title: Treatment escalation options for patients with type 2 diabetes after failure of exenatide twice daily or glimepiride added to metformin: results from the prospective European Exenatide (EUREXA) study.
abstract: OBJECTIVE
  To evaluate third-line thiazolidinedione (TZD) or glimepiride therapy in patients inadequately controlled on metformin + exenatide twice daily, and third-line exenatide twice daily in patients inadequately controlled on metformin + glimepiride.
  
  
  METHODS
  In this randomized, open-label, multicentre trial, 144 patients with type 2 diabetes inadequately controlled [glycated haemoglobin (HbA1c) >9% (75 mmol/mol) after 3 months' treatment or >7% (53 mmol/mol) at two consecutive visits 3 months apart, after 6 months' treatment] on metformin + exenatide twice daily were re-randomized to add-on TZD or glimepiride, and 166 patients inadequately controlled on metformin + glimepiride received add-on exenatide twice daily. Changes in HbA1c, body mass index (BMI), lipids, hypoglycaemia and vital signs were evaluated.
  
  
  RESULTS
  The median duration of triple therapy was ∼2 years. In patients inadequately controlled on metformin + exenatide twice daily, add-on TZD decreased HbA1c levels significantly better than add-on glimepiride: 130-week difference 0.48% [95% confidence interval (CI) 0.19-0.77] or 5.2 mmol/mol (95% CI 2.1-8.4; p = 0.001), but with significantly increased BMI and systolic blood pressure. The ratio of documented symptomatic (blood glucose ≤70 mg/dl [3.9 mmol/l]) hypoglycaemia rates for add-on glimepiride to add-on TZD was 8.48 (p < 0.0001). Add-on exenatide twice daily after metformin + glimepiride significantly reduced HbA1c levels: mean [standard deviation (s.d.)] change from baseline -0.35 (0.89)% [-3.8 (9.7) mmol/mol] and BMI: mean (s.d.) change from baseline -0.82 (1.9) kg/m(2) at 130 weeks, with a slightly increased rate of documented symptomatic hypoglycaemia from metformin + glimepiride (ratio 1.49).
  
  
  CONCLUSIONS
  TZD, but not glimepiride, was an effective and well tolerated third-line therapy in patients without glycaemic control after long-term therapy with metformin + exenatide twice daily. Exenatide twice daily was an effective and well tolerated third-line therapy in patients inadequately controlled on metformin + glimepiride.
authors.affiliation: Rudolfstiftung Hospital, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Schernthaner
authors.affiliation: Celaya Center for Specialist Medicine, Guanajuato, Mexico.
authors.forename: J
authors.initials: J
authors.lastname: Rosas-Guzmán
authors.affiliation: Diabetes Unit, Policlinico Le Scotte, University of Siena, Siena, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Dotta
authors.affiliation: Hospital Brabois and CIC Inserm, University of Lorraine, Vandoeuvre-Lès-Nancy, France.
authors.forename: B
authors.initials: B
authors.lastname: Guerci
authors.affiliation: Vall d'Hebron Research Institute and CIBERDEM Carlos III Health Institute, Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Simó
authors.affiliation: Eli Lilly and Company, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Festa
authors.affiliation: Eli Lilly Polska, Warsaw, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Kiljański
authors.affiliation: Bristol-Myers Squibb, San Diego, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Medicine IV, Eberhard-Karls-University Tübingen, Tübingen, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Gallwitz
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005060:Europe; D000077270:Exenatide; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage*; D011446:Prospective Studies; D013453:Sulfonylurea Compounds / Q000008:administration & dosage*; D045162:Thiazolidinediones / Q000008:administration & dosage*; D017211:Treatment Failure; D014688:Venoms / Q000008:administration & dosage*
chemical_list: D001786:Blood Glucose; D000077270:Exenatide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008055:Lipids; D008687:Metformin; D010455:Peptides; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; D014688:Venoms; C517652:hemoglobin A1c protein, human; C057619:glimepiride; C089946:2,4-thiazolidinedione
keywords: HbA1c; body mass index; exenatide twice daily; glimepiride; thiazolidinedione; triple therapy; type 2 diabetes