Fibroblast growth factor 21 (FGF21), a hormone with pleiotropic metabolic effects, is inactivated by fibroblast activation protein (FAP), a member of the dipeptidyl peptidase-IV (DPP-IV) family. We investigate if sitagliptin (DPP-IV inhibitor) inhibits FAP-activity and increases intact FGF21.

Patients with impaired glucose metabolism were randomized to 100 mg sitagliptin (n = 34) or placebo (n = 37) treatment for 12 weeks. Plasma samples obtained at study entry and at 12-weeks were analysed for FAP-activity, FAP, total FGF21 and intact FGF21.

Sitagliptin significantly inhibited FAP-activity (497 ± 553 vs. 48 ± 712 RFU/min, p < 0.01) and correspondingly increased intact FGF21 (253 ± 182 vs 141 ± 80 ng/L, p < 0.01) compared to placebo in plasma. Sitagliptin dose-dependently inhibited the FAP-activity in vitro. Intact FGF21 was higher in patients obtaining a normal glucose tolerance regardless of treatment (p = 0.03).

A sitagliptin-induced increase of intact FGF21 may contribute to an improved metabolic effect in patients with impaired glucose metabolism.