Current Pharmaceutical Design - Volume 17, Issue 9, 2011

Atherosclerotic vascular disease is the most prevalent medical condition in Western societies and is associated with significant morbidity and mortality. One of the most important factors for atherogenesis is the low-density lipoprotein (LDL)-cholesterol. The review articles included in this issue, authored by international experts in the field, are aiming to summarize in a multidisciplinary manner the current knowledge on the subject of dyslipidemia and cardiovascular disease and to discuss future and alternative therapeutic options for the management of dyslipidemia. In the first article [1], the author offers a review of the existing evidence on lipid-lowering therapy with statins in primary and secondary prevention of cardiovascular disease. Poss et al. [2] discuss the other key lipoprotein in cardiovascular disease pathophysiology, namely high density lipoprotein (HDL)-cholesterol. The authors discuss the epidemiological evidence supporting the role of low HDL-cholesterol as a cardiovascular risk factor, offer pathophysiological mechanisms through which HDL may exert its anti-atherosclerotic effects and review currently available strategies as well as therapeutic options under development for increasing HDL-cholesterol concentrations. They furthermore discuss the role that triglycerides may play in the pathogenesis of atherosclerosis reviewing the epidemiological evidence supporting such an association, and the therapeutic modalities available for the treatment of hypertriglyceridemia. The review by Parhofer [3] addresses the treatment options available for decreasing the blood concentrations of another pro-atherogenic lipoprotein, namely lipoprotein (a). The effects of currently available therapeutic options (albeit of limited potency) such as aspirin, thyroid and sex hormones, L-carnitine, statins and niacin are being evaluated and emerging therapeutic options such as CETP-inhibitors are being reviewed. The role of lipoprotein (a) apheresis is critically discussed. Berthold [4] tackles the complex problem of lipid-lowering drug therapy in a rapidly rising part of the population, namely the elderly. In a comprehensive review he addresses questions such as for which of the lipid-lowering drugs there is evidence of benefit for the elderly, how should the risk assessment be performed in this population, what do the American and European guidelines recommend, what is the evidence for primary and for secondary cardiovascular disease prevention, what do meta-analytic evaluations show, what evidence is there for statin use and cerebrovascular endpoints and the role (if any) of other (non-statin) lipid-lowering drugs. Furthermore, the author discusses the very relevant issue of safety of lipid-lowering therapy in the elderly, as well as the question whether statins may affect cognitive function and their role (if any) in preventing and/or treating dementia. Burst [5] reviews the subject of dyslipidemia and cardiovascular disease in the patient with chronic kidney disease (CKD). Issues discussed are the epidemiology of cardiovascular disease in the patient with CKD, the lipid disorders associated with renal disease and the available evidence regarding the use of lipid-lowering treatment in this population. Moreover, the dyslipidemia of the nephrotic syndrome and the dyslipidemia that develops after liver transplantation are addressed as well as the respective guidelines. Economou et al. [6] discuss the dyslipidemia observed in women with the polycystic ovary syndrome (PCOS). In specific, the authors address the pathophysiologic mechanisms of dyslipidemia in PCOS, the pattern of dyslipidemia, the issue of the potentially increased risk of cardiovascular disease in this population and the pluripotential effects of lipid-lowering treatment. Moreover, they address the effects of the various drugs used in women with PCOS, such as metformin, thiazolidinediones and antiandrogens, on the lipid profile. The review of Baumgartner et al. [7] examines the role of plant sterols and stanols in the treatment of dyslipidemia as well as their effects beyond LDL-cholesterol lowering such as effects on triacylglycerol concentrations and endothelial function. The controversial issue of the potential atherogenicity of plant sterols is comprehensively discussed. A known authority in the area of vitamin D research Armin Zittermann [8] reviews the role of vitamin D in dyslipidemia and cardiovascular disease. Experimental studies on the role of vitamin D and atherosclerosis as well as epidemiological studies on the association between vitamin D and blood lipids, the role of vitamin D supplementation on blood lipids, and the effects of statins on vitamin D metabolite concentrations are addressed. Moreover, the trials examining the association between vitamin D, vascular calcification and cardiovascular disease are critically discussed. Rizzo [9] reviews the role of a new class of lipid-modulating drugs, namely the microsomal transport protein inhibitors. Pre-clinical and clinical data available on these agents are being presented and their adverse events addressed. Subject of the last review [10] of this issue is the potential role of antisense oligonucleotides (ASO) in the treatment of dyslipidemia. The development of ASO is being discussed, from first to third generation, with emphasis put on the efficacy and safety data of the first ASO to soon become commercially available, namely mipomersen, an ASO against apolipoprotein B-100. The role of proprotein convertase subtilisin-like/kexin type 9 (PCSK9), diacylglycerol acyltransferase (DGAT), the peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1), the adipose differentiation-related protein (ADRP) and the steatoryl-CoA desaturase 1 (SCD1) as potential targets of antisense technology for the treatment of dyslipidemia is also discussed. I would like to thank the contributors to this special issue for their participation and hope that this issue will provide some insights for all scientists working on the challenging field of cardiovascular disease....

Lowering low density lipoprotein (LDL) - cholesterol is one of the key issues in modern preventive cardiology by which we are able to interact with the natural course of atherosclerosis. Diet and healthy life style are mandatory for the treatment of CAD high risk patients. Numerous lipid lowering trials confirmed the beneficial effect of statins in primary as well as secondary prevention. By this statins are the basic treatment in patients with coronary artery disease (CAD) or diabetes mellitus or both. In order to reach LDL - cholesterol target levels (LDL - cholesterol < 100 mg/dl) in patients with CAD the use of potent statins or a lipid lowering combination therapy might be necessary. In our days we are able to lower LDL-cholesterol by more than 50% with drug treatment, which should enable us to reach the optimal LDL-cholesterol level in most patients.

Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to “off-target” effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.

Elevated levels of lipoprotein(a) are causally related to premature atherosclerosis. It is therefore of interested to evaluate by which treatment modalities elevated lipoprotein(a) levels can be decreased. With the exception of niacin, currently available lipidmodifying drugs have only little effect on lipoprotein(a) levels. Niacin can decrease lipoprotein(a) concentration in a dose dependent fashion by approximately 20-30%. Similarly, acetylsalicylic acid and L-carnitine as well as some medications in development (mipomersen, eprotirome, Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, Cholesterol-ester-transfer protein (CETPinhibitors) can decrease elevated lipoprotein(a) concentrations. It is unclear whether this lipoprotein(a) reduction also translates into a decreased cardio-vascular morbidity or mortality. Estrogen (with or without progesterone) and tibolone but not tamoxifene or raloxifene can also decrease elevated lipoprotein(a) concentrations. The most dramatic change in lipoprotein(a) concentration can be achieved with regular lipid apheresis.

Coronary heart disease (CHD) is the leading cause of death among elderly patients and >80% of all coronary deaths occur in patients >65 years. Cerebrovascular events are also associated with older age. Since elevated cholesterol concentrations are a risk factor for cardiovascular disease, lipid-lowering drugs, especially statins, are in widespread use for prevention. There is substantial underutilization of statins in the elderly population although meta-analyses of randomized trials have shown that in elderly secondary prevention patients they reduce all-cause mortality by approximately 22%, CHD mortality by 30%, non-fatal myocardial infarction (MI) by 26% and stroke by 25% over a treatment period of 5 years. Relative risk reduction is greater or at least equal to the one in younger patients, but absolute risk reduction is greater in the elderly because the event rate is higher. The benefit from statin treatment seems to start beyond 1 year of treatment. Data on primary prevention in the elderly are less clear. There is a significant reduction in CHD events, CHD deaths and all-cause mortality but numbers needed to treat (NNT) are higher than in secondary prevention. Treatment decisions have to consider the individual patient's situation regarding multimorbidity, polypharmacy and patient wishes. Economic considerations have to be made in some health systems. Statins have no role in the prevention or the treatment of dementia. Statins are generally safe and safety is equal in younger and older age groups. Their prescription should not be denied to patients for reasons of age alone. Other lipid-lowering drugs play only a minor role in cardiovascular disease (CVD) event prevention because convincing outcome studies are largely missing. A primary prevention statin trial in the very elderly is urgently needed.

Cardiovascular disease is the most prevalent cause of death in patients with chronic kidney disease (CKD), even at an early stage of the disease and is considered a coronary heart disease risk equivalent. Therefore, therapeutic efforts to control modifiable additional cardiovascular risk factors such as dyslipidemia in this population seems reasonable. Indeed, abnormalities of lipid metabolism are often encountered in patients with CKD, end stage renal disease or after kidney transplantation. In this review we will summarize the currently available data on etiology, epidemiology, and impact on cardiovascular morbidity in patients with CKD, renal pathologies like the nephrotic syndrome and after kidney transplantation and give a brief overview of the existing guidelines on treating dyslipidemia.

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterized by oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenemia and polycystic ovaries. Clinical expression is determined by both genetic and environmental factors. Dyslipidemia is very common in lean as well as in obese women with PCOS and should be considered in the therapeutic management of the syndrome. Additionally to dyslipidemia, other risk factors for cardiovascular disease strongly associated with PCOS include insulin resistance, impaired glucose tolerance and metabolic syndrome. Therefore, the ideal therapeutic approach for PCOS would be multi targeted treatment ameliorating not only ovarian dysfunction but also cardiometabolic aspects, including dyslipidemia. Recently, a new era of hypolipidemic agents like statins has been initiated with regard to PCOS. The spectrum of statins' targets has been expanded and in vitro and in vivo studies have explored the specific effect of statins on androgen production, insulin resistance and inflammatory markers in PCOS. Statins are potentially promising therapeutic agents targeting hormonal and metabolic disturbances in PCOS, though conclusive results are still pending. Since several hormonal and metabolic aberrations characterizing this multifaceted syndrome cluster and interact with each other, their effects on the lipid profile are interweaving and the therapeutic modalities targeting dyslipidemia appear to have a more broad beneficial effect.

Plant sterols and stanols are naturally occurring constituents of plants and as such normal components of our daily diet. The consumption of foods enriched in plant sterols and stanols may help to reduce low-density lipoprotein cholesterol (LDL-C) concentrations. Meta-analyses have shown that consuming approximately 2.5 g plant sterols or stanols per day lowers serum LDL-C concentrations up to 10%, with little additional benefit achieved at higher intakes. However, recent studies evaluating plant stanol intakes up to 9 g/d have indicated that LDL-C concentrations can be reduced up to 17%, which suggests that more pronounced reductions can be achieved at higher intakes. Studies describing effects of high plant sterol intakes on serum LDL-C concentrations are not consistent. Besides the effects of higher than advocated intakes on serum LDL-C concentrations, several topics will be discussed in this review. First, besides the well-characterized effect of plant sterols and stanols on serum LDL-C concentrations, evidence is now emerging of their effects on triacylglycerol metabolism, which makes them highly attractive for interventions in metabolic syndrome-like populations. Secondly, there is an ongoing debate whether increased plant sterol concentrations are associated with an increased cardiovascular disease risk or not. For this there are at least two possible explanations. First, the potential atherogenicity of increased plant sterol concentrations might be ascribed to the formation of plant sterol oxidation products (so-called oxyphytosterols) or secondly, elevated serum plant sterol concentrations should only be seen as surrogate markers for characterizing subjects with high intestinal cholesterol absorption. Finally, we discuss recent studies, which suggest that plant sterols and stanols can improve endothelial dysfunction in subjects at risk, although evidence is limited and more research is needed.

Dyslipidemia and vascular calcification are important predictors of cardiovascular disease (CVD). Vitamin D may have an influence on these two CVD risk markers. We performed a systematic review on vitamin D, dyslipidemia, statins, vascular calcification and CVD. The vast majority of intervention studies did not show an effect of vitamin D on serum cholesterol levels. There is however evidence for a triglyceride-lowering effect of vitamin D which primarily comes from studies with chronic kidney disease patients, a group with elevated triglyceride levels. The previously presumed influence of statins on circulating 25-hydroxyvitamin D levels and on cellular vitamin D actions remains obscure. Experimental studies on vascular calcification and CVD suggest a biphasic effect of vitamin D with harmful effects at both low and high vitamin D levels. Epidemiological studies on vitamin D and vascular calcification are inconsistent at present, but are probably biased by confounding. Prospective cohort studies consistently indicate an enhanced multivariableadjusted CVD mortality risk when circulating 25-hydroxyvitamin D levels are below 25 nmol/l. Adequately designed randomised controlled trials investigating the dose-response effect of vitamin D on different CVD outcome parameters are now warranted.

Microsomal triglyceride transfer protein (MTP) is involved in the synthesis of very low density lipoprotein in the liver. Its deficiency results in abetalipoproteinemia. MTP inhibitors target the assembly and secretion of apolipoprotein B-containing lipoproteins. These agents may potentially play a role, alone or in combination, in the treatment of hypercholesterolemia or hypertriglyceridemia. Clinical applications of MTP inhibitors initially focused primarily on high-dose monotherapy in order to produce substantial reductions in LDL-cholesterol levels but these proved to induce significant hepatic steatosis and transaminase elevations. However, likely orphan indications for MTP inhibitors, where a different risk-benefit profile applies, which includes patients with homozygous familial hypercholesterolemia where statins often show a low response. Development of MTP inhibitors has continued to enter clinical trials at lower doses or in formulations aimed at utilizing their efficacy while avoiding their side effects. These have shown promising results in reducing cholesterol, triglycerides and apolipoprotein B with a far lower incidence of, often, transient side-effects. The clinical efficacy and safety of MTP inhibition in patients with hyperlipidemia remains to be fully determined and to be proven in both surrogate and clinical endpoint trials but there may be a role for these agents in orphan indications for rarer sever hyperlipidemias.

New studies further demonstrate that lowering low-density lipoprotein (LDL)-cholesterol, at least with the use of statins, decreases the risk of cardiovascular disease (CVD). Subsequently national and international guidelines have set target levels for LDLcholesterol that are progressively lower, making the likelihood of patients attaining them progressively more limited, even with the use of all currently available medications. Thus, there is a clear need for new therapeutic approaches to lower LDL-cholesterol. Antisense oligonucleotides (ASO) represent a new paradigm for the discovery of potentially powerful and selective drugs with a mechanism of action based on the concept of base-pair hybridization as described by Watson and Crick, resulting in decreased production of target proteins. In mouse and human genetic models it has been shown that decreasing hepatic apolipoprotein B-100 (ApoB-100) as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) production is associated with lower circulating LDL-cholesterol levels. Purpose of this review is to discuss the available data on the effects of various ASO used for the treatment of dyslipidemia, with the main focus on ASO against ApoB-100, the most advanced in clinical development, and on PCSK9.