Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial

Background Metformin is the recommended first-line pharmacotherapy for patients with type 2 diabetes. There is no consensus on the optimum second-line pharmacotherapy. We compared the efficacy and safety of the sodium glucose cotransporter 2 inhibitor empagliflozin and the sulfonylurea glimepiride as add-on to metformin in patients with type 2 diabetes. Methods In this double-blind phase 3 trial, patients (aged >= 18 years) with type 2 diabetes and HbA(1c) concentrations of 7-10%, despite metformin treatment and diet and exercise counselling, were randomly assigned in a 1: 1 ratio with a computer-generated random sequence, stratified by HbA(1c), estimated glomerular filtration rate (eGFR), and region, to empagliflozin (25 mg once daily, orally) or glimepiride (1-4 mg once daily, orally) as add-on to metformin for 104 weeks. Patients and investigators were masked to treatment assignment. The primary endpoint was change from baseline in HbA 1c levels at weeks 52 and 104. Differences in the primary endpoint were first tested for non-inferiority (based on a margin of 0.3%). If non-inferiority was shown, differences in the primary endpoint at week 104 were then tested for superiority. Analysis was done on the full-analysis set-ie, patients who were treated with at least one dose of study drug and had a baseline HbA(1c) value. This study is registered with ClinicalTrials.gov, number NCT01167881. A 104-week extension is ongoing. Findings Between August, 2010, and June, 2011, 1549 patients were randomly assigned to receive empagliflozin (n=769) or glimepiride (n=780); four patients in the empagliflozin group did not receive the assigned treatment. Empagliflozin was non-inferior to glimepiride at both timepoints. At week 104, adjusted mean difference in change from baseline in HbA(1c) with empagliflozin versus glimepiride was -0.11% (95% CI -0.19 to -0.02; p=0.0153 for superiority). Adverse events were reported in 661 (86%) patients treated with empagliflozin and 673 (86%) patients treated with glimepiride. Severe adverse events were reported in 72 (9%) patients in the empagliflozin group and 68 (9%) in the glimepiride group. Serious adverse events were reported in 119 (16%) patients in the empagliflozin group and 89 (11%) in the glimepiride group. Confirmed hypoglycaemic adverse events (plasma glucose <= 3.9 mmol/L or requiring assistance) at week 104 were reported in 19 (2%) patients treated with empagliflozin and 189 (24%) patients treated with glimepiride. Interpretation Empagliflozin might be an effective and a well tolerated second-line treatment option for patients with type 2 diabetes who have not achieved good glycaemic control on metformin.