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 HbA1c 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 HbA1c, 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 HbA1c 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 HbA1c 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 HbA1c 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.
FUNDING: Boehringer Ingelheim and Eli Lilly.