and non-obese animals despite an increased food intake, largely due to a loss of adipose tissue; on the other hand, empagliflozin preserved body weight in models of type 1 diabetes. Empagliflozin improved endothelial dysfunction in diabetic rats and arterial stiffness, reduced blood pressure in diabetic patients, and attenuated early signs of nephropathy in diabetic animal models. Taken together, the SGLT2 inhibitor empagliflozin improves glucose metabolism by enhancing urinary glucose excretion; upon chronic administration, at least in animal models, the reductions in blood glucose levels are associated with beneficial effects on cardiovascular and renal complications of diabetes.

Fig. 1

Chemical structure of the C-glucoside empagliflozin (BI 10773; 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yl-oxy)-benzyl]-benzene). Taken from US prescribing information (www.jardiance.com)

Fig. 2

Potency of empagliflozin and C-glucoside comparator compounds for inhibition of human SGLTs expressed in HEK cells. Data are means ± SEM. Created using data from Grempler et al. (2012b)

Fig. 3

Empagliflozin-induced glucosuria in normoglycemic mice. a In metabolic cages, acute oral application of empagliflozin dose-dependently increased urinary glucose excretion in wild-type mice (WT). Compared with WT, the empagliflozin-induced glucosuric response was shifted leftward and the maximum response doubled in mice lacking SGLT1 (Sglt1^−/−). The difference between dose response curves, which reflects the glucose reabsorption mediated via SGLT1 in WT mice, reached a maximum at 0.4 mg/kg (indicated at the left of the vertical lines) and was maintained (all vertical lines have same length) for higher doses up to 10 mg/kg, indicating a high selectivity of empagliflozin vs. SGLT1 in this dose range. Note that empagliflozin began to increase glucose excretion in WT when reabsorption via SGLT1 reached its maximum. b Fractional renal glucose reabsorption (FGR) was determined in inulin clearance studies following empagliflozin treatment (300 mg/kg of diet) for 3 weeks. Each dot represents 1 clearance experiment period. c Free plasma concentrations of empagliflozin, corresponding to early tubular concentrations, were similar to reported IC₅₀ for mouse SGLT2 (1–2 nM), when the drug was given “in the diet” only. Additional application of empagliflozin 1 h before the study increased free plasma concentrations to 20–22 nM and reduced FGR in WT to values of 40–45 % (similar to FGR reported in Sglt2^−/−) and completely prevented renal glucose reabsorption in Sglt1^−/− mice. Taken from Rieg et al. (2014)

Fig. 4

Chronic empagliflozin treatment dose-dependently improves fasting blood glucose (upper panel) and HbA_1c (lower panel) in 12-week-old Zucker rats, a model mimicking the course of type 2 diabetes. Data represent basal (study day −5) and end of treatment (study day 37) and are adapted with permission from Thomas et al. (2012) *: p<0.05, **: p<0.01 and ***: p<0.001 vs. vehicle

Fig.5

Effects of treating rats with STZ-induced diabetes, a model of type 1 diabetes, for 28 days with a single insulin implant, empagliflozin (10 mg/kg twice daily), their combination, and two insulin implants on blood glucose concentrations. Data are shown as calculated 12-h blood glucose profiles (AUC_{0–12 h}, mM h). ***P < 0.001 vs. control and ^###P < 0.001 vs. combination. Created using data from Luippold et al. (2012)

Fig. 6

Effects of empagliflozin treatment on oxidative stress parameters in aorta of STZ-diabetic rats. Vascular oxidative stress was assessed by dihydroethidine (DHE, 1 μM)-dependent fluorescence microtopography in aortic cryosections. a Densitometric quantifications and b representative microscopic images are shown. SGLT2i: empagliflozin. Taken from Oelze et al. (2014) *: p < 0.05 vs. control, #: p < 0.05 vs. STZ

Fig. 7

Empagliflozin prevented the diabetes-induced increase in glomerular filtration rate (GFR) and attenuated the increase in kidney weight, glomerular size, and albuminuria in proportion to hyperglycemia in Akita/+ mice, a model of type 1 diabetes. Empagliflozin (300 mg/kg of diet) or vehicle were given to Akita/⁺ and wild-type (WT) mice for 15 weeks. Depicted are results for a GFR, b kidney weight, c urinary albumin/creatinine ratios, and d glomerular size. *P < 0.05 vs. vehicle treatment in same genotype; #P < 0.05 vs. WT. ANOVA and unpaired Student’s t test and linear regression analysis. Linear regression lines were included when statistical significance was achieved. Taken from Vallon et al. (2014)