When platelets are activated, they increase in size and change from a quiescent disc to a swollen sphere. Large platelets are more reactive and likely aggregate more than small ones [1]. Mean platelet volume (MPV), an indicator of platelet size and activation, has been shown to predict ischemic stroke, myocardial infarction, and overall vascular mortality [2,3]. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVEIT) study showed that ezetimibe added to statin therapy further decreases low density lipoprotein cholesterol (LDL-C) levels and prevented acute coronary syndromes [4]. In this study, we investigated the lowering effect of LDL-C and MPV changes in patients who are on statin-ezetimibe combination therapy and those who receive statin monotherapy.

Patients with acute ischemic cerebral infarctions (n=120) were divided into those who were on statin therapy (n=60) and those on statin plus ezetimibe (n=60). The statin group received either atorvastatin (20 mg; n=13) or rosuvastatin (10 mg; n=48). The statin plus ezetimibe group received ezetimibe (10 mg) on top of the same dose of statin (atorvastatin plus ezetimibe, n=14; rosuvastatin plus ezetimibe, n=47). Student’s t-tests showed that MPV and serum LDL-C levels were more significantly decreased (MPV: P<0.001; LDL-C: P=0.017) by statin plus ezetimibe combination therapy (MPV: from 7.39±1.04 [5.8-9.2] to 6.04±0.58 [4.9-7.3] fL; LDL-C: from 160.1±21.9 [122-212] to 79.5±22.9 [33-158] mg/dL) than statin monotherapy (MPV: from 7.47±0.74 [5.6-11.6] to 6.56±1.04 [4.9-9.2] fL; LDL-C: from 143.4±29.4 [52-238] to 95.6±21.7 [41-150] mg/dL). Total cholesterol and triglycerides, but not high-density lipoprotein-cholesterol, were more significantly altered with combination therapy than with statin monotherapy (Table 1). A multivariate regression analysis showed that only LDL-C in the lipid profile correlated significantly with the MPV change. A Pearson correlation analysis showed a positive correlation between the post-treatment MPV and post-treatment LDL-C levels (r=0.230, P=0.012).

Statin has pleiotrophic effects and modulates platelet function by direct interactions with platelet membranes or by influencing signaling pathways, irrespective of the cholesterol-lowering effects. Aydin et al. reported that high doses of statin decrease MPV and LDL-C levels in patients with diabetes, but the changes in LDL-C and MPV did not correlate [5]. Nevertheless, Marek et al. reported that MPV was correlated with small dense LDL-C [6]. The possible mechanisms through which small dense LDL-C increases MPV include easier oxidation and glycation, which enhances the mobilization of arachidonic acid from phospholipids and decreases membrane fluidity. However, small dense-LDL-C measurements are time consuming and expensive in real life. In general, statin and ezetimibe induce reductions in all LDL-C subclasses. Ezetimibe blocks the critical mediator of cholesterol absorption, the Niemann-Pick C1-like 1 (NPC1L1) protein, on gastrointestinal tract epithelial cells as well as in hepatocytes, which causes them to absorb more LDL-C from the circulation and lower the circulating cholesterol level.

The previously proposed mechanisms of hypercholesterolemia in platelet activation are increased thromboxane A2 biosynthesis, inhibition of the platelet Na+/H+ antiport, decreased platelet endogenous nitric oxide production, and diminished endothelial nitric oxide synthase (eNOS) protein expression [7]. In addition, platelet activation by high LDL-C through platelet signaling pathways has been reported [8]. The effects of ezetimibe monotherapy on the LDL subclass profile are controversial. Kasper et al. reported that ezetimibe increases small dense LDL-C in healthy men [9]. In contrast, other studies have reported that ezetimibe decreases all LDL-C subclasses, including small dense LDL-C [10].

Our results showed that MPV and LDL-C levels were more significantly decreased by statin and ezetimibe combination therapy than statin monotherapy and that their levels are closely correlated. Our data suggest that the lowering of LDL-C may causally related with MPV changes and support the “Lower LDL-C, better outcome” findings of the IMPROVE-IT study [4].