Editorial [Hot Topic:Are the Pleiotropic Effects of Drugs Used for the Prevention of Cardiovascular Disease Clinically Relevant?(Executive Editors: M. Elisaf and E.N. Liberopoulos)]

Cardiovascular disease (CVD) is the leading cause of death worldwide. Many drugs are currently used for CVD prevention. Some of these drugs seem to exhibit effects beyond their main indication that they are administered for. These so called ‘pleiotropic’ effects are believed to contribute to the clinical benefits these drugs offer. Furthermore, they may differentiate drugs within the same category. The aim of the present issue of Current Pharmaceutical Design is to comprehensively review the pleiotropic actions associated with drugs commonly used for CVD prevention. Authors are leading experts in their field and they also present their own research contribution. Statins are the mainstay of lipid-lowering therapy [1]. Statin treatment is associated with less CVD evens and deaths both in primary and secondary prevention [2]. It has been suggested that the main mechanism by which statins reduce CVD events is lowering of low-density lipoprotein cholesterol (LDL-C) [3]. Indeed, lowering of LDL-C by other means also leads to reduced CVD events [4,5]. However, the lag time for these CVD benefits to become apparent is approximately 5 years when LDL-C is lowered by non-statin means, but much lower (i.e. <1 year) when statins are used, for the same degree of LDL-C lowering [6,7]. Newer statins (such as atorvastatin) may require only 15 days to differentiate from older statins (such as pravastatin) in terms of CVD protection in very high-risk patients [8]. Moreover, statin pretreatment for only 12 hours before a percutaneous coronary intervention may be associated with a large reduction of CVD events as compared with placebo [9]. It is clear that LDL-C lowering itself cannot fully explain these immediate vascular statin effects. It should be remembered that mevalonic acid, the product of 3-hydroxyl-3-methylgloutaryl coenzyme A (HMG-CoA) reductase, is the precursor not only of cholesterol but also of non-steroidal isoprenoid compounds. These compounds serve as important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42 and mediate a number of adverse vascular and metabolic reactions. Thus, inhibition of HMG-CoA reductase by statins leads not only to reduced cholesterol synthesis, but also to a decrease in these intracellular signaling molecules. It has been suggested that LDL-C decrease is responsible for the long-term beneficial effects of statins, while the elimination of isoprenoid compounds is associated with the immediate vasculoprotective actions seen with statin treatment. In this issue, Zhou and Liao extensively review the underlying molecular mechanisms responsible for the cholesterol-independent statin effects [10]. These mainly include improvement of endothelial function, antiiflammatory and antioxidant effects as well as normalization of coagulation-fibrinolysis system [10]. Statins may also decrease blood pressure [11], have antiarrhythmic properties [12], as well as reduce serum uric acid levels and improve renal function [13]. In this issue, Athyros et al. comprehensively review current evidence from clinical trials regarding the contribution of these pleiotropic effects to improved clinical outcomes [14]. They conclude that these effects do indeed contribute to the clinical benefit afforded by statins. The very recently published Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) may be relevant in this context [15]. In JUPITER 17,802 primary prevention subjects with LDL-C <130 mg/dL but elevated levels of high sensitivity C-reactive protein (hsCRP) (>2 mg/L) were randomly assigned to either placebo or rosuvastatin 20 mg/day. LDL-C and hsCRP levels were reduced by 50% and 37%, respectively, in the active treatment group. The trial was prematurely stopped after only 1.9 years due to impressive reductions in CVD events (by 44%, p<0.00001) and all-cause death (20%, p=0.02). Which is the relative contribution of LDL-C and hsCRP reduction to this clinical benefit remains to be determined.