Dapagliflozin and metformin in combination ameliorates diabetic nephropathy by suppressing oxidative stress, inflammation, and apoptosis and activating autophagy in diabetic rats

Considering the effects of sodium-glucose cotransporter inhibitors and metformin on the kidneys, a combination of both agents is postulated to provide protection against diabetic nephropathy (DN). We examined the potential protective effects of dapagliflozin, metformin, and their combination on kidney injury in rats with type 2 diabetes. Diabetic (DM) rats were administered dapagliflozin (1.0 mg/kg/day), metformin (100 mg/kg/day), or a combination (dapagliflozin 0.5 mg/kg/day plus metformin 50 mg/kg/day) by oral gavage for 4 weeks. Dapagliflozin monotherapy or in combination with metformin was more effective than metformin monotherapy in attenuating renal dysfunction, improving renal organic anion transporter 3 expression, and activating renal autophagy by modulating the AMPK/mTOR/SIRT1 axis in DM rats. Interestingly, dapagliflozin monotherapy exhibited greater efficacy in suppressing renal oxidative stress in DM rats than metformin or the combination treatment. Renal and pancreatic injury scores decreased in all treatment groups. Apoptotic markers were predominantly reduced in dapagliflozin monotherapy and combination treatment groups. The low-dose combination treatment, through synergistic coordination, appeared to modulate oxidative, autophagic, and apoptotic signaling and confer significant renoprotective effects against DM-induced complications. In addition, a low dose of the combination might be beneficial to patients by avoiding the risk of side effects of the medication. Future clinical trials are necessary to study the nephroprotective effects of the combined treatment at a low dosage in patients with diabetes.