Safety of Empagliflozin in Patients With Type 2 Diabetes and Chronic Kidney Disease: Pooled Analysis of Placebo-Controlled Clinical Trials

<b>O</b><b>bjective</b><b> </b> <p>To assess safety of empagliflozin in patients with type 2 diabetes and moderate-to-severe chronic kidney disease ([CKD] category G3–4) enrolled in clinical trials. <b></b></p> <p><b>Research Design and Methods</b><b> <br> </b>This analysis pooled data from 19 randomized, placebo-controlled, phase 1–4 clinical trials and one randomized, placebo-controlled extension study in which patients received empagliflozin 10 mg or 25 mg daily. Time to first occurrence of adverse events (AEs) was evaluated using Kaplan-Meier analysis and multivariable Cox regression models.<b></b></p> <p><b>Results</b><b> </b></p> <p>Among a total of 15,081 patients who received at least one study drug dose,1522, 722, and 123 individuals were classified as CKD categories G3A, G3B, and G4, respectively, at baseline. Demographics and clinical characteristics were similar between treatment groups across categories of CKD. Rates of serious AEs, AEs leading to discontinuation, and events of special interest (including lower limb amputations and acute renal failure [ARF]) were also similar between empagliflozin and placebo across CKD subgroups. In adjusted Cox regression analyses, risks for volume depletion and ARF were similar for empagliflozin and placebo in the combined group with CKD categories G3B–G4 and the G3A group. Notably lower risks (HR [95% CI]) were observed in both groups for hyperkalemia (0.59 [0.37–0.96], <i>P</i> = 0.0323; and 0.48 [0.26–0.91], <i>P</i> = 0.0243, respectively) and edema (0.47 [0.33–0.68], <i>P</i> < 0.0001; and 0.44 [0.28–0.68], <i>P</i> = 0.0002, respectively). </p> <p><b>Conclusions</b><b> </b></p> <p>Use of empagliflozin in patients with type 2 diabetes and advanced CKD raised no new safety concerns and may have beneficial effects on development of hyperkalemia and edema.</p>