title: Rosiglitazone/metformin fixed-dose combination compared with uptitrated metformin alone in type 2 diabetes mellitus: a 24-week, multicenter, randomized, double-blind, parallel-group study.
abstract: BACKGROUND
  Management of type 2 diabetes mellitus (DM) that involves uptitration of monotherapy to the maximum dose has been associated with delays in achieving glycemic control and an increased number of adverse events (AEs). Studies have reported the benefits of adding a thiazolidinedione to metformin (MET), but none has compared the effect of adding a thiazolidinedione to MET versus increasing the daily dose of MET to 3 g.
  
  
  OBJECTIVE
  The goal of this study was to investigate the benefits of fixed-dose combination rosiglitazone and MET (RSG/MET) compared with high-dose MET monotherapy in patients with type 2 DM.
  
  
  METHODS
  This was a 24-week, multicenter, randomized, double-blind, parallel-group study. Patients previously treated with MET entered a 4-week, single-blind, run-in period with MET 2 g/d and were then randomized to RSG/MET 4 mg/2 g per day or MET 2.5 g/d. At week 8, medication was escalated to RSG/MET 8 mg/2 g per day or MET 3 g/d. The primary efficacy end point was change in glycosylated hemoglobin (HbA1c) at week 24. Tolerability was assessed, including the frequency and severity of AEs.
  
  
  RESULTS
  A total of 568 patients comprised the safety population (MET, 280; RSG/MET, 288) and 551 formed the intent-to-treat group (MET, 272; RSG/MET, 279). Baseline characteristics of the safety population were comparable in the 2 groups; body mass index (mean [SD]) was 32.2 (4.8) kg/m(2) and 32.1 (4.9) kg/m(2) in the RSG/MET and MET groups, respectively. RSG/MET reduced HbA(1c) (mean [SD]) from 7.4% (1.0%) to 7.1% (1.1%) at week 24, compared with a reduction from 7.5% (1.0%) to 7.4% (1.1%) with MET (treatment difference, -0.22%; P = 0.001). Fasting plasma glucose (mean [SD]) was reduced from 166.2 (29) to 144.1 (33) mg/dL with RSG/MET and from 169.3 (33) to 164.0 (37) mg/dL with MET (treatment difference, -18.3 mg/dL; P < 0.001). In addition, 54% of patients treated with RSG/MET achieved HbA(1c) levels <7.0%, compared with 36% with MET (odds ratio, 2.42; P < 0.001). RSG/MET increased homeostasis model assessment (HOMA) estimates of insulin sensitivity by 34.4% versus 6.5% with MET (treatment difference, 24.8%; P < 0.001). HOMA beta-cell function increased by 15.9% with RSG/MET versus 2.5% with MET (treatment difference, 14.0%; P < 0.001). RSG/MET decreased C-reactive protein by a mean of 39.4% versus 16.0% with MET (treatment difference, -33.8%; P < 0.001). RSG/MET was generally well tolerated, with the majority of AEs mild to moderate in nature. Serious AEs were reported in 3% of patients receiving RSG/MET and 2% with MET. Overall rates of gastrointestinal AEs were 23% with RSG/MET and 26% with MET; however, there was an increased incidence of diarrhea (14% vs 6%) and abdominal pain (9% vs 6%) with MET. There was a mean (SE) increase in weight with RSG/MET (1.3 [0.22] kg) and a mean decrease (-0.9 [0.26] kg) with MET. Patients receiving RSG/MET reported improvements in treatment satisfaction compared with MET.
  
  
  CONCLUSIONS
  In this study, the RSG/MET fixed-dose combination (8 mg/2 g per day) was an effective and well-tolerated treatment for type 2 DM and enabled more patients to reach glycemic targets than high-dose MET (3 g/d).
authors.affiliation: Aston University, Aston Triangle, Birmingham, UK. C.J.Bailey@aston.ac.uk
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Bailey
authors.forename: Alfredas
authors.initials: A
authors.lastname: Bagdonas
authors.forename: Josip
authors.initials: J
authors.lastname: Rubes
authors.forename: Stephen O
authors.initials: SO
authors.lastname: McMorn
authors.forename: Jill
authors.initials: J
authors.lastname: Donaldson
authors.forename: Nandita
authors.initials: N
authors.lastname: Biswas
authors.forename: Murray W
authors.initials: MW
authors.lastname: Stewart
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000465:Algorithms; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004338:Drug Combinations; D005060:Europe; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D004338:Drug Combinations; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D008687:Metformin; D000077154:Rosiglitazone; D045162:Thiazolidinediones