title: DPP-4 inhibitors and cardiovascular disease in type 2 diabetes mellitus. Expectations, observations and perspectives.
abstract: OBJECTIVE
  Cardiovascular disease (CVD) is the greatest burden of type 2 diabetes mellitus (T2DM) in terms of morbility, mortality and costs for individuals and societies. Therefore, its prevention is a major goal in diabetes care. Optimal treatment of hyperglycemia is certainly instrumental to CVD prevention. Optimal treatment means both establishing the most appropriate glycemic target for the given individual and selecting the medication(s) with the most favourable benefit/safety ratio. CVD safety, if not a clear CVD benefit, is certainly required for all antidiabetic agents. Dipeptidyl-peptidase-4 (DPP-4) inhibitors are among the classes of antidiabetic agents most recently made available for diabetes care. A major question to be addressed is the effect of these compounds on CVD. Expectations were high for their mechanism of action, which targets also post-prandial glucose and minimize hypoglycemia risk, thereby providing a sort of global glucose control, and for some potentially beneficial extra-glycemic effects. This article reviews the existing literature on this issue.
  
  
  RESULTS
  Data published so far document that DPP-4 inhibitors have a wide spectrum of glycemic and extra-glycemic effects potentially reducing the risk of CVD as well as favourable effects on intermediate or surrogate CVD endpoints. These data heralded a better CVD outcome. Accordingly, pooling CVD safety data from phase 3 and 4 studies conducted with DPP-4 inhibitors suggested that their use might translate into a better CVD outcome. Data from three CVD outcome RCTs with alogliptin, saxagliptin and sitagliptin documented no harm but did not show any benefit on major CVD events. A modest but significant increased risk of hospitalization for heart failure was observed with saxagliptin and with alogliptin (only in subjects with no history of heart failure before randomization) but not with sitagliptin. A study currently in progress with linagliptin will provide further insights in the issue of CVD safety and benefit.
  
  
  CONCLUSIONS
  It should be considered that most alternative oral antidiabetic agents generally do not possess a better CVD risk profile than DPP-4 inhibitors and that some of them, indeed, should be used with caution because of potentially adverse effects on heart and vasculature. Overall, the selection of antidiabetic agent(s) with the most favourable CVD profile is mandatory but still challenging in diabetes care.
authors.affiliation: Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy. Electronic address: enzo.bonora@univr.it.
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonora
authors.affiliation: Endocrinology, Diabetes and Metabolism, University and Hospital Trust of Verona, Verona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cigolini
mesh_terms: D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000209:etiology; D017326:Clinical Trials, Phase III as Topic; D017327:Clinical Trials, Phase IV as Topic; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D023381:Endpoint Determination; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000069476:Linagliptin / Q000008:administration & dosage / Q000009:adverse effects; D015201:Meta-Analysis as Topic; D064887:Observational Studies as Topic; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D000068900:Sitagliptin Phosphate / Q000008:administration & dosage / Q000009:adverse effects; D014498:Uracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines; D000069476:Linagliptin; D014498:Uracil; C520853:alogliptin; D000068900:Sitagliptin Phosphate
keywords: Antidiabetic agents; Cardiovascular disease; Dipeptidyl peptidase 4 inhibitors; Type 2 diabetes mellitus