title: Effect of dipeptidyl peptidase-4 inhibitors on heart failure: A meta-analysis of randomized clinical trials.
abstract: BACKGROUND
  Recent studies have suggested that dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) may be associated with increased risk of heart failure (HF), but evidence was inconclusive. We aimed to determine the effects of DPP-4 inhibitors on risk of HF.
  
  
  METHODS
  An extensive search in PubMed, EMBASE, CINAHL, IPA, Cochrane, ClinicalTrial.gov and the manufacturers' websites for randomized controlled trials (RCT) of all DPP-4 inhibitors was performed up to June 2015. All RCTs comparing DPP-4 inhibitors to any comparators with minimum follow-up of 12 weeks were included. The primary outcome was the occurrence of HF.
  
  
  RESULTS
  A total of 54 studies with 74,737 participants were included for analysis. Overall, DPP-4 inhibitors were not associated with an increased risk of HF compared to comparators (relative risk (RR) 1.106; 95% CI 0.995-1.228; p=0.062). When analyzed individually, saxagliptin was significantly associated with the increased risk of HF (RR 1.215; 95% CI, 1.028-1.437; p=0.022), while others were not. Age ≥ 6 5 years, diabetes duration of ≥ 10 years and BMI ≥ 30 kg/m(2) were associated with an increased risk of HF among patients using saxagliptin.
  
  
  CONCLUSIONS
  Our meta-analysis suggested a differential effect of each DPP-4 inhibitor on the risk of HF. Use of saxagliptin significantly increases the risk of HF by 21% especially among patients with high CV risk while no signals were detected with other agents. This information should be taken into consideration when prescribing DDP-4 inhibitors.
authors.affiliation: Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
authors.forename: J
authors.initials: J
authors.lastname: Kongwatcharapong
authors.affiliation: Center for Pharmaceutical Outcomes Research, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA; Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Muang, Phitsanulok, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Dilokthornsakul
authors.affiliation: Clinical Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand.
authors.forename: S
authors.initials: S
authors.lastname: Nathisuwan
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: A
authors.initials: A
authors.lastname: Phrommintikul
authors.affiliation: Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Muang, Phitsanulok, Thailand; School of Pharmacy, Monash University Malaysia, Malaysia; School of Population Health, University of Queensland, Brisbane, Australia; School of Pharmacy, University of Wisconsin-Madison, Madison, WI, USA. Electronic address: nathorn.chaiyakunapruk@monash.edu.
authors.forename: N
authors.initials: N
authors.lastname: Chaiyakunapruk
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives; D004151:Dipeptides / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D006333:Heart Failure / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology*; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D000218:Adamantane
keywords: Cardiovascular; Dipeptidyl-peptidase-4 inhibitors; Heart failure; Type 2 diabetes mellitus