BACKGROUND: Sulfonylureas (SUs) are commonly used in the treatment of type 2 
diabetes (T2DM), usually as second-line treatment after the failure of 
metformin. However, SUs are associated with poor durability, hypoglycemia and 
weight gain. Empagliflozin is a sodium glucose cotransporter 2 (SGLT2) inhibitor 
in development for the treatment of T2DM. In Phase II/III trials, empagliflozin 
reduced hyperglycemia, body weight and blood pressure, with a low incidence of 
hypoglycemia. The aim of this Phase III study is to compare the effects of 
empagliflozin and the SU glimepiride as second-line therapy in patients with 
T2DM inadequately controlled with metformin immediate release (IR) and 
diet/exercise.
METHOD: After a 2-week placebo run-in, patients were randomized to receive 
empagliflozin 25 mg once daily (qd) or glimepiride 1-4 mg qd double-blind for 2 
years, in addition to metformin IR. Patients who participate in the initial 
2-year randomization period will be eligible for a 2-year double-blind 
extension. The primary endpoint is change from baseline in HbA1c. Secondary 
endpoints are change from baseline in body weight, the incidence of confirmed 
hypoglycemia and changes in systolic and diastolic blood pressure. Exploratory 
endpoints include markers of insulin secretion, body composition and responder 
analyses. Safety endpoints include the incidence of adverse events (AEs) 
(including macro- and microvascular adverse events) and changes from baseline in 
clinical laboratory parameters.
RESULTS: Between August 2010 and June 2011, 1549 patients were randomized and 
1545 patients were treated. At baseline, mean (SD) age was 55.9 (10.4) years, 
HbA1c was 7.92 (0.84)%, body mass index was 30.11 (5.59) kg/m², systolic blood 
pressure was 133.5 (15.9) mmHg and diastolic blood pressure was 79.5 (9.4) mmHg.
DISCUSSION: This is the largest study to compare the efficacy and safety of an 
SGLT2 inhibitor with an SU in patients with T2DM inadequately controlled on 
metformin to date. In addition to determining the effects of these treatments on 
glycemic control over the long term, this study will investigate effects on 
beta-cell function, cardiovascular risk factors and markers of renal 
function/damage. The results will help to inform the choice of second-line 
treatment in patients with T2DM who have failed on metformin.
TRIAL REGISTRATION: Clinicaltrials.gov NCT01167881.