Current Pharmaceutical Design - Volume 16, Issue 34, 2010

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.

The contribution of diet to the development of several chronic diseases, such as vascular disease, diabetes or lipid abnormalities has been established. Therefore, clinical trials dealing with these diseases need to adjust for individual dietary habits in order to account for potential confounding. Common practice in the majority of studies that collect dietary information is to record individual habits using specific questionnaires (e.g. Food Frequency questionnaires, FFQ). Nevertheless, a major challenge in nutrition assessment is the correct measurement of dietary exposure. This can be expressed as the reliability and validity of the retrieved information. These issues refer to how close the food records and the energy intake estimated by a tool represent actual food intake. To establish accuracy of a tool is of major importance in order to avoid inconsistent estimates of dietary intake that can distort any potential relation between diet, pharmacological treatment and disease. The aim of this review is to critically present commonly used statistical methods in reliability and validity studies.

Diabetes is one of the most prevalent chronic diseases throughout the world. The majority of its complications arise from vascular- related inflammation apparently initiated by endothelial cell injury. One cause of this injury has been attributed to hyperglycaemia induced reactive oxygen species. Consequently, current drug developmental strategy has targeted specific inflammatory and oxidative stress pathways for the prevention of diabetic vascular complications. Herbal medicines have traditionally been used for the treatment of diabetes and its complications. In fact, current pre-clinical and clinical studies have demonstrated that many of them exhibit potent anti- inflammatory and anti-oxidative properties, and have also identified the active phytochemicals responsible for their activities. The present review summarises the latest research on the molecular mechanisms of diabetic vascular complications, and evaluates the level of scientific evidence for common herbal medicines and their bioactive phytochemicals. These agents have been shown to be effective through various mechanisms, particularly the NF-κB signalling pathways. Overall, herbal medicines and nutraceuticals, as well as their bioactive components, which exhibit anti-inflammatory and anti-oxidative properties, provide a promising approach for the prevention and treatment of diabetic complications.

Several studies over the last years have demonstrated that statins exhibit actions beyond that of lipid-lowering (pleiotropic effects) ranging from improving endothelial function, modulating the inflammatory response, maintaining plaque stability and preventing thrombus formation. Since the interplay among platelets, cells and other components of atherosclerotic lesions as well as the coagulation system play an important role in the progression of atherosclerosis and in the development of acute coronary syndromes, these non-lipid properties of statins may help to explain the early and significant reduction of cardiovascular events reported in several clinical trials of statin therapy. This review focuses on the experimental and clinical results regarding the antiplatelet/antithrombotic effects of statins.

Transsexualism refers to individuals that identify themselves as members of the opposite gender and who strive to acquire the physical appearance and psychosocial role compatible with that gender. Gender reassignment therapy is applied through hormonal treatment ± surgical intervention in addition to psychological support. Hormone treatment for male-to-female transsexuals includes estrogen supplementation ± suppression of androgen secretion or action. Sex hormones are important determinants of the metabolic profile. The impact on cardiovascular disease appears to be gender-related but overall evidence remains conflicting. Gender reassignment therapy has been associated with elevated triglyceride concentrations, often accompanied by an increase in high density lipoprotein levels, reduced circulating homocysteine (Hcy), uric acid and creatinine levels as well as an adverse effect on glycemic control. Markers of inflammation, oxidative stress and endothelial function are also affected in various ways, while alterations in hemostatic and fibrinolytic factors favor thrombosis (arterial and/or venous). Male-to-female transsexuals may be adversely affected by both estrogen administration and androgen deprivation, as reported in prostate cancer. Therefore, vascular risk factor screening and potential intervention may be required prior to and during gender reassignment therapy (both hormone and surgical).

The role of hepatitis C virus (HCV) infection in the development of vascular disease is controversial. Insulin resistance (IR) is a recognized risk factor for cardiovascular disease (CVD) and is associated with chronic hepatitis C (CHC). Thus, IR may promote atherosclerosis and vascular disease in CHC patients. HCV-associated IR may also cause hepatic steatosis and resistance to antiviral treatment. In addition, HCV may contribute a direct, proatherogenetic action on the vascular wall. This review considers the impact of IR on interferon-α based therapy of HCV infection and the role of insulin-sensitizing agents on the response to antiviral treatment and prevention of IR complications, including CVD.

The sodium-glucose co-transporter 2 (SGLT2), located in the plasma membrane of cells lining the proximal tubule, facilitates the reabsorption of glucose in the kidney. Inhibition of SGLT2 has the potential to reduce blood glucose and represents an opportune target for managing blood glucose. By promoting the excretion of glucose, SGLT2 inhibitors are the first anti-diabetic treatment to target the removal rather than the metabolic redirection of glucose. Their mechanism of action is independent of that of endogenous insulin status and thus provides a means of managing plasma glucose irrespective of a patient's glycaemic status or treatments being used in combination. Several candidate SGLT2 inhibitors based on the core glucoside structure of phlorizin are currently being developed, of which, the metabolically more stable aromatic and heteroaromatic C-glucosides have demonstrated the most promising preclinical and clinical data. The inhibition of SGLT2 by messenger antisense technology is also being investigated. Current indications suggest that short-term benefits, in terms of HbA1c reductions, are modest and it remains to be seen whether encouraging exogenous glucose disposal will result in long term patient benefits in terms of returning metabolic balance or even weight loss. Indications are that clinical efficacy will be greater with molecules based on an O-glucoside structure. Concerns have been raised over the safety of these agents, particularly a possible predisposition to urinary tract infections, but these concerns have yet to be confirmed in clinical studies. Clinical development programs will need to establish those patients most likely to benefit from inhibition of SGLT2.

It is well known that type 2 diabetes mellitus (T2DM) is a major risk factor for cardiovascular diseases (CVD). A predicted worldwide increase in the incidence of T2DM, taking the form of an epidemic, is expected to induce a substantial increase in CVD incidence. Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are related to an increased risk of developing T2DM, especially in obese people. Prevention of T2DM aiming to reversal of pre-diabetes to normal glucose tolerance seems to be a very attractive target, and favourably affects CVD risk factors. The Diabetes Prevention Program and the Finnish Diabetes Prevention studies showed that changes in lifestyle prevented or delayed the onset of new cases of T2DM in subjects with pre-diabetes by 58%. However, a fraction of participants still developed T2DM, suggesting a residual risk. Moreover, lifestyle changes are not usually followed on a long-term basis as shown in EUROASPIRE with an increase in new onset T2DM by 60% in subjects with CVD in just over a decade. T2DM is characterized by insulin resistance and/or β-cell dysfunction (impaired insulin secretion). Various interventions targeting those two mechanisms (e.g. metformin, thiazolidinediones, acarbose, orlistat, bariatric surgery, renin-angiotensin-aldosterone system inhibitors, fibrates, incretin mimetics or enhancers) can prevent or delay T2DM. Widespread application of these measures has, however, been limited by financial considerations, even though cost-effectiveness might be achieved at the population level. This review will investigate feasibility and usefulness of T2DM prevention, further to that achieved with lifestyle changes, in a cost-effective manner.

Stem cell therapy heralds a new chapter in cardiovascular regenerative medicine. Cardiovascular implants are often used in both surgery and interventional cardiology. Cardiovascular stents are utilized in percutaneous coronary interventions (PCI), and are classified as either bare metal stents (BMS) or drug-eluting stents (DES). Although DES might decrease the risk of vascular restenosis, there are complications (e.g. thrombosis) associated with it as well. Many new and novel composite materials are increasingly being developed along the premise of mobilizing and attracting endogenous stem cells to home-in and differentiate into a confluent layer of endothelial cell around the vessel wall. One of the main forces acting on cells in a blood vessel wall is fluid shear stress. Fluid shear stress is vital in establishing the vasculature of the embryo, and different shear stress patterns have been both implicated in maintaining vascular physiology, and also associated with certain pathological conditions. Recent evidence suggests that via a plethora of mechanosensors and mechanotransduction signaling pathways, stem cells differentiate into endothelial cells when exposed to fluid shear stress. Here we review the current knowledge pertaining to the roles that mechanosensors and mechanotransducers play in stem cell differentiation into endothelial cells via fluid shear stress, and its implications for pharmacological applications and cardiovascular implants in the realm of regenerative medicine.