Dipeptydil-peptidase-4 (DPP-4) inhibitors are available as oral anti-hyperglycemic drugs for the treatment of type 2 diabetes. Their metabolic effect is mediated through sparing incretin hormones (such as glucagon-like peptide-1, GLP-1) from the rapid degradation by DPP-4. In turn, GLP-1 improves meal-stimulated insulin secretion by pancreatic β-cells thus reducing hyperglycemia. It has been shown that GLP-1 signaling is also active in the cardiovascular system, where it may exert beneficial effects. However, DPP-4 has several non-incretin substrates, and its immunomodulatory activity is known from decades. DPP-4 physiologically cleaves cytokines, chemokines and neuropeptides involved in inflammation, immunity, and vascular function. Owing to these off-target mechanisms, DPP-4 inhibitors hold promise for cardiovascular protection, but may also face unexpected side effects. Herein, we review available data on the cardiovascular effects of DPP-4 inhibitors, with a special interest in GLP-1-independent mechanisms. The modulation of endothelial progenitor cells, inflammatory pathway and ischemic response emerges as the major cardiovascular target of DPP-4 inhibitors.
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