Sitagliptin Exerts an Antinflammatory Action

Context: Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase-IV (DPP-IV), which degrades the incretins, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, and thus, sitagliptin increases their bioavailability. The stimulation of insulin and the suppression of glucagon secretion that follow exert a glucose lowering effect and hence its use as an antidiabetic drug. Because DPP-IV is expressed as CD26 on cell membranes and because CD26 mediates proinflammatory signals, we hypothesized that sitagliptin may exert an antiinflammatory effect. Patients and Methods: Twenty-two patients with type 2 diabetes were randomized to receive either 100 mg daily of sitagliptin or placebo for 12 wk. Fasting blood samples were obtained at baseline and at 2, 4, and 6 hours after a single dose of sitagliptin and at 2, 4, 8, and 12 wk of treatment. Results: Glycosylated hemoglobin fell significantly from 7.6 +/- 0.4 to 6.9 +/- 3% in patients treated with sitagliptin. Fasting glucagon-like peptide-1 concentrations increased significantly, whereas the mRNA expression in mononuclear cell of CD26, the proinflammatory cytokine, TNF alpha, the receptor for endotoxin, Toll-like receptor (TLR)-4, TLR-2, and proinflammatory kinases, c-Jun N-terminal kinase-1 and inhibitory-kappa B kinase (IKK beta), and that of the chemokine receptor CCR-2 fell significantly after 12 wk of sitagliptin. TLR-2, IKK beta, CCR-2, and CD26 expression and nuclear factor-kappa B binding also fell after a single dose of sitagliptin. There was a fall in protein expression of c-Jun N-terminal kinase-1, IKK beta, and TLR-4 and in plasma concentrations of C-reactive protein, IL-6, and free fatty acids after 12 wk of sitagliptin. Conclusions: These effects are consistent with a potent and rapid antiinflammatory effect of sitagliptin and may potentially contribute to the inhibition of atherosclerosis. The suppression of CD26 expression suggests that sitagliptin may inhibit the synthesis of DPP-IV in addition to inhibiting its action. (J Clin Endocrinol Metab 97: 3333-3341, 2012)