title: Oral hypoglycemic agents and the heart failure conundrum: Lessons from and for outcome trials.
abstract: OBJECTIVE
  Type 2 diabetes is not only an independent risk factor for cardiovascular (CV) disease but is also associated with a greater incidence of heart failure (HF). The aim of this review is to examine the effects of oral antidiabetic drugs on CV disease and HF.
  
  
  RESULTS
  Trials of anti-diabetic agents are now designed to assess CV safety, but frequently HF is not included as a primary endpoint. However, HF in patients with diabetes is more frequent than other CV events and seems to be underestimated. A burning question is therefore if the most used trial design to monitor CV safety, i.e. non-inferiority, allows clinical translation of trial findings. Available data further suggest that the CV effects of anti-diabetic drugs may be rather class-specific and are only partly due to their glucose-lowering actions. Metformin, recommended as first line in most guidelines, shows positive CV effects while other classes like thiazolidinediones may precipitate HF. Experimental results on the relatively novel dipeptidyl peptidase IV (DPP IV) inhibitors imply CV protective effects, but the non-inferiority trials published to date show an overall neutral CV outcome and a potential increase in HF by saxagliptin. However, results on sitagliptin of the recently released TECOS indicate that HF is not a class-dependent effect of DPP IV inhibitors.
  
  
  CONCLUSIONS
  Further basic research and long-term outcome studies to clarify the effects of antidiabetic agents on CV and HF are required so that we can select the optimal antidiabetic therapy for our patients.
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Department of Internal Medicine I, University Hospital Aachen, Germany.
authors.forename: B A
authors.initials: BA
authors.lastname: Kappel
authors.affiliation: Department of Internal Medicine I, University Hospital Aachen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Marx
authors.affiliation: Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Center for Atherosclerosis, Policlinico Tor Vergata, Rome, Italy. Electronic address: federicm@uniroma2.it.
authors.forename: M
authors.initials: M
authors.lastname: Federici
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives; D000284:Administration, Oral; D001786:Blood Glucose / Q000187:drug effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D002986:Clinical Trials as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004151:Dipeptides / Q000009:adverse effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D008687:Metformin / Q000009:adverse effects; D012307:Risk Factors; D000068900:Sitagliptin Phosphate / Q000009:adverse effects; D045162:Thiazolidinediones / Q000009:adverse effects
chemical_list: D001786:Blood Glucose; D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; D008687:Metformin; C502994:saxagliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate
keywords: Cardiovascular disease; Cardiovascular safety; Heart failure; Oral antidiabetic agents; TECOS