oa Editorial [Hot topic: New Developments in the Treatment and Prevention of Vascular Disease - Part 1 (Executive Editors: N. Katsiki, V.G. Athyros and D.P. Mikhailidis)]

This issue of Current Pharmaceutical Design covers several topics in the field of vascular disease. Bountziouka and Panagiotakos [1] critically discuss the statistical methods used to evaluate the reliability and validity of nutrition assessment tools in clinical trials. This is an important topic because the outcome of studies involving vascular risk can easily be influenced by changes in diet, as well as other lifestyle measures. Omar et al. consider [2] herbal medicines and nutraceuticals which exert anti-inflammatory and anti-oxidative actions and are relevant to the prevention and treatment of diabetic complications. These options could expand our armoury for the management of diabetes mellitus (DM). Mitsios et al. [3] review the antiplatelet and antithrombotic properties of statins. These drugs are thought to exert ‘pleiotropic’ actions including mild inhibition of haemostasis. This is a significant area of research since it may explain, at least in part, the benefits associated with the use of statins. Lioudaki et al. [4] focus on a specific group of individuals that may be at an increased risk of vascular events. Gender reassignment (male to female) includes estrogen-based hormonal therapy combined with antiandrogens. Such treatment has been associated with several adverse effects on predictors of cardiovascular disease (CVD). This population may help understand the effects of hormones on vascular risk in other situations (e.g. post-menopausal hormone replacement therapy, polycystic ovary syndrome and the ‘andropause’). Trpkovic et al. [5] consider the links between hepatitis C virus (HCV) infection, insulin resistance and CVD. These relationships are complex; for example, treatment with statins may influence HCV clearance. Hardman et al. [6] critically review the sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new class of drugs that may prove useful in the treatment of DM. These agents act by increasing the urinary loss of glucose. Prevention is better than cure. Athyros et al. [7] discuss measures (e.g. lifestyle and pharmacological options) to prevent DM. In this context, the prevalence of DM is increasing [7]. Tan et al. [8] review several mechanosensors and mechanotransduction signaling pathways by which stem cells differentiate into endothelial cells when exposed to fluid shear stress. This is relevant to the development of new stent devices that will produce better outcomes. Prevention and treatment of CVD is a broad field that cannot be covered by a single issue of a journal. Therefore, in this Editorial we will also briefly consider some areas of current interest. Regarding lipids, there are several topics that are the subject of debate. Among these is that statins cannot always achieve the low density lipoprotein cholesterol (LDL-C) targets set by current guidelines. Therefore, it has been proposed that statins can be combined with other lipid lowering drugs. Among these options, ezetimibe when added to a statin has been shown to allow a greater proportion of patients to reach LDL-C goals than with statin monotherapy; this is due to an additional decrease of approximately 23.6% in LDL-C levels [9]. However, there is still a need for evidence showing that this further fall in LDL-C is associated with event reduction. Colesevelam is a relatively new formulation of a resin [10]. Although compliance is less than that expected with a statin or ezetimibe, it is a worthwhile alternative for patients who are intolerant to statins [10]. Furthermore, colesevelam also exerts a favourable effect on glycaemia [11]. There may also be an option for “triple” therapy (i.e. statin, ezetimibe and colesevelam) [12]. A new formulation of modified release (MR) nicotinic acid with laropiprant (an inhibitor of nicotinic acid-induced flushing) has been marketed [13]. There is evidence that nicotinic acid significantly reduces the risk of CVD events [13]. This lipid lowering drug has the additional advantage of acting on high density lipoprotein cholesterol (HDL-C) and triglyceride levels as well as LDL-C [13]. However, compliance remains the main issue that will determine the success of this drug [13]. The evidence supporting the use of fibrates as monotherapy is controversial [14-16]. Nevertheless, it is of interest that new evidence suggests that fibrates act beneficially on microvascular complications in patients with DM [17]. Another topic of interest is whether primary prevention with statins is cost effective. A recent meta-analysis concluded that such an intervention will not significantly alter mortality [18]. In contrast, 2 earlier meta-analyses suggest that vascular events are significantly reduced by statins in the primary prevention setting [19-20]. It is also a matter of debate whether cost effectiveness should be focused on mortality rather than morbidity in primary prevention where the death rate is expected to be low. This issue may never be definitively resolved by meta-analyses; appropriately designed very large trials are needed. There are other lipid lowering drugs on the horizon. Mipomersen, an antisense oligonucleotide directed against apolipoprotein B-100, is being investigated for the treatment of patients with familial hypercholesterolaemia [21]. Although trials with the first cholesteryl ester transfer protein (CETP) inhibitor (torcetrapib) were disappointing [22-26], other drugs in this class are being evaluated (e.g. anacetrapib and dalcetrapib) [22]. These drugs have a marked HDL-C raising capacity together with some LDL-C lowering effect [22-26]. In the field of antiplatelet treatment, there are “new kids on the block”. These include prasugrel and ticagrelor [27-29]. The key issue will be if the additional cost of these options is justified when compared with older drugs (i.e. aspirin, dipyridamole and clopidogrel). Also, platelet inhibition will always remain a question of balance between the risk of bleeding and that of thrombosis. In this context, we need to establish how the new drugs can be combined with other agents. It has been argued whether very strict glycaemic control is ideal in terms of vascular event reduction [30]; this should be addressed in future trials. Apart from the SGLT2 inhibitors discussed in this issue [6], there are several “new” glucose lowering drugs (e.g. glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors) [31]. Their role in terms of CVD event prevention needs to be established. Regarding metabolic syndrome, a new consensus definition should replace the multiple definitions that were available [32]. This may help produce uniform results from trials and epidemiological surveys. In the field of obesity, 2 drugs (rimonabant and sibutramine) were withdrawn from several markets [33, 34]. Orlistat continues to be available but has its limitations [35]. There are other drug combinations that are being evaluated (e.g. naltrexone + bupropion) [36,37]. This issue of the journal also considers specific populations that may be at a high risk of vascular events [4,5,7]. Other such groups that deserve attention include those with rheumatoid arthritis [38], impaired renal function [39] and some ethnicities (e.g. South Asians) [40]. The value of emerging CVD risk factors (e.g. high sensitivity C-reactive protein, lipoprotein (a), fibrinogen and homocysteine) will remain the subject of discussion for some time [41-45]. This is an area where new studies may help identify high risk patients and develop new treatments. Future issues of Current Pharmaceutical Design will cover some of the topics listed above. We hope that you will enjoy reading the reviews in this issue.