Mechanisms leading to calcification of the aortic valve are unclear. Dipeptidyl peptidase 4 (DPP4), an enzyme involved in glucose metabolism, might contribute to this process, according to a new study. In human, cultured valvular interstitial cells (VICs), activation of nuclear factor-κB induced the expression of DPP4, which then promoted osteogenic differentiation through inhibition of insulin-like growth factor 1 (IGF1) signalling. Inhibition of DPP4 blocked in vitro VIC osteogenic differentiation and in vivo aortic valve calcification in Nos3−/− mice. In a rabbit model of calcific aortic valve disease, administration of the DPP4 inhibitor sitagliptin improved clinical parameters, reduced calcium deposits in aortic valve cusps, and increased IGF1 levels in plasma.