Table 2.

Pleiotrophic effect of hypogycemic drugs on the cardiovascular and coagulation system.

Drug	Cardiovascular	Effect		Coagulation	Effect
		↑	↓		↑	↓
Acarbose	Risk of cardiovascular events		x	PLT—bound fibrinogen		x
	Progression of carotid intima–media thickness		x	P—selectin platelet exposure		x
				Platelet—monocytes aggregates formation		x
Dipeptyl peptidase-4 inhibitors	Benefit on MACE	- -		PLT activation and oxidative stress markers		x
				cAMP formation and PKA activation	x
				Plasma fibrinogen and PAI-1		x
				Soluble levels of CD40		x
				Inflammatory and thrombogenic gene expression		x
				Platelet mitochondrial respiration and aggregaton	x
				Intracellular free calcium and tyrosine phosphorylation leading to PLT aggregation		x
GLP-1 receptor agonists	MACE and fatal or non-fatal MI		x	Thrombin, ADP, and collagen—induced PLT aggregation mediated by cAMP—induced PKA activation and increased eNOS enzymatic activity		x
				ROS production		x
				cGMP production	x
				VASP-ser239 phosphorylation	x
				PI3-K/Akt and MAPK/erk-2 pathways		x
				NO bioavaliability	x
				ROS production		x
				Platelet P-selectin expression		x
Metformin	MI, stroke and all-cause mortality		x	ADP, collagen and arachidonic acid induced platelet aggregation		x
	Macrovascular complicatrions (MI, stroke, peripheral vascular disease)		x	Production od superoxide ion (O2-)		x
				PLT activation and axtracellular mitochondrial DNA release		x
				11-dhTXB2 urinary excretion		x
				8-iso-pg F2 α excretion		x
				Mean PLT volume		x
Sodium-glucose cotransporter 2 inhibitors	Incidence of MACE, cardiovascular death and hospitalization for HF		x	ADP—induced PLT activation		x
				P selectin mRNA expression		x
				ROS bioavaliability		x
				NO bioavaliability	x
				Advanced glycation end products		x
				e NOS activation	x
				Interstitial and periarterial NO stress		x
Sulphonyloureas	Cardiovascular benefit vs. metformin alone		x	ADP-induced PLT activation		x
	Risk of hospitalization/mortality	x		PLT adhesiveness		x
	Risk of stroke and overall mortality	x		Oxidative stress		x
	MACE	- -	- -	Cyclooxygenase and lipoxygenase pathways		x
	All—cause mortality, cardiovascular mortality, MI or stroke with 2nd or 3rd generation drugs
Thiasolidynediones	Pioglitasone—MACE	-	-	ADP-induced PLT aggregation		x
	Pioglitasone—MI/stroke		x	P selectin levels		x
	Rosiglitasone-Risk of cardiovascular events	x		Inflammation and macrophage recruitment		x
	Rosiglitasone-MI/cardiovascular death	-	-	E-selectin		x
	Rosiglitasone-HF hospitalisations	x		vWillebrand, SCD40L, PAI-1, 11-dhTXB2		x

ADP—adenosine diphosphate, ERK—extracellular signal-regulated kinases, eNOS—endothelial nitric oxide synthase, GLP-1 glucagon like peptide-1, HF—heart failure, MAcEs-major cardiac adverse events, MAPK—mitogen- activated protein kinases, MI—myocardial infarction, NO—nitric oxide, PAI-1—plasminogen activator inhibitor-1, PI3K—phosphatidyl inositol-3 kinase, PKA—protein kinase A, PLT—platelet, ROS—reactive oxygen species, TXB—thromboxane, VASP—vasodilator-stimulatedphosphoprotein, ↑—increase, ↓—decrease.