The effect of anti-B-cell therapy on the development of atherosclerosis in patients with rheumatoid arthritis

Accelerated development of atherosclerosis (AT) in rheumatoid arthritis (RA) stems from common immune-inflammatory mechanisms underlying the diseases. While the key role of activation of the T-cell immune system component is considered to be proved, the role of B-lymphocytes has been investigated insufficiently. Earlier experimental models demonstrated the "atheroprotective" role of B-cells. At the same time, AT development is associated with activation of the B-cell immune system component and manifested by hyperproduction of antibodies to oxidized low density lipoproteins (oxLDL), heat shock proteins, etc. Wide applications of anti-B-cell therapy stimulate active research on effects of B-lymphocytes and their depletion on AT development in RA patients that have a high risk of cardiovascular events (CVE). Experimental models demonstrated that depletion of B2 cells instead of B1 cells under anti-CD20 treatment resulted in a slower development and progression of AT. Research on cardiovascular effects of chimeric antiCD20 monoclonal antibody (rituximab, RTX) in RA is definitely of high interest. Use of RTX in a combination with methotrexate does not increase the risk of serious side effects, including CVE, compared with the sole use of methotrexate. Currently, only few pilot research reports on favorable effects of RTX on the lipid profile and endothelial function in RA patients have been published. According to other authors, the frequency of CVE in RA patients receiving RTX therapy was somewhat higher than that in patients not treated with RTX. In rare cases such side effects as hypotension and arrhythmia were reported under RTX infusion. In addition, investigation of the combined use of statins and RTX is important, since some data are available on a reduced efficacy of RTX when administered with statins. Therefore, further research is required to clarify the role of the B-cell immune system component in AT development and the impact of anti-B cell therapy on the pathogenetic mechanisms of AT and CVE in RA patients.     

Adverse cardiovascular effects of antirheumatic drugs: implications for clinical practice and research

Clinical manifestations of most rheumatic diseases have changed over the past few decades, largely due to advances in therapies targeting autoimmune and (auto)inflammatory pathways. Improvements in the management of rheumatic diseases have also now brought to the fore the issue of comorbidities. It has become evident that the burden of cardiovascular morbidity and mortality is increased in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and the spondyloarthropathies, amongst other conditions. As a result, efforts have switched toward investigating the effects of conventional antirheumatic and new biologic agents on inflammationinduced atherothrombosis. Evidence is accumulating suggesting a beneficial cardiovascular profile of some antirheumatic drugs, such as methotrexate and hydroxychloroquine, but it also indicates the possibility of a variety of adverse events developing in the short- and long-term. The aim of this review is to highlight cardiovascular adverse effects of the drugs widely used in the treatment of rheumatic diseases. The literature search was performed through PubMed, the Cochrane Library, Scopus, and Web of Science databases using the following terms: "antirheumatic drugs", "inflammation", "rheumatic diseases", "cardiovascular diseases", "adverse events", "toxicity", "drug design", and "drug interactions". Adverse events ranging from infusion-related hypertension and myocardial ischemia, to restrictive cardiomyopathy and congestive heart failure have been reported in large trials and case series on most antirheumatic drugs. Clinicians should be alert of the wide variety of cardiovascular adverse effects of individual antirheumatic drugs, and should carefully monitor blood pressure and markers of inflammation, thrombosis, myocardial ischemia, electrolytes, and lipid disturbances while administering these drugs. Future prospective studies should specifically investigate the cardiovascular safety of most antirheumatic drugs as part of mono- or combination therapy in relation to different dosage regimens, duration of therapy, age, and gender.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

Introduction: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia.

Areas covered: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material.

Expert opinion: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Impact of traditional therapies and biologics on cardiovascular diseases in rheumatoid arthritis

In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.     

Update on Treatment of Rheumatoid Arthritis

Objective:To review current treatment of rheumatoid arthritis (RA), as well as recent advances.Data Sources:MEDLINE search from 1990 to 1998 for human studies using search terms “rheumatoid arthritis”; “cyclooxygenase inhibitors” combined with “anti-inflammatory agents, nonsteroidal”; “tumor necrosis factor” limited to “antagonists and inhibitors”; “isoxazoles.”Data Synthesis:RA is a chronic inflammatory disease characterized by symmetrical joint involvement, usually of the small joints of the hands and feet. Although the hallmark of the disease is inflammation of joints, other organ systems—including the eyes, blood vessels, lungs, and car-diopulmonary system—may also be involved. Treatment of RA requires both drug and non drug approaches. Current drug therapy consists of combinations of nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). Corticosteroids are also used either for short-term treatment during initiation of therapy, in bursts during acute disease flares, or chronically in low doses. A number of promising new agents are in development. NSAIDs with preferential inhibition of cyclooxygenase II may offer a better safety profile than existing agents. Leflunomide and biological agents such as etanercept may provide benefit for patients who fail to achieve adequate response from conventional therapy.Conclusion:Traditional approaches to treatment of RA include NSAIDs combined with DMARDs. New agents just reaching the market represent important advances and have the potential to make a positive impact on treatment of RA.     

An update on methotrexate pharmacogenetics in rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that mainly affects the joints. When left untreated, the disease can result in irreversible joint damage with high morbidity and mortality. Disease-modifying antirheumatic drugs are the cornerstones of treatment in RA. Disease-modifying antirheumatic drugs not only ameliorate the clinical signs and symptoms of disease, but also prevent the radiographic progression of joint damage. Methotrexate is one such disease-modifying antirheumatic drug that has been used in the treatment of RA for over two decades with excellent long-term efficacy and safety. However, there is significant variability in patients' response to methotrexate, both in terms of efficacy and toxicity. At the present time, there are no reliable means of predicting, a priori, an individual patient's response to methotrexate. In this review, recent published literature on the pharmacogenetics of methotrexate in RA is highlighted. Pharmacogenetics may be a powerful tool for optimizing methotrexate therapy in patients with RA.     

Advances in the treatment of rheumatoid arthritis: old versus new therapies

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.     

Advances in the treatment of rheumatoid arthritis: old versus new therapies

Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.     

Beyond LDL-C – The Importance of Raising HDL-C

Summary

Epidemiological studies have established that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with an increased risk of coronary heart disease (CHD). Recent studies have demonstrated that low HDL-C levels, and high triglycerides and total cholesterol levels are independent predictors of CHD, and that the combination of these lipid abnormalities increases the risk of coronary events. In lipid-modifying intervention studies, agents that raise HDL-C levels have been shown to reduce the incidence of major coronary events. The VA-HIT study consisted of patients with low-density lipoprotein cholesterol (LDL-C) levels similar to those recommended by several guidelines but with low levels of HDL-C. This trial demonstrated that raising HDL-C levels with gemfibrozil reduced the risk of CHD-related events. While the mechanisms by which HDL-C exerts its anti-atherogenic effects have yet to be fully elucidated, its role in the reverse transport of cholesterol and the beneficial effects on endothelial function are plausible explanations for these actions.

Although LDL-C reduction is the primary goal in the treatment of dyslipidaemia, current guidelines recognise low HDL-C levels as a major risk factor for CHD. Indeed, the NCEP ATP III guidelines suggest that the treatment of isolated low HDL-C levels in CHD patients or individuals with CHD risk equivalents should be considered. The differing abilities of statins to raise HDL-C levels may be an important factor when making treatment decisions. New lipid-modifying drugs with beneficial effects on both HDL-C and LDL-C levels would be desirable additions to the currently available therapeutic options.     

Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques

BackgroundMacrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages.Methods and resultsWe evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery.ConclusionThis dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.     

Emerging anti-inflammatory drugs for atherosclerosis

Introduction: Cardiovascular disease is the most common cause of morbidity and mortality worldwide. Inflammation is responsible for initiation and progression of atherosclerosis, and leads to plaque vulnerability. Evidence-based therapies reduce the risk of initial and recurrent cardiovascular events but many patients experience recurrent events due to the failure of conventional therapies to adequately address inflammation.

Areas covered: Statins were originally developed for their LDL cholesterol-lowering effects, but are now thought to improve cardiovascular morbidity and mortality through anti-inflammatory effects as well. Drugs that inhibit the various inflammatory pathways responsible for atherosclerosis are the subject of current research. These include antioxidants, phospholipase A₂ inhibitors, leukotriene pathway inhibitors, CCL2-CCR2 pathway inhibitors, non-specific anti-inflammatory drugs (i.e., methotrexate), IL-1 inhibitors and p-selectin inhibitors.

Expert opinion: Currently, only three anti-inflammatory drugs (methotrexate, darapladib and canakinumab) are being investigated in Phase III clinical trials of atherosclerosis. The development of cardiovascular drugs requires long, expensive Phase III trials to demonstrate incremental improvement in cardiovascular events. Imaging end points and soluble biomarkers accelerate Phase II development, but further validation is needed before these can be used as surrogate end points in the large trials leading to drug approval. Improved access to currently available therapies like statins would decrease the burden of cardiovascular disease worldwide.     

Emerging drugs for hyperlipidemia

Importance of the field: Elevated concentrations of low-density lipoprotein (LDL) cholesterol are associated with increased risk of coronary atherosclerosis, and morbidity and mortality from coronary heart disease (CHD). Lowering of LDL cholesterol leads to a reduction in cardiovascular morbidity and all-cause mortality in individuals at risk for cardiovascular events and patients with established CHD. The mainstays of lipid lowering therapy today are the HMG-CoA reductase inhibitors (statins); however, the residual risk of cardiovascular events amongst individuals treated with statins remains a major healthcare concern.

Areas covered in this review: Emerging targets for lipid lowering therapy target pathways that regulate lipoprotein assembly, lipoprotein clearance and pro-atherogenic lipoprotein modification. These emerging drugs have novel mechanisms that include inhibition of lipoprotein assembly (antisense mRNA inhibitors of apolipoprotein B and microsomal transfer protein inhibitors), enhanced lipoprotein clearance (proprotein convertase subtilisin kexin type 9, thyroid hormone analogues), inhibition of pro-atherogenic lipoprotein remodeling (cholesterol ester transfer protein inhibitors (dalcetrapib, anacetrapib) and peroxisome proliferator activator agents (GFT-505, aleglitazar)) and inhibition of lipoprotein modification (heme oxygenase-1 inhibitor (succinobucol), phospholipase A₂ inhibitors (varespladib, darapladib)).

What the reader will gain: A review of the most recent data on emerging drugs in the treatment of hyperlipidemia.

Take home message: With these medications, we will achieve more effective reductions in cardiovascular morbidity and mortality than achieved with current lipid lowering therapies.     

Cardiovascular disease and dyslipidemia: beyond LDL

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 rather 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.     

调节高密度脂蛋白药物的研究进展

动脉粥样硬化性心血管疾病是引起患者死亡的一个主要原因。高密度脂蛋白(HDL)不仅具有抗动脉粥样硬化的作用,同时高密度脂蛋白胆固醇(HDL-C)水平与患心血管疾病的危险性呈负相关。因此,HDL成为抗动脉粥样硬化和冠心病药物的作用靶点。目前,临床上常用的调节血脂药物并非特异性地作用于HDL-C,对调节HDL作用较弱。研究和开发新的调节HDL的药物可从不同途径升高HDL-C水平或者改善HDL-C的功能,对预防和治疗心血管疾病具有重要意义。本文对调节或改善HDL的药物进行了综述。     

Anti-TNF agents for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory, autoimmune disease with a prevalence of approximately 1% and an annual incidence of 0.04%. Up to 50% of patients with RA are unable to work 10 years after diagnosis. The disease is associated with significant morbidity and mortality with associated medical costs to the UK of between £240 m and £600 m per year.Non steroidal anti-inflammatory drugs (NSAIDs) have little effect on the underlying course of RA, but they have some anti-inflammatory and analgesic properties. Disease modifying antirheumatic drugs (DMARDs) have been shown to slow progression of RA and are currently recommended early in the course of treatment of RA which is when disease progression is most rapid.Etanercept and infliximab belong to a new group of parentally administered antitumour necrosis factor (TNF) drugs.Etanercept is licensed in the UK for the treatment of active rheumatoid arthritis in patients who have not responded to other DMARDs and in children with polyarticular-course juvenile arthritis who have not responded to or are intolerant of methotrexate. In adults it produces significant improvements in all measures of rheumatic disease activity compared to placebo. In patients whose disease remains active despite methotrexate treatment, further improvement in control is obtained with the addition of etanercept without an increase in toxicity. In one small trial, etanercept was found to be more effective than placebo in a selected group of children.Infliximab is a monoclonal antibody which is currently licensed in the UK for Crohn''s disease and, in combination with methotrexate for the treatment of rheumatoid arthritis in patients with active disease when the response to disease-modifying drugs, including methotrexate, has been inadequate. In clinical trials infliximab produced significant improvements in all measures of rheumatic disease activity compared with placebo. Infliximab in combination with methotrexate was shown to be superior to methotrexate or infliximab alone.There are currently no predictors of a good response to anti-TNF drugs and a percentage of patients fail to respond to treatment (25% to 38% of etanercept patients; 21% to 42% of infliximab patients). Infliximab monotherapy induces the production of anti-infliximab antibodies, which may reduce its effectiveness. Adding methotrexate to infliximab therapy may prevent this response.Anti-TNF drugs may affect host defences against infection and malignancy; whether these agents affect the development and course of malignancies and chronic infections is unknown and safety and efficacy in patients with immunosuppression or chronic infections has not been investigated. With infliximab, upper respiratory tract infections, general infections and those requiring antimicrobial treatment were more common in patients than placebo. Likewise, upper respiratory tract infections were more common in patients treated with etanercept than with placebo. Injection site reactions occur with both infliximab (16%–20%) and etanercept (37%).There are approximately 600 000 patients with RA in the UK, and of these between 2% and 3.5% may have severe disease which has failed to respond to conventional treatment and who might be eligible for anti-TNF therapy. If between 50% and 70% of patients treated with anti-TNF drugs respond and continue on long-term treatment then the recurrent annual cost to the NHS could be between £48 m and £129 m.     

The potential for CETP inhibition to reduce cardiovascular disease risk

ABSTRACT

Background: Although reductions in cardiovascular risk can be achieved by lowering low-density lipoprotein cholesterol, treated patients remain at substantial risk. Epidemiological studies have established that higher levels of high-density lipoprotein cholesterol (HDL-C) are strongly associated with reduced cardiovascular risk, and therefore raising levels of HDL-C may be beneficial. The activity of cholesteryl ester transfer protein (CETP) appears to be inversely correlated with HDL-C levels and thus CETP is an attractive target for intervention to raise levels of HDL-C and potentially reduce residual cardiovascular risk.

Objectives: This paper reviews the evidence for an atheroprotective role of higher levels of HDL‐C, the function of CETP in cholesterol metabolism, and the concept of CETP inhibition as a potential new strategy for decreasing cardiovascular risk. An analysis of clinical studies of CETP inhibition was also performed.

Methods: MEDLINE (1966 to June 2006), EMBASE (1974 to June 2006), and cardiology conference proceedings were searched for clinical trials of CETP inhibition.

Results: Thirteen reports involving vaccine-based and pharmacological inhibition of CETP were found. Modest and inconsistent elevation of HDL‐C was observed with vaccine-based therapy, whereas HDL-C elevation with pharmacological inhibitors was greater and more consistent.

Conclusions: Elevation of HDL‐C via CETP inhibition appears to be a potentially promising approach to reduce cardiovascular disease. Preliminary studies suggest benefits of CETP inhibition on serum lipid levels, and ongoing studies should establish the effects on atherosclerosis and cardiovascular events.     

Inhibitory effects of amlodipine and fluvastatin on the deposition of advanced glycation end products in aortic wall of cholesterol and fructose-fed rabbits

Recent studies suggest that advanced glycation end products (AGEs) can promote the development of atherosclerotic lesions in a similar manner to oxidatively modified low density lipoproteins. As oxidative stress accelerates the formation of AGEs, antioxidant drugs may exert atheroprotective effects via suppression of AGE formation. Although amlodipine, a calcium channel blocker, and fluvastatin, a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, show antioxidant and atheroprotective effects, the relation of AGEs to their effects is unknown. We immunohistochemically investigated the inhibitory effects of chronic treatment with amlodipine (5 mg/kg per day) or fluvastatin at a dose insufficient to reduce plasma cholesterol levels (2 mg/kg per day) on the accumulation of AGEs in atherosclerotic aortas of rabbits fed 1% cholesterol diet and 10% fructose containing water. After eight weeks of treatment, AGEs, namely argpyrimidine, carboxymethyllysine and pyrraline, markedly accumulated with intimal thickening in cholesterol and fructose-fed control rabbits, while the drugs inhibited those changes other than the pyrraline deposition without plasma lipid-lowering effects. Enhanced lipid peroxidation was observed in plasma from cholesterol and fructose-fed rabbits only, and lipid peroxidation was not suppressed by the drugs. These results suggest that the atheroprotective effects of the drugs are at least partly due to the suppression of AGE accumulation although the exact mechanism of AGE suppression is ambiguous.     

Cilostazol and atherogenic dyslipidemia: a clinically relevant effect?

INTRODUCTION: Cilostazol is a reversible, selective inhibitor of PDE3A able to significantly improve walking distance in patients with intermittent claudication. However, beyond its antiplatelet and vasodilator properties, cilostazol seems to have significant effects on atherogenic dyslipidemia. AREAS COVERED: The effects of cilostazol on plasma lipids, lipoproteins, apolipoproteins and postprandial lipemia are reviewed. A literature search (using Medline and Scopus) was performed up to 24 October 2010. The authors also manually reviewed the references of selected articles for any pertinent material. EXPERT OPINION: Cilostazol is able to significantly lower plasma triglyceride levels, with a concomitant increase in high-density lipoprotein (HDL) cholesterol concentrations. Additional effects on pro-atherogenic lipoproteins and apolipoproteins include those on remnant-like particles, HDL subclasses, apolipoprotein B and postprandial lipemia. Cilostazol can improve the pro-atherogenic lipid profile in patients with peripheral arterial disease or type 2 diabetes. Further studies are needed to establish whether cilostazol treatment exerts clinically relevant effects on atherogenic dyslipidemia in high-risk patients.     

Combination lipid therapy in type 2 diabetes mellitus

Introduction: A significant drop in cardiovascular risk has been seen in patients with type 2 diabetes treated with statins. However, this cardiovascular risk remains high, compared with nondiabetic individuals. This is partly due to the typical abnormalities of diabetic dyslipidemia – hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) – that are uncontrolled by statins. For this reason, combination lipid therapy may be considered in patients with type 2 diabetes.

Areas covered: This review presents the main reasons for a combination lipid therapy in type 2 diabetes and the effects of several drugs, including fibrates, pioglitazone, niacin and omega 3, on diabetic dyslipidemia and the prevention of cardiovascular events. The real cardiovascular benefit of fibrates in patients with type 2 diabetes is not totally clear, but they may produce a significant benefit in patients with type 2 diabetes and diabetic dyslipidemia (hypertriglyceridemia, low HDL-C). Pioglitazone, which reduces triglycerides and increases HDL-C, has been shown to reduce the risk for major cardiovascular events in type 2 diabetes. Niacin and omega 3 fatty acids have a positive effect on diabetic dyslipidemia, but warrants clinical trials to demonstrate a clear cardiovascular benefit in type 2 diabetes.

Expert opinion: Although combination lipid therapy seems to be useful to control diabetic dyslipidemia, the efficacy of such combined therapies on significantly reducing cardiovascular risk has still to be confirmed by additional clinical trials.     

Effects of the selective COX-2 inhibitors celecoxib and rofecoxib on human vascular cells

Rheumatoid arthritis (RA) is associated with a reduced life expectancy considered to be partly caused by cardiovascular events. A growing concern is that accelerated atherosclerosis is driven by inflammatory mechanisms similar to those responsible for RA. Therefore, selective COX-2 inhibitors, which are widely used for the symptomatic treatment of pain and inflammation in RA, may have an impact on atherosclerotic processes. Their anti-inflammatory properties might provoke anti-atherogenic effects but on the other hand, selective inhibition of anti-thrombotic prostacyclin and COX-2 independent effects might promote the risk of increased prothrombotic activity. In the current study, the effects of the presently marketed selective COX-2 inhibitors celecoxib and rofecoxib on vascular cells have been investigated. Celecoxib inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. At high concentrations, it induced apoptosis and the modulation of inhibitory cell cycle proteins. In contrast rofecoxib-even at high concentrations-had no effect on cell proliferation, apoptosis or cell cycle distribution indicating that celecoxib and rofecoxib do not affect the same signal transduction pathways in endothelial cells. Both drugs did not affect apoptosis induction or cell cycle proliferation in human vascular smooth muscle cells. The observed effects on endothelial cells appear to be COX-independent since both drugs selectively inhibited COX-2-activity and the applied concentrations lay beyond the IC(50) for inhibition of prostacyclin production. Regarding endothelial apoptosis as a relevant event in the initiation and progression of atherosclerosis the present data put forward the hypothesis that the presently marketed COX-2 inhibitors have a different impact on atherosclerotic processes.