Effects of SGLT2 Inhibitors in Rodent Models of Diabetic Nephropathy

Clinical outcome studies have established sodium glucose transporter 2 (SGLT2) inhibitors such as canagliflozin, dapagliflozin, and empagliflozin as nephroprotective agents in diabetic patients. To elucidate underlying mechanisms, a wide range of mouse and rat models of both type 1 and type 2 diabetes (T1DM and T2DM, respectively) have been tested with regard to effects of SGLT2 inhibitors on renal morphology and function in more than 170 studies. T1DM models are largely based on injection of streptozotocin (STZ), whereas T2DM models cover a wider range of models including db/db mice and various combination of high-fat diets plus (low-dose) STZ. While approved only in patients with T2DM, SGLT2 inhibitors lower glucose in models of T1DM and T2DM. Study designs included treatment starting within 7 days of diabetes induction, 1-4 weeks, and more than 4 weeks thereafter. The latter is used most often, probably because it appears to have the greatest translational value. In male rodents, SGLT2 inhibitors improved nephropathy as determined by serum levels of creatinine or blood urea nitrogen, albuminuria, renal fibrosis in general, glomerulosclerosis, and tubulointerstitial fibrosis. They also improved oxidative stress and inflammatory markers. However, most of the available evidence comes from studies in male rodents. In contrast, only 4% of studies report on female animals including two directly comparing outcomes in male and female rodents. Improvements in female animals tended to be weaker or absent for parameters that were consistently improved in male rodents. Whether this is a peculiarity of the rodent studies or a similar situation exists in diabetic patients remains to be tested.