Direct effects of DPP-4 inhibition on the vasculature. Reconciling basic evidence with lack of clinical evidence.

Diabetes is burdened by macrovascular and microvascular complications that collectively reduce life expectancy. As the ultimate goal of diabetes treatment is to prevent excess morbidity and mortality associated with its complications, the interest on cardiovascular effects of glucose lowering medications is high. Dipeptidyl peptidase-4 inhibitors (DPP-4i) lower blood glucose by protecting the incretin hormone glucagon-like peptide-1 (GLP-1) from enzymatic degradation, thereby restoring meal-stimulated insulin release. DPP-4 has several non-incretin substrates, including cytokines, chemokines, and neurohormones, which can exert favourable, but also unpredictable, vascular effects, once they are stabilized by DPP-4i. Choi et al. now provide additional evidence that DPP-4i counteracts vascular smooth muscle cell proliferation and migration, resulting in an attenuation of neointimal hyperplasia. Though several other in vitro, preclinical, and preliminary clinical studies on surrogate end-points suggest that DPP-4i can exert similar direct vasculoprotective actions, results of placebo-controlled phase IV trials have so far shown no reduction cardiovascular endpoints by DPP-4i. In this commentary, we put DPP-4 pleiotropy and complexity into context, trying to reconcile why results from basic science have not yet translated into clinical evidence of cardiovascular protection.