title: Dipeptidyl peptidase-4 inhibitors and heart failure: Analysis of spontaneous reports submitted to the FDA Adverse Event Reporting System.
abstract: We tested the possible association between dipeptidyl peptidase-4 inhibitors (DPP-4-I) use and heart failure (HF) occurrence by assessing the publicly available US-FDA Adverse Event Reporting System (FAERS).
  
  
  
  FAERS data reporting HF and DPP-4-Is use in the period from the fourth quarter of 2006 through 2013 were extracted, using the Standardized MedDRA Query "Cardiac failure". Disproportionality (case/non-case method) was implemented by calculating Reporting Odds Ratios (RORs) with 95% Confidence Interval (CI): (1) exploratory analysis on the entire FAERS (using rosiglitazone as positive control); (2) consolidated analyses by therapeutic area (within antidiabetics), correcting for event- and drug-related competition bias and adjusting for co-reported drugs as confounders.
  
  
  
  HF during DPP4-I use was recorded in 390 reports (4.4% of total reports). In exploratory analysis, statistically significant ROR emerged for DPP-4-I as a class (ROR = 1.17; 95% CI = 1.05-1.29), saxagliptin (1.68; 1.29-2.17), vildagliptin (2.39; 1.38-4.14), and rosiglitazone (13.98; 13.30-14.70). In consolidated analyses, the ROR for saxagliptin (2.60; 1.92-3.50) and vildagliptin (4.07; 2.28-7.27) increased, and became also significant for sitagliptin (1.61; 1.40-1.86). Concomitant drugs were reported in more than 50% of cases; the adjusted RORs of saxagliptin (2.30; 1.70-3.10), vildagliptin (3.15; 1.76-5.63), and sitagliptin (1.48; 1.28-1.71) were nonetheless significant.
  
  
  
  FAERS data are consistent with clinical studies on a possible association between saxagliptin and HF. The disproportionate reporting of HF with sitagliptin, conflicting with a recent phase IV trial, suggests that cardiovascular safety requires close post-marketing vigilance by clinicians of individual DPP-4-I in the community until the issue of class effect is solved.
authors.affiliation: Alma Mater Studiorum - University of Bologna, Dept. of Medical and Surgical Sciences, Pharmacology Unit, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Raschi
authors.affiliation: Alma Mater Studiorum - University of Bologna, Dept. of Medical and Surgical Sciences, Pharmacology Unit, Bologna, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Poluzzi
authors.affiliation: Alma Mater Studiorum - University of Bologna, Dept. of Medical and Surgical Sciences, Pharmacology Unit, Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Koci
authors.affiliation: Alma Mater Studiorum - University of Bologna, Dept. of Medical and Surgical Sciences, Pharmacology Unit, Bologna, Italy.
authors.forename: I C
authors.initials: IC
authors.lastname: Antonazzo
authors.affiliation: Alma Mater Studiorum - University of Bologna, Dept. of Medical and Surgical Sciences, Unit of Metabolic Diseases & Clinical Dietetics, Bologna, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Marchesini
authors.affiliation: Alma Mater Studiorum - University of Bologna, Dept. of Medical and Surgical Sciences, Pharmacology Unit, Bologna, Italy. Electronic address: fabrizio.deponti@unibo.it.
authors.forename: F
authors.initials: F
authors.lastname: De Ponti
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives*; D000293:Adolescent; D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D004151:Dipeptides / Q000009:adverse effects*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects*; D005060:Europe / Q000453:epidemiology; D005260:Female; D006333:Heart Failure / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D000068900:Sitagliptin Phosphate / Q000009:adverse effects*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000218:Adamantane; D000068900:Sitagliptin Phosphate
keywords: Dipeptidyl peptidase-4 inhibitors; Disproportionality; Drug safety; FAERS; Heart failure; Saxagliptin; Sitagliptin; Spontaneous reporting system