Initial Combination Empagliflozin and Linagliptin Improves Kidney Fibrotic Marker in Patients With Type 2 Diabetes: A Randomized Controlled Trial

Background: Transforming growth factor-beta 1 (TGF- ß1) is a novel cytokine marker and also one of the therapeutic targets in the treatment of diabetic kidney disease. Both sodium glucose co-transporter 2 inhibitor and dipeptidyl-peptides 4 inhibitor reduce TGF- ß 1 level in animal studies, but whether it is effective in human is unknown. Objective: To evaluate the effects of combinations of empagliflozin/linagliptin, comparing with empagliflozin alone, in patients with type 2 diabetes. Material and Methods: Subjects are randomized to a combination of empagliflozin 10 mg and linagliptin 5 mg (n = 23), or empagliflozin 10 mg (n = 22) as add-on to standard treatment for 12 weeks. The primary end point is changed from baseline in serum TGF- ß1 at 12 weeks. Results: Among the 45 subjects who completed the study, mean change in TGF-ß1 was -928.2 + 1,204.2 pg/mL, and +206.6 + 592.5 pg/mL in the empagliflozin/linagliptin group and empagliflozin group, respectively (p <0.001). Mean change in estimated glomerular filtration rate (eGFR) increased in the empagliflozin /linagliptin group 4.4 + 7.59 mL/min/1.73m2, whereas mean eGFR decreased in empagliflozin group -0.06 + 11.16 mL/min/1.73m2 (p =0.133). Mean change in HbA1c was -1.3 + 0.6% and -0.4 + 0.6% in empagliflozin/linagliptin and empagliflozin group, respectively (p<0.001). Baseline level of eGFR significantly correlated with baseline TGF- ß1 but did not predict response to therapy. Conclusion: Initial combination empagliflozin and linagliptin may delay progression of kidney fibrosis as early as 12 weeks of treatment. Our study supports that this combination had synergistic action not only glycemic control but also beneficial in kidney protection. Keyword: transforming growth factor - ß1, diabetic kidney disease, combination empagliflozin and linagliptin