Current Pharmaceutical Design - Volume 15, Issue 5, 2009

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.

Statins are 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are prescribed extensively for cholesterol lowering in the primary and secondary prevention of cardiovascular disease. Recent compelling evidence suggests that the beneficial effects of statins may not only be due to their cholesterol lowering effects, but also, to their cholesterol-independent or pleiotropic effects. Through these so-called pleiotropic effects, statins are directly involved in restoring or improving endothelial function, attenuating vascular remodeling, inhibiting vascular inflammatory response, and perhaps, stabilizing atherosclerotic plaques. These cholesterol-independent effects of statins are predominantly due to their ability to inhibit isoprenoid synthesis, the products of which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac and Cdc42. In particular, inhibition of Rho and its downstream target, Rhoassociated coiled-coil containing protein kinase (ROCK), has emerged as the principle mechanisms underlying the pleiotropic effects of statins. This review provides an update of statin-mediated vascular effects beyond cholesterol lowering and highlights recent findings from bench to bedside to support the concept of statin pleiotropy.

The present review considers the potential pleiotropic effects of statins and the evidence indicative of the “real world” benefit from these effects in patients with cardiovascular disease (CVD). Some of these cholesterol-independent effects of statins involve improved endothelial function, stability of atherosclerotic plaques, attenuation of oxidative stress and inflammation, as well as inhibition of the thrombogenic response. Clinical evidence from early statin administration in acute coronary syndromes and in revascularisation procedures is reported. Moreover, the “metabolic” effects of statin treatment, such as renal function improvement and reduction in serum uric acid levels, in patients with stable coronary heart disease are discussed. Evidence suggests that in high CVD risk patient groups pleiotropic effects of statins may play a role in the reduction of morbidity and mortality. However, this concept requires proof in appropriately designed trials that will include clinically relevant end points in order to set specific targets in new CVD-related biomarkers, in addition to lipid levels, that should be used to fully assess the statin contribution to CVD treatment.

This review considers the hypolipidaemic drugs that act on the gastrointestinal (GI) tract. We searched PubMed up to April 2008 and included randomized controlled trials, original papers, review articles and case reports. Bile acid sequestrants (BAS) have a well-established low density lipoprotein cholesterol (LDL-C) lowering effect, but may increase triglyceride (TG) levels. BAS have no systematic adverse effects, but are associated with increased GI adverse effects and interactions with the absorption of other drugs. Ezetimibe improves LDL-C, high density lipoprotein cholesterol and TG levels, as monotherapy or especially when given with a statin. Ezetimibe has not been associated with serious adverse effects. Ezetimibe has not been evaluated in large clinical trials with cardiovascular disease (CVD) endpoints. Phytosterols are not licensed drugs; they have a well-established LDL-C lowering effect, but there are no large long-term randomized clinical trials investigating their effects on CVD events. Orlistat is an antiobesity drug with a small additional LDL-C lowering effect independent of weight loss. Orlistat-assisted weight loss improves the overall lipid profile, carbohydrate metabolism and transaminase activities. However, its use should be limited to weight reduction. This drug is associated with increased GI adverse effects.

Fenofibrate represents the most commonly used fibric acid derivative. The drug exerts its metabolic effects by modulating the expression of several genes involved in lipoprotein metabolism. In addition, numerous studies suggest that fenofibrate may also affect the progression of the atherosclerotic process by several lipid-independent mechanisms. This review considers the clinical pharmacology of fenofibrate and the current evidence on the pleiotropic effects of this fibric acid derivative.

The incidence of type 2 diabetes continues to increase in the western world over the past decade. Consequently, complications of this disease have reached crisis proportions. In addition to the classical oral hypoglycaemic agents, i.e. sulfonylureas, newer classes have emerged that work by different mechanisms such as insulin sensitizers. One such class are the thiazolidinediones (rosiglitazone and pioglitazone). These agents act as ligands for the gamma peroxisome proliferator- activated receptors (PPARs) and result in a lower glucose. Data from animal and human studies supports the concept that thiazolidinediones exert several other beneficial metabolic and vascular effects, in addition to glycaemic control, including improvement in lipid profile, blood pressure lowering, redistribution of body fat away from the central compartment, anti-inflammatory effects such as reduction in hs-CRP and microalbuminuria as well as subclinical vascular inflammation, improvement in endothelial function. Conversely, thiazolidinediones have well-established side effects, most important of which are fluid retention leading to weight gain and development of heart failure as well as an increased incidence of bone fractures. Moreover, evidence from clinical trials suggests that these agents do not reduce cardiovascular risk. This article discusses the pleiotropic effects of thiazolidinediones focusing on clinical cardiovascular outcomes as well as other potential therapeutic uses in the context of their side-effect profile.

Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor (PPAR) alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, a marked reduction in triglycerides (TG) and an increase in high-density lipoprotein cholesterol (HDL-C), usually dependent of their baseline levels and dyslipidemia type. A beneficial effect on cardiovascular outcomes but also on inflammatory and thrombogenesis pathways as well as antioxidant properties have been evidenced conferring other pleiotropic effects to fibrates. Diabetic retinopathy, nephropathy and neuropathy are the major microvascular complications of Type 2 diabetes mellitus (T2DM) and their presence can accentuate the risk of cardiovascular disease. Hyperglycemia, hypertension, genetic susceptibility among other risk factors play a significant role in the development and progression of these complications. Plasma lipid abnormalities are also involved in the pathogenesis of microvascular diseases suggesting a potential benefit of lipid lowering drugs in their prevention. Clofibrate was the first fibrate in the 60's to show an improvement in the retinal hard exudation in subjects with diabetic retinopathy. Recently, in the Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) study fenofibrate treatment demonstrated a significant 30% reduction in the need for laser therapy in patients with and without known diabetic retinopathy, and more particularly in the first course of laser treatment for both macular edema and proliferative retinopathy. In addition, fenofibrate treatment was associated with less albuminuria progression and reduced risk of non traumatic distal amputations. These results, along with previous evidence of positive effects on microvascular complications, suggest that fibrates, and particularly fenofibrate, offer good opportunity to prevent the most serious complications of diabetes.

Abdominal obesity (high waist circumference) is more strongly associated with cardiovascular disease and type 2 diabetes than generalized adiposity (high body mass index). Recent research has highlighted the role of chronic overactivation of the endogenous endocannabinoid system, acting through its CB1 receptor, as a key factor involved in the development of abdominal obesity and related cardiometabolic risk abnormalities such as insulin resistance, low HDLcholesterol, hypertriglyceridemia, inflammation and low adiponectin. Evidence suggests that these cardiometabolic risk factors/markers are not optimally managed by current treatments. Improving the nutrition and physical activity/exercise habits of patients remains the cornerstone of management of elevated global cardiometabolic risk. Antagonism of the endocannabinoid system provides a novel strategy to target several unaddressed cardiometabolic risk markers/factors. Randomized trials of rimonabant in patients with overweight or obesity and/or type 2 diabetes have demonstrated marked and significant improvements in body weight, waist circumference, glycemic control (in patients with type 2 diabetes), features of atherogenic dyslipidemia, insulin resistance, adipose tissue-derived cytokines (leptin and adiponectin) and Creactive protein (a marker of systemic inflammation). Further analyses suggested that about half of the improvements of several cardiometabolic risk markers were independent from concomitant weight loss. Blood pressure also improved with rimonabant treatment, this effect being consistent with the blood pressure lowering effect of weight loss. The tolerability and safety of rimonabant have been extensively studied and most transient side effects include some gastrointestinal side effects, anxiety, mood changes and incidence of depressive disorders, particularly in patients with previous history of depression. Rimonabant is a useful option for patients with abdominal obesity and with related cardiometabolic risk abnormalities such as an atherogenic dyslipidemia and/or type 2 diabetes.

The renin-angiotensin-aldosterone system blockade is a key component in the modern management of cardiovascular diseases. Agents that interfere with the different components of this system such as angiotensin converting enzyme inhibitors, sartans and mineralocorticoid receptor antagonists represent valuable therapeutic tools to reduce cardiovascular risk in brachial blood pressure independent mechanisms. Indeed, antagonists of the renin-angiotensin-aldosterone system reduce inflammation, oxidative stress and vascular remodeling in hypertension beyond blood pressure reduction and have demonstrated better cardiovascular protection compared with some of the other antihypertensive agents, especially in selected populations such as patients with diabetes and renal failure. These advantages were confirmed recently in several large-scale randomized trials. Latest evidence suggests that the effect of some antihypertensive drugs on central blood pressure is greater when compared with the effect on peripheral pressure. Nowadays, there is growing agreement that relatively greater influence of agents blocking renin-angiotensin system on central blood pressure may at least partly explain their advantages over other antihypertensives in many clinical situations. Clinical consequences of overestimation of the antihypertensive effect of some drug classes and underestimation blood pressure changes in patients treated with angiotensin converting enzyme inhibitors when analyzing brachial instead of central blood pressure is being increasingly recognized recently.