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

Abstract

Objective: To assess the safety of empagliflozin in patients with type 2 diabetes and moderate to severe chronic kidney disease (CKD) (category G3-4) enrolled in clinical trials.

Research design and methods: This analysis pooled data from 19 randomized, placebo-controlled, phase 1-4 clinical trials and 1 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.

Results: Among a total of 15,081 patients who received at least one study drug dose, 1,522, 722, and 123 were classified as having G3A, G3B, and G4 CKD, respectively, at baseline. Demographic and clinical characteristics were similar between treatment groups across CKD categories. 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 and G4 and the G3A group. Notably lower risks were observed in both groups for hyperkalemia (hazard ratio 0.59 [95% CI 0.37-0.96, P = 0.0323] and 0.48 [0.26-0.91, P = 0.0243], respectively) and edema (0.47 [0.33-0.68, P < 0.0001] and 0.44 [0.28-0.68, P = 0.0002], respectively).

Conclusions: Use of empagliflozin in patients with type 2 diabetes and advanced CKD raised no new safety concerns and may have beneficial effects on the development of hyperkalemia and edema.

Trial registration: ClinicalTrials.gov NCT03594110 NCT00885118 NCT00789035 NCT00558571 NCT00749190 NCT01011868 NCT01193218 NCT01210001 NCT01177813 NCT01159600 NCT01289990 NCT01131676 NCT01164501 NCT01370005 NCT01306214 NCT01649297 NCT01947855 NCT02589639.

Figure 1

Kaplan-Meier estimates of time to first event of hyperkalemia (A), volume depletion (B), edema (C), and ARF (D) in patients with eGFR <45 mL/min/1.73 m² (left) and 45 to <60 mL/min/1.73 m² (right). eGFR was calculated using the CKD-EPI equation.