Effect of Empagliflozin/Linagliptin on Oxidative Stress Markers among patients with Chronic Kidney Disease and Type 2 Diabetes:  a Randomized, Open-label, Controlled Trial

Background: Combined therapies employing sodium-glucose cotransporter 2 inhibitor (SGLT2i) and dipeptidyl peptidase-4 inhibitor (DPP-4i) are expected to produce additive glycemic and reactive oxygen species (ROS) effects among patients with type 2 diabetes (T2DM). The present study evaluated whether SGLT2i and DPP-4i attenuate renal oxidative stress evoked by chronic hyperglycemia. Methods A clinical trial was conducted among patients with T2DM and CKD stage 3. The patients were randomized 1:1 to receive empagliflozin (10 mg/day)/linagliptin (5 mg/day) or standard treatment for 12 weeks. Renal oxidative stress and renal biomarker were measured using urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) and urine albumin creatinine ratio, respectively. Results Forty-eight patients were analyzed. At week 12, the empagliflozin/linagliptin group significantly reduced urine 8-OHdG compared with that in the control group [-53.90 ng/mgCr; 95%CI -102.93 to -4.84, P = 0.034] and the empagliflozin/linagliptin group also significantly reduced urine albumin compared with that in the control [-159.64 mg/gCr; 95% CI -318.23 to -1.06, P = 0.049]. Additionally, reduced HbA1c with empagliflozin/linagliptin treatment was superior to those with the control treatment. No between-group differences were observed regarding body weight, blood pressure, and estimated glomerular filtration rate at the end of follow-up. The proportion of subjects with adverse events over 12 weeks was similar across treatment arms with no hypoglycemic event requiring assistance. Conclusion Combined SGLT2i and DPP-4i treatment for 12 weeks improved renal oxidative stress and glycemic control among patients with T2DM and CKD, which could play a key role in reducing the progression of diabetic nephropathy and appeared to be well tolerated.