Effects of contemporary glucose-lowering agents on the hemostatic system: From molecular mechanisms to clinical practice

Abstract

This publication is devoted to a comparative analysis of the hemostasiological effects of different classes of glucose-lowering agents in patients with type 2 diabetes, with a particular focus on the molecular and cellular mechanisms underlying their impact on coagulation status. It has been demonstrated that the influence of glucose-lowering therapy (GLT) on the hemostatic system is determined by a spectrum of specific pleiotropic effects that may not be directly associated with the antihyperglycemic efficacy of the drugs and often occur independently of the degree of glycemic control. The most robust evidence for an antithrombotic effect has been obtained for glucagon-like peptide-1 receptor agonists (GLP-1) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), which achieve a multilevel reduction of prothrombotic potential through direct inhibition of platelet activation, lowering of plasminogen activator inhibitor-1 (PAI-1) levels, and enhancement of fibrinolysis. Metformin exhibits a pronounced antithrombotic potential via mitochondria-dependent suppression of platelet activity and inhibition of the release of pro-inflammatory mitochondrial danger signals, which is accompanied by a reduction in venous and arterial thrombosis without an increase in bleeding risk. Thiazolidinediones also exert favorable effects on hemostasis through PPARγ/ AMP-activated protein kinase–mediated mechanisms, providing profibrinolytic and anti-aggregatory actions. Insulin and most sulfonylurea derivatives do not demonstrate clinically meaningful beneficial hemostasiological effects; the exception is gliclazide, which is distinguished by a more favorable antiplatelet profile within its class. Tirzepatide has proven cardiovascular safety, being non-inferior to dulaglutide with respect to the risk of major adverse cardiovascular events, which allows one to hypothesize a high anticoagulant potential of this agent; however, dedicated trials with primary hemostasiological endpoints are still lacking. The analysis performed supports the rationale for incorporating coagulation status into the personalization of glucose-lowering therapy, particularly in patients at high thrombotic risk.