title: Safety and effectiveness of dipeptidyl peptidase-4 inhibitors versus intermediate-acting insulin or placebo for patients with type 2 diabetes failing two oral antihyperglycaemic agents: a systematic review and network meta-analysis.
abstract: OBJECTIVE
  To evaluate the effectiveness and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors versus intermediate-acting insulin for adults with type 2 diabetes mellitus (T2DM) and poor glycaemic control despite treatment with two oral agents.
  
  
  METHODS
  Studies were multicentre and multinational.
  
  
  METHODS
  Ten studies including 2967 patients with T2DM.
  
  
  METHODS
  Studies that examined DPP-4 inhibitors compared with each other, intermediate-acting insulin, no treatment or placebo in patients with T2DM.
  
  
  METHODS
  Primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes were healthcare utilisation, body weight, fractures, quality of life, microvascular complications, macrovascular complications, all-cause mortality, harms, cost and cost-effectiveness.
  
  
  RESULTS
  10 randomised clinical trials with 2967 patients were included after screening 5831 titles and abstracts, and 180 full-text articles. DPP-4 inhibitors significantly reduced HbA1c versus placebo in network meta-analysis (NMA; mean difference (MD) -0.62%, 95% CI -0.93% to -0.33%) and meta-analysis (MD -0.61%, 95% CI -0.81% to -0.41%), respectively. Significant differences in HbA1c were not observed for neutral protamine Hagedorn (NPH) insulin versus placebo and DPP-4 inhibitors versus NPH insulin in NMA. In meta-analysis, no significant differences were observed between DPP-4 inhibitors and placebo for severe hypoglycaemia, weight gain, cardiovascular disease, overall harms, treatment-related harms and mortality, although patients receiving DPP-4 inhibitors experienced less infections (relative risk 0.72, 95% CI 0.57 to 0.91).
  
  
  CONCLUSIONS
  DPP-4 inhibitors were superior to placebo in reducing HbA1c levels in adults with T2DM taking at least two oral agents. Compared with placebo, no safety signals were detected with DPP-4 inhibitors and there was a reduced risk of infection. There was no significant difference in HbA1c observed between NPH and placebo or NPH and DPP-4 inhibitors.
  
  
  BACKGROUND
  PROSPERO # CRD42013003624.
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Tricco
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Jesmin
authors.initials: J
authors.lastname: Antony
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khan
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Ghassemi
authors.affiliation: Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jemila S
authors.initials: JS
authors.lastname: Hamid
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Huda
authors.initials: H
authors.lastname: Ashoor
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Erik
authors.initials: E
authors.lastname: Blondal
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Charlene
authors.initials: C
authors.lastname: Soobiah
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute and the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: Hutton
authors.affiliation: Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Brenda R
authors.initials: BR
authors.lastname: Hemmelgarn
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute and the Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Moher
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sumit R
authors.initials: SR
authors.lastname: Majumdar
authors.affiliation: Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Department of Geriatric Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Straus
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000009:adverse effects / Q000627:therapeutic use; D007336:Insulin, Isophane / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D007336:Insulin, Isophane
keywords: meta-analysis; systematic review