title: Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes.
abstract: Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are oral incretin-based glucose-lowering agents with proven efficacy and safety in the management of type 2 diabetes mellitus (T2DM). In addition, preclinical data and mechanistic studies suggest a possible additional non-glycemic beneficial action on blood vessels and the heart, via both glucagon-like peptide-1-dependent and glucagon-like peptide-1-independent effects. As a matter of fact, DPP-4 inhibitors improve several cardiovascular risk factors: they improve glucose control (mainly by reducing the risk of postprandial hyperglycemia) and are weight neutral; may lower blood pressure somewhat; improve postprandial (and even fasting) lipemia; reduce inflammatory markers; diminish oxidative stress; improve endothelial function; and reduce platelet aggregation in patients with T2DM. In addition, positive effects on the myocardium have been described in patients with ischemic heart disease. Results of post hoc analyses of phase 2/3 controlled trials suggest a possible cardioprotective effect with a trend (sometimes significant) toward lower incidence of major cardiovascular events with sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin compared with placebo or other active glucose-lowering agents. However, the definite relationship between DPP-4 inhibition and better cardiovascular outcomes remains to be proven. Major prospective clinical trials involving various DPP-4 inhibitors with predefined cardiovascular outcomes are under way in patients with T2DM and a high-risk cardiovascular profile: the Sitagliptin Cardiovascular Outcome Study (TECOS) on sitagliptin, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial on saxagliptin, the Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE) trial on alogliptin, and the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) on linagliptin. If these trials confirm that a DPP-4 inhibitor can reduce the cardiovascular burden of T2DM, it would be major progress that would dramatically influence the management of the disease.
authors.affiliation: Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Sart Tilman, University of Liège, Liège, Belgium. andre.scheen@chu.ulg.ac.be
authors.forename: André J
authors.initials: AJ
authors.lastname: Scheen
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D003324:Coronary Artery Disease / Q000139:chemically induced; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D009570:Nitriles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011759:Pyrrolidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D012307:Risk Factors; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000077597:Vildagliptin
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D008055:Lipids; D009570:Nitriles; D011719:Pyrazines; D011759:Pyrrolidines; D014230:Triazoles; D000077597:Vildagliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate