The Effects of Statins, Ezetimibe, PCSK9-Inhibitors, Inclisiran, and Icosapent Ethyl on Platelet Function

Abstract

This review aims to examine the complex interaction between dyslipidemia, platelet function, and related drug treatments. In particular, the manuscript provides an overview of the effects of major hypolipidemic drugs on platelet function. Indeed, growing evidence supports the view that statins, ezetimibe, PCSK9 inhibitors, inclisiran, and icosapent ethyl also act as antithrombotics. It is known that platelets play a key role not only in the acute phase of coronary syndromes but also in the early phase of atherosclerotic plaque formation. The goal of cholesterol-lowering therapy is to reduce cardiovascular events. The direct effects of cholesterol-lowering drugs are widely described in the literature. Lowering LDL-c (low-density lipoprotein cholesterol) by 1 mmol/L results in a 22-23% reduction in cardiovascular risk. Numerous studies have examined the direct antithrombotic effects of these drugs on platelets, endothelium, monocytes, and smooth muscle cells, and thus, potentially independent of blood LDL-cholesterol reduction. We reviewed in vitro and in vivo studies evaluating the complex interaction between hypercholesterolemia, hypertriglyceridemia, platelet function, and related drug treatments. First, we discussed the role of statins in modulating platelet activation. Discontinuation of statin therapy was associated with increased cardiovascular events with increased ox-LDL, P-selectin, and platelet aggregation. The effect of PCSK9-I (inhibitors of proprotein convertase subtilisin/kexin type 9, PCSK9 involved in the degradation of LDL receptors in the liver) was associated with a statistically significant reduction in platelet reactivity, calculated in P2Y12 reaction units (PRU), in the first 14 days and no difference at 30 days compared to placebo. Finally, in patients with hypertriglyceridemia, the REDUCE-IT study showed that icosapent ethyl (an ethyl ester of eicosapentaenoic acid that reduces triglyceride synthesis and improves triglyceride clearance) resulted in a 25% reduction in ischemic events and cardiovascular death. However, to date, there is not yet clear clinical evidence that the direct antithrombotic effects of the drugs may have a beneficial impact on outcomes independently from the reduction in LDL-C or triglycerides.

Keywords: LDL-C; PCSK9i; anticholesterolemic drugs; ezetimibe; hypercholesterolemia; icosapent ethyl; inclisiran; platelet; residual platelet reactivity; statin; triglycerides.

Figure 1

The evolution of hypercholesterolemic therapy. On the timeline, the figure shows the randomized clinical trial on hypercholesterolemia treatment. The value in the arrows indicates the reduction in the risk of cardiovascular events associated with the different treatments used. CVD, cardiovascular disease; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitors.

Figure 2

Plaque stability. A vulnerable plaque is defined as having an FCT of ≤65 μm with a pronounced lipid core. The anticholesterolemic drugs work through a reduction in lipid core and an increase in FCT. The severity of the lesion usually does not impact the transition from stable to unstable plaque.

Figure 3

Interaction between atherosclerotic plaque and platelet activity. The figure shows the mechanism of platelet activation at the endothelial level. Based on in vitro and in vivo studies, platelets play a key role in the genesis of atherosclerotic plaque. PSGL-1, P-selectin glycoprotein ligand-1; PF4, platelet factor 4; MCP-1, endothelial monocyte chemotactic protein-1; MMPs, metalloproteinases; LOX-1, lectin-like receptor-1.

Figure 4

Underlying causes of acute coronary syndromes. The most frequent cause of acute coronary syndrome (ACS) is plaque rupture (60%). The second mechanism of ACS is the erosion of fibrous caps. In both cases, the exposure of the lipid core to the blood is the initial mechanism of platelet aggregation and intracoronary thrombus formation.