title: Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis.
abstract: OBJECTIVE
  Numerous glucose-lowering drugs are used to treat type 2 diabetes.
  
  
  OBJECTIVE
  To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin.
  
  
  METHODS
  Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016.
  
  
  METHODS
  Randomized clinical trials of 24 weeks' or longer duration.
  
  
  METHODS
  Random-effects network meta-analysis.
  
  
  METHODS
  The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A1c (HbA1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight.
  
  
  RESULTS
  A total of 301 clinical trials (1,417,367 patient-months) were included; 177 trials (56,598 patients) of drugs given as monotherapy; 109 trials (53,030 patients) of drugs added to metformin (dual therapy); and 29 trials (10,598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, -22% [-27% to -18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, -10% [95% CI, -18% to -2%]).
  
  
  CONCLUSIONS
  Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Suetonia C
authors.initials: SC
authors.lastname: Palmer
authors.affiliation: Department of Primary Education, School of Education, University of Ioannina, University Campus, Dourouti, Ioannina, Greece3Department of Hygiene and Epidemiology, School of Health Sciences, University of Ioannina, University Campus, Dourouti, Ioannina, G.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Mavridis
authors.affiliation: Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Nicolucci
authors.affiliation: Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia6Translational Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: David W
authors.initials: DW
authors.lastname: Johnson
authors.affiliation: Cumming School of Medicine, Health Sciences Centre, University of Calgary, Foothills Campus, Calgary, Alberta, Canada.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tonelli
authors.affiliation: Sydney School of Public Health, University of Sydney, Sydney, Australia.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Craig
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Jasjot
authors.initials: J
authors.lastname: Maggo
authors.affiliation: Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gray
authors.affiliation: Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: De Berardis
authors.affiliation: Division of Nephrology and Transplantation, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy10Diaverum Medical Scientific Office, Lund, Sweden.
authors.forename: Marinella
authors.initials: M
authors.lastname: Ruospo
authors.affiliation: Diaverum Medical Scientific Office, Lund, Sweden.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Natale
authors.affiliation: Diaverum Medical Scientific Office, Lund, Sweden.
authors.forename: Valeria
authors.initials: V
authors.lastname: Saglimbene
authors.affiliation: Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia11The George Institute for Global Health, Sydney, Australia.
authors.forename: Sunil V
authors.initials: SV
authors.lastname: Badve
authors.affiliation: Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia.
authors.forename: Yeoungjee
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Nephrology Division, Department of Medicine, University of Montreal, Montreal, Quebec, Canada.
authors.forename: Annie-Claire
authors.initials: AC
authors.lastname: Nadeau-Fredette
authors.affiliation: Division of Medicine, Department of Renal Medicine, University of Queensland at the Princess Alexandra Hospital, Woolloongabba, Australia6Translational Research Institute, University of Queensland, Woolloongabba, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Burke
authors.affiliation: Department of Medicine, Royal Alexandra Hospital, Edmonton, Alberta, Canada.
authors.forename: Labib
authors.initials: L
authors.lastname: Faruque
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Anita
authors.initials: A
authors.lastname: Lloyd
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Nasreen
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Yuanchen
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sophanny
authors.initials: S
authors.lastname: Tiv
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Natasha
authors.initials: N
authors.lastname: Wiebe
authors.affiliation: Sydney School of Public Health, University of Sydney, Sydney, Australia10Diaverum Medical Scientific Office, Lund, Sweden15Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
authors.forename: Giovanni F M
authors.initials: GF
authors.lastname: Strippoli
mesh_terms: D002318:Cardiovascular Diseases / Q000453:epidemiology*; D002423:Cause of Death; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use; D008687:Metformin / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D012306:Risk; D017211:Treatment Failure
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; C517652:hemoglobin A1c protein, human