title: Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks.
abstract: OBJECTIVE
  To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24-week short-term + 52-week long-term extension) in treatment-naÏve type 2 diabetes mellitus patients with inadequate glycaemic control.
  
  
  METHODS
  In this phase 3, parallel-group, double-blind, active-controlled study, 1306 patients 18-77 years of age (HbA1c 8.0-12.0%) were randomized to saxagliptin 5 mg + 500 mg metformin, saxagliptin 10 mg + 500 mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1-5 of the short-term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin-based treatment groups. No titration of metformin was permitted during the long-term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120-min postprandial glucose (PPG) and PPG-area under the curve (AUC) from baseline to week 76 were analysed using a repeated-measures model.
  
  
  RESULTS
  At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin, saxagliptin 10 mg and metformin were -2.31 (-2.44, -2.18), -2.33 (-2.46, -2.20), -1.55 (-1.70, -1.40) and -1.79% (-1.93, -1.65), respectively (post hoc and nominal p < 0.0001 vs. metformin and saxagliptin monotherapies for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG-AUC or 120-min PPG was observed between weeks 24 and 76 for saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency.
  
  
  CONCLUSIONS
  Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone.
authors.affiliation: Institute for Clinical Research and Development, Mainz, Germany The Medical City, Pasig City, Philippines Bristol-Myers Squibb, Princeton, NJ, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pfützner
authors.forename: E
authors.initials: E
authors.lastname: Paz-Pacheco
authors.forename: E
authors.initials: E
authors.lastname: Allen
authors.forename: R
authors.initials: R
authors.lastname: Frederich
authors.forename: R
authors.initials: R
authors.lastname: Chen
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004151:Dipeptides / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000218:Adamantane; D001786:Blood Glucose; D004151:Dipeptides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; C502994:saxagliptin