title: Rationale, design and baseline characteristics of a 4-year (208-week) phase III trial of empagliflozin, an SGLT2 inhibitor, versus glimepiride as add-on to metformin in patients with type 2 diabetes mellitus with insufficient glycemic control.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01167881.
authors.affiliation: Steno Diabetes Center, Niels Steensens Vej 2-4, DK-2820, Gentofte, Denmark. mtrd@steno.dk.
authors.forename: Martin
authors.initials: M
authors.lastname: Ridderstråle
authors.forename: Robbyna
authors.initials: R
authors.lastname: Svaerd
authors.forename: Cordula
authors.initials: C
authors.lastname: Zeller
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kim
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Woerle
authors.forename: Uli C
authors.initials: UC
authors.lastname: Broedl
mesh_terms: D000368:Aged; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D015992:Body Mass Index; D002985:Clinical Protocols; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005960:Glucosides / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D012107:Research Design; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001559:Benzhydryl Compounds; D015415:Biomarkers; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013453:Sulfonylurea Compounds; C089180:SLC5A2 protein, human; C517652:hemoglobin A1c protein, human; C057619:glimepiride; C570240:empagliflozin