title: Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies.
abstract: OBJECTIVE
  To examine the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and the risk of heart failure or hospital admission for heart failure in patients with type 2 diabetes.
  
  
  METHODS
  Systematic review and meta-analysis of randomised and observational studies.
  
  
  METHODS
  Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov searched up to 25 June 2015, and communication with experts.
  
  
  METHODS
  Randomised controlled trials, non-randomised controlled trials, cohort studies, and case-control studies that compared DPP-4 inhibitors against placebo, lifestyle modification, or active antidiabetic drugs in adults with type 2 diabetes, and explicitly reported the outcome of heart failure or hospital admission for heart failure.
  
  
  METHODS
  Teams of paired reviewers independently screened for eligible studies, assessed risk of bias, and extracted data using standardised, pilot tested forms. Data from trials and observational studies were pooled separately; quality of evidence was assessed by the GRADE approach.
  
  
  RESULTS
  Eligible studies included 43 trials (n=68,775) and 12 observational studies (nine cohort studies, three nested case-control studies; n=1,777,358). Pooling of 38 trials reporting heart failure provided low quality evidence for a possible similar risk of heart failure between DPP-4 inhibitor use versus control (42/15,701 v 33/12,591; odds ratio 0.97 (95% confidence interval 0.61 to 1.56); risk difference 2 fewer (19 fewer to 28 more) events per 1000 patients with type 2 diabetes over five years). The observational studies provided effect estimates generally consistent with trial findings, but with very low quality evidence. Pooling of the five trials reporting admission for heart failure provided moderate quality evidence for an increased risk in patients treated with DPP-4 inhibitors versus control (622/18,554 v 552/18,474; 1.13 (1.00 to 1.26); 8 more (0 more to 16 more)). The pooling of adjusted estimates from observational studies similarly suggested (with very low quality evidence) a possible increased risk of admission for heart failure (adjusted odds ratio 1.41, 95% confidence interval 0.95 to 2.09) in patients treated with DPP-4 inhibitors (exclusively sitagliptin) versus no use.
  
  
  CONCLUSIONS
  The relative effect of DPP-4 inhibitors on the risk of heart failure in patients with type 2 diabetes is uncertain, given the relatively short follow-up and low quality of evidence. Both randomised controlled trials and observational studies, however, suggest that these drugs may increase the risk of hospital admission for heart failure in those patients with existing cardiovascular diseases or multiple risk factors for vascular diseases, compared with no use.
authors.affiliation: Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Endocrinology and Metabolism, West China Hospita, Chengdu.
authors.forename: Sheyu
authors.initials: S
authors.lastname: Li
authors.affiliation: West China School of Pharmacy, Sichuan University, Chengdu.
authors.forename: Ke
authors.initials: K
authors.lastname: Deng
authors.affiliation: Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Liu
authors.affiliation: Norwegian Knowledge Centre for the Health Services, Oslo, Norway Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway.
authors.forename: Per Olav
authors.initials: PO
authors.lastname: Vandvik
authors.affiliation: Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Pujing
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Longhao
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors.forename: Jiantong
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Hygiene and Dietetics, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Malgorzata M
authors.initials: MM
authors.lastname: Bala
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Zahra N
authors.initials: ZN
authors.lastname: Sohani
authors.affiliation: Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Wong
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Anesthesia, McMaster University, Hamilton Michael G DeGroote Institute for Pain Research and Care, McMaster University, Hamilton.
authors.forename: Jason W
authors.initials: JW
authors.lastname: Busse
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Anesthesia, McMaster University, Hamilton Stanford Prevention Research Center, Department of Medicine, Stanford University, Stanford, CA, USA Department of Anaesthesia and Pain Medicine, Hospital for Sick Children, Toronto, ON Canada.
authors.forename: Shanil
authors.initials: S
authors.lastname: Ebrahim
authors.affiliation: Department of Medicine, Universidad Peruana Cayetano Heredia, Lima, Peru.
authors.forename: German
authors.initials: G
authors.lastname: Malaga
authors.affiliation: Internal Medicine Unit, Hospital Clinico FUSAT, Rancagua, Chile.
authors.forename: Lorena P
authors.initials: LP
authors.lastname: Rios
authors.affiliation: Department of Medical Administration, 363 Hospital, Chengdu, Sichuan, China.
authors.forename: Yingqiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Second Hospital of Lanzhou University, Lanzhou, Gansu, China.
authors.forename: Qunfei
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON Canada Department of Medicine, McMaster University, Hamilton.
authors.forename: Gordon H
authors.initials: GH
authors.lastname: Guyatt
authors.affiliation: Chinese Evidence-based Medicine Centre, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China sunx26@gmail.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Sun
mesh_terms: D002318:Cardiovascular Diseases / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006333:Heart Failure / Q000139:chemically induced*; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D064887:Observational Studies as Topic; D016017:Odds Ratio; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents