Sitagliptin: Anti-platelet effect in diabetes and healthy volunteers

Abstract

Sitagliptin, a selective dipeptidyl peptidase-4 inhibitor drug is used to treat type-2 diabetes (T2DM). We investigated the anti-platelet activity of sitagliptin in patients with T2DM and in in vitro samples obtained from healthy humans. Patients with T2DM (27 male + 23 female) were selected and followed up before (control) and after treatment with sitagliptin for up to 3 months. Platelets were isolated from the blood of sitagliptin treated patients and controls. Patients with T2DM treated with sitagliptin for 1and 3 months, showed 10 ± 2% and 30 ± 5% inhibition of platelet aggregation, respectively. For the in vitro study, platelets from 10 normal humans (n = 10) were isolated. Platelet aggregation, intracellular free calcium and tyrosine phosphorylation of multiple proteins were measured by aggregometer, spectrofluorometer and western blotting, respectively. Platelets pre-treated with 5 and 10 µg/ml of sitagliptin, showed 25 ± 4% and 40 ± 6% inhibition of thrombin-induced platelet aggregation, respectively. Sitagliptin decreased intracellular free calcium (2.5-fold) and tyrosine phosphorylation of multiple proteins in thrombin-induced platelet activation. Sitagliptin inhibited platelet aggregation in T2DM as well as in healthy humans. Sitagliptin has significant concentration-dependent anti-platelet activity. This activity was due to its inhibitory effect on intracellular free calcium and tyrosine phosphorylation.

Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis

“…Given that there should have been no GLP-1 present in their platelet preparations, and that we have been unable to document any DPP-4 activity in platelets (or MEG-01 cells) (Supplementary Fig. 3), the results of Gupta et al (17) are somewhat surprising. We can only speculate as to whether their results in vitro suggest a "direct" action of sitagliptin on platelet biology (i.e., independent of GLP-1 or DPP-4).…”

“…Because the rather modest and brief improvements in glycemic control observed in these studies are unlikely to explain the observed benefits, we wondered whether GLP-1-targeted therapies may reduce macrovascular event rates in these particular patient populations by directly inhibiting platelet aggregation and thrombus formation. Indeed, this premise could be extrapolated from the one small uncontrolled study (17) that demonstrated the curious ability of DPP-4i sitagliptin to inhibit thrombin-induced platelet aggregation in vitro.…”

Sitagliptin in Patients with Non-Alcoholic Steatohepatitis: A Randomized, Placebo-Controlled Trial

“…Thus, DPP-IV itself may be important to the pathogenesis of NASH. Use of the DPP-IV inhibitor, sitagliptin, improves lipid metabolism, and attenuates the progression of hepatic fibrosis in mice with NASH, as well as decreases platelet aggregation in vitro [20,21] . Thus, sitagliptin may be an attractive therapeutic option for NASH, especially given its low risk of hypoglycemia, weight-neutrality, and demonstrated safety profile in individuals with moderate hepatic insufficiency [22,23] .…”

DPP-4 inhibitors: a patent review (2012 – 2014)

“…DPP-4 inhibitors are now considered as one of the well-established therapies available for diabetes mellitus type 2 (T2DM): in addition to the well-known anti-hyperglycemic and pancreatic islet protective effects, other effects of novel DPP-4 inhibitors have been observed, such as immune regulation [2][3][4][5], cardiovascular protection [6][7][8][9][10] and anti-inflammatory effects [11][12][13][14].…”