Rosuvastatin and Mean Platelet Volume in Diabetes.

Abstract

Increased mean platelet volume (MPV) is a marker of platelet activation, as shown in diabetes mellitus (DM), especially in the presence of its vascular complications. Additionally, increased MPV is encountered in atherosclerosis, dyslipidemia, hypertension, and ischemic heart disease (IHD), while it is also linked with inflammation and increased vascular morbidity in diverse conditions, such as obstructive sleep apnea, chronic obstructive pulmonary disease, or Behcet disease. Interestingly, elevated MPV can serve as a predictor of acute cardiovascular events in patients with IHD or stroke, irrespective of the presence of DM. Statins, the most important class of hypolipidemic agents, may exert an antiplatelet action. Indeed, they may reduce platelet reactivity and thromboxane formation. Moreover, simvastatin therapy has very recently been shown to reduce P-selectin, platelet-derived microparticles, and expression of CD62P on resting and thrombin-activated platelets after ischemic stroke. In acute coronary syndrome, rosuvastatin has been shown to improve platelet–leukocyte interaction. There is also evidence that simvastatin harbors antiplatelet actions via peroxisome proliferator-activated receptor g, such as inhibition of the phosphorylation of mitogen-activated protein kinases, increase in cyclic adenosine monophosphate formation, and inhibition of protein kinase B phosphorylation and intracellular calcium. Finally, atorvastatin has been demonstrated to exert antiplatelet activity by inhibiting the formation of reactive oxygen species in the platelets. There is evidence from 2 studies that rosuvastatin administration reduces MPV. It has been shown for the 10, 20, and 40 mg/d dosages for a follow-up period of 8 to 12 weeks. Of note, there was no correlation between reduction in MPV and improvement in serum lipids following treatment. Atorvastatin can also decrease the MPV. Of note, this beneficial effect appears to be more pronounced in patients exhibiting the strongest lipid reduction. Conversely, pravastatin treatment did not lower the MPV. More recently, the study of Akyuz et al examined 178 patients with DM receiving high-dose rosuvastatin (40 mg/d) for dyslipidemia. After 6 months of treatment, there was a significant (P < .001) decrease in MPV. At the same time, significant improvements were observed in total cholesterol, triglyceride, low-density lipoprotein cholesterol, and highdensity lipoprotein cholesterol. However, MPV reduction was not correlated with any improvements in serum lipids. The strengths of the study by Akyuz et al include specific examination of patients with DM in whom MPV is more frequently elevated, longer study period, use of a steady statin dosage, and the adequate number (n 1⁄4 178) of patients included. This study also has some limitations. Of foremost importance, it was not a double-blind randomized controlled trial, and, indeed, the effect of rosuvastatin on MPV was seen only in a single treatment arm and not judged against a comparator (other treatment or placebo). Second, observations were made retrospectively. Furthermore, most patients also received aspirin or clopidogrel, which may have, to some extent, affected MPV, although their dosages were unaltered during the study period. Moreover, MPV was the sole index of platelet function evaluated in the study. Finally, seasonal variations in MPV were not considered, but this is the case in the vast majority of studies on MPV. Taken together, the more recent findings and those from the earlier studies suggest that rosuvastatin and atorvastatin, but not pravastatin, exert an additional beneficial action on MPV. With rosuvastatin this action is not mediated by the improved serum lipids, whereas atorvastatin achieved a significant MPV reduction in patients with the strongest concomitant lipid changes. This emerging difference needs to be revisited. Given the importance of MPV as a marker of activated platelets and as a predictor of vascular events, including DM, this effect of rosuvastatin and atorvastatin is encouraging. In contrast, it is worth mentioning that nicotinic acid/laropiprant increases MPV. At present, the underlying mechanism and why this action is not shared by pravastatin, and perhaps by other statins, needs to be determined. Such knowledge will help us better appreciate the clinical relevance of this effect. In conclusion, rosuvastatin and atorvastatin reduce MPV by a hitherto unknown mechanism, which may be lipid independent. However, the evidence may be criticized for being rather