title: Assessment of the relative effectiveness and tolerability of treatments of type 2 diabetes mellitus: a network meta-analysis.
abstract: OBJECTIVE
  The relative effectiveness and tolerability of treatments for type 2 diabetes mellitus (T2DM) is not well understood because few randomized, controlled trials (RCTs) have compared these treatments directly. The purpose of the present study was to evaluate the relative effectiveness and tolerability of treatments of T2DM.
  
  
  METHODS
  We performed a network meta-analysis of available RCTs with pharmacologic interventions in T2DM and compared antidiabetic drugs and combination regimens with metformin (the reference drug). Glycemic control (proportion achieving HbA1c goal) and tolerability (risk of hypoglycemia) were the primary outcomes of interest. Direct and indirect relative effects (unadjusted) were expressed as odds ratios and 95% CIs.
  
  
  RESULTS
  Eight treatments (glucagon-like peptide-1 [GLP-1] agonists plus metformin, sulfonylureas plus metformin, dipeptidyl peptidase-4 [DPP-4] inhibitors] plus metformin, colesevelan plus metformin, thiazolidinediones plus metformin, meglitinides plus metformin, α-glucosidase inhibitor plus metformin, and rosiglitazone monotherapy) outperformed metformin (direct effects). Triple combinations of GLP-1, thiazolinedione, insulin, metiglinide, or sulfonylureas added to a metformin backbone improved glycemic control (indirect effects). Higher risk of hypoglycemia was noted for sulfonylureas, α-glycosidases, and metiglinides when added to metformin (direct effects). Across indirect effects, only 17% of comparisons yielded less risk of hypoglycemia (70% were worse and 13% were comparable).
  
  
  CONCLUSIONS
  Our results point out the relative superiority of 2- and 3-drug combination regimens over metformin and summarize treatment effects and tolerability in a comprehensive manner, which adds to our knowledge regarding T2DM treatment options.
authors.affiliation: Center for Clinical Evidence Synthesis, The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts; Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Elias
authors.initials: E
authors.lastname: Zintzaras
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Michael
authors.initials: M
authors.lastname: Miligkos
authors.affiliation: Division of Infectious Diseases, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
authors.forename: Panayiotis
authors.initials: P
authors.lastname: Ziakas
authors.affiliation: Center for Clinical Evidence Synthesis, The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Balk
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Despoina
authors.initials: D
authors.lastname: Mademtzoglou
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Doxani
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Mprotsis
authors.affiliation: Center for Clinical Evidence Synthesis, The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Raman
authors.initials: R
authors.lastname: Gowri
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Xanthopoulou
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Mpoulimari
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Kokkali
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Dimoulou
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Rodopolou
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
authors.affiliation: Predictive Analytics and Comparative Effectiveness Center, The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: David M
authors.initials: DM
authors.lastname: Kent
authors.affiliation: Evidence-Based Medicine Unit, Department of Biomathematics, University of Thessaly School of Medicine, Larissa, Greece. Electronic address: gmhadji@med.uth.gr.
authors.forename: Georgios M
authors.initials: GM
authors.lastname: Hadjigeorgiou
mesh_terms: D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007003:Hypoglycemia / Q000097:blood / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use; D008687:Metformin / Q000009:adverse effects / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013453:Sulfonylurea Compounds / Q000009:adverse effects / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human
keywords: diabetes type 2; effectiveness; network meta-analysis; tolerability; treatment