title: Do dipeptidyl peptidase IV (DPP-IV) inhibitors cause heart failure?
abstract: OBJECTIVE
  Although recent reports suggest an association between saxagliptin and an increased risk of admissions for heart failure, it is not clear whether dipeptidyl peptidase IV (DPP-IV) inhibition contributes to heart failure in high-risk patients. The purpose of this research is to understand heart failure risk among high-risk patients with type 2 diabetes.
  
  
  METHODS
  This is a systematic review of data published in full papers and abstract form using the terms DPP-IV inhibitors and heart failure published since October 2013. Data from insurance and hospital databases were combined with those from multiple published trials, including the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial; Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE), and Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) trial as well as pooled analyses of linagliptin and saxagliptin placebo-controlled trials to examine heart failure among patients represented in those datasets.
  
  
  RESULTS
  A meta-analysis of the 9 datasets showed an increase in heart failure with dipeptidyl peptidase IV inhibitors of 15% (P = 0.017). There was no statistical heterogeneity, nor was there a statistical difference between cohort studies and randomized, controlled trials (P = 0.3), even though cohort studies alone were not significant (relative risk: 1.1; P = 0.32). Removing SAVOR-TIMI 53 data produced an insignificant increase in heart failure of 12% (P = 0.09) in the rest of the studies. In the randomized, controlled trials, the increased risk was 24% (P = 0.002). There was no statistical difference between those studies with and without baseline cardiovascular disease (P = 0.58), although the cardiovascular disease studies were borderline significant (P = 0.06). There was no publication bias.
  
  
  CONCLUSIONS
  There are data from studies using sitagliptin, saxagliptin, and alogliptin showing that these agents may increase the risk of hospitalization for heart failure. More data are required for a definitive conclusion.
authors.affiliation: University of South Australia, Adelaide, South Australia, Australia. Electronic address: Peter.clifton@unisa.edu.au.
authors.forename: Peter
authors.initials: P
authors.lastname: Clifton
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004151:Dipeptides / Q000009:adverse effects / Q000627:therapeutic use; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006333:Heart Failure / Q000139:chemically induced*; D006760:Hospitalization; D006801:Humans; D009570:Nitriles / Q000009:adverse effects / Q000627:therapeutic use; D010880:Piperidines / Q000009:adverse effects / Q000627:therapeutic use; D011759:Pyrrolidines / Q000009:adverse effects / Q000627:therapeutic use; D000068900:Sitagliptin Phosphate / Q000009:adverse effects / Q000627:therapeutic use; D014498:Uracil / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077597:Vildagliptin
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D010880:Piperidines; D011759:Pyrrolidines; D014498:Uracil; C502994:saxagliptin; D000077597:Vildagliptin; C520853:alogliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate
keywords: DPP-IV inhibition; Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE); Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial; Vildagliptin in Ventricular Dysfunction Diabetes Trial (VIVIDD); cardiovascular disease; heart failure; type 2 diabetes