title: Association Between Sitagliptin Use and Heart Failure Hospitalization and Related Outcomes in Type 2 Diabetes Mellitus: Secondary Analysis of a Randomized Clinical Trial.
abstract: Previous trial results have suggested that dipeptidyl peptidase 4 inhibitor (DPP4i) use might increase heart failure (HF) risk in type 2 diabetes mellitus (T2DM). The DPP4i sitagliptin has been shown to be noninferior to placebo with regard to primary and secondary composite atherosclerotic cardiovascular (CV) outcomes in the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS).
  
  
  
  To assess the association of sitagliptin use with hospitalization for HF (hHF) and related outcomes.
  
  
  
  TECOS was a randomized, double-blind, placebo-controlled study evaluating the CV safety of sitagliptin vs placebo, each added to usual antihyperglycemic therapy and CV care among patients with T2DM and prevalent atherosclerotic vascular disease. The median follow-up was 2.9 years. The setting was 673 sites in 38 countries. Participants included 14 671 patients with T2DM and atherosclerotic vascular disease. The study dates were December 2008 through March 2015.
  
  
  
  Patients were randomized to sitagliptin vs placebo added to standard care.
  
  
  
  Prespecified secondary analyses compared the effect on hHF, hHF or CV death, and hHF or all-cause death composite outcomes overall and in prespecified subgroups. Supportive analyses included total hHF events (first plus recurrent) and post-hHF death. Meta-analyses evaluated DPP4i effects on hHF and on hHF or CV death.
  
  
  
  Of 14 671 patients, 7332 were randomized to sitagliptin and 7339 to placebo. Hospitalization for HF occurred in 3.1% (n = 228) and 3.1% (n = 229) of the sitagliptin and placebo groups, respectively (unadjusted hazard ratio, 1.00; 95% CI, 0.83-1.19). There was also no difference in total hHF events between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted hazard ratio, 1.00; 95% CI, 0.80-1.25). Post-hHF all-cause death was similar in the sitagliptin and placebo groups (29.8% vs 28.8%, respectively), as was CV death (22.4% vs 23.1%, respectively). No heterogeneity for the effect of sitagliptin on hHF was observed in subgroup analyses across 21 factors (P > .10 for all interactions). Meta-analysis of the hHF results from the 3 reported DPP4i CV outcomes trials revealed moderate heterogeneity (I2 = 44.9, P = .16).
  
  
  
  Sitagliptin use does not affect the risk for hHF in T2DM, both overall and among high-risk patient subgroups.
  
  
  
  clinicaltrials.gov Identifier: NCT00790205.
authors.affiliation: Division of Cardiology, Department of Medicine, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Darren K
authors.initials: DK
authors.lastname: McGuire
authors.affiliation: Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.affiliation: Canadian Virtual Coordinating Centre for Global Collaborative Cardiovascular Research (VIGOUR) Centre, Department of Medicine (Cardiology), University of Alberta, Edmonton.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Munich Diabetes Research Group e.V. at Helmholtz Centre, Neuherberg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Standl
authors.affiliation: Global Clinical Development, Merck Research Laboratories, Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Joerg
authors.initials: J
authors.lastname: Koglin
authors.affiliation: Division of Endocrinology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: Green
authors.affiliation: Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, England.
authors.forename: M Angelyn
authors.initials: MA
authors.lastname: Bethel
authors.affiliation: Department of Cardiology, Medisch Centrum Alkmaar, Alkmaar, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Cornel
authors.affiliation: Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Renato D
authors.initials: RD
authors.lastname: Lopes
authors.affiliation: Department of Cardiology, Oslo University Hospital Ulleval and University of Oslo, Oslo, Norway.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Halvorsen
authors.affiliation: Division of Cardiology, University of Perugia School of Medicine, Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Ambrosio
authors.affiliation: Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine at Chapel Hill.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
authors.affiliation: Division of Endocrinology and Metabolism, St Michael's Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Josse
authors.affiliation: The Biostatistics Center, George Washington University Biostatistics Center, Rockville, Maryland.
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pencina
authors.affiliation: Department of Clinical Trials Statistics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Garg
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lokhnygina
authors.affiliation: Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, England.
authors.forename: Rury R
authors.initials: RR
authors.lastname: Holman
authors.affiliation: Division of Cardiology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Peterson
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000139:chemically induced / Q000453:epidemiology; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000150:complications* / Q000401:mortality; D002423:Cause of Death / Q000639:trends; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000139:chemically induced* / Q000150:complications; D017052:Hospital Mortality / Q000639:trends; D006760:Hospitalization / Q000706:statistics & numerical data* / Q000639:trends; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D015995:Prevalence; D012307:Risk Factors; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D000068900:Sitagliptin Phosphate