Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial

Background Diabetes is a leading cause of chronic kidney disease (CKD) worldwide. Optimum glycaemic control in patients with type 2 diabetes is important to minimise the risk of microvascular and macrovascular complications and to slow the progression of CKD. We assessed the efficacy and safety of empagliflozin as an add-on treatment in patients with type 2 diabetes and CKD. Methods We did a phase 3, randomised, double-blind, parallel-group, placebo-controlled trial at 127 centres in 15 countries. Patients with HbA(1c) of 7% or greater to 10% or less were eligible for inclusion. Patients with stage 2 CKD (estimated glomerular filtration rate [eGFR] >= 60 to <90 mL/min per 1.73 m(2); n=290) were randomly assigned (1:1:1) to receive empagliflozin 10 mg or 25 mg or placebo once daily for 52 weeks. Patients with stage 3 CKD (eGFR >= 30 to <60 mL/min per 1.73 m(2); n=374) were randomly assigned (1:1) to receive empagliflozin 25 mg or placebo for 52 weeks. Randomisation was done with a computer-generated random sequence and stratified by renal impairment, HbA(1c), and background antidiabetes medication. Treatment assignment was masked from patients and investigators. The primary endpoint was change from baseline in HbA(1c) at week 24 by ANCOVA in the full analysis set. This study is registered with ClinicalTrials.gov, number NCT01164501. Findings In patients with stage 2 CKD, adjusted mean treatment differences versus placebo in changes from baseline in HbA(1c) at week 24 were -0.52% (95% CI -0.72 to -0.32) for empagliflozin 10 mg and -0.68% (-0.88 to -0.49) for empagliflozin 25 mg (both p<0.0001). In patients with stage 3 CKD, adjusted mean treatment difference versus placebo in change from baseline in HbA(1c) at week 24 was -0.42% (-0.56 to -0.28) for empagliflozin 25 mg (p<0.0001). In patients with stage 2 CKD, adverse events were reported over 52 weeks by 83 patients (87%) on placebo (15 severe [16%] and 11 serious [12%]), 86 (88%) on empagliflozin 10 mg (six severe [6%] and six serious [6%]) and 78 (80%) on empagliflozin 25 mg (eight severe [8%] and seven serious [7%]). In patients with stage 3 CKD, adverse events were reported over 52 weeks by 156 patients (83%) on placebo (15 severe [8%] and 23 serious [12%]) and 156 (83%) on empagliflozin 25 mg (18 severe [10%] and 22 serious [12%]). Interpretation In patients with type 2 diabetes and stage 2 or 3 CKD, empagliflozin reduced HbA(1c) and was well tolerated. However, our findings might not be applicable to the general population of patients with type 2 diabetes and renal impairment.