Can a polypill one single tablet combat different cardiovascular risk factors?

Polypharmacy is defined as the use of two or more drugs simultaneously. Cardiovascular drugs and antihypertensives are commonly prescribed for treatment of cardiovascular disease (CVD), especially in elderly patients. Recent studies in patients with a history of CVD demonstrated that the fixed-dose combination of cardiovascular drugs in a polypill retain their individual efficacy, safety, and tolerability, thus have the potential to improve medication adherence and multiple risk factor control, thereby improving patient outcomes in secondary cardiovascular prevention. Since the initial conception of the fixed-dose polypill, just over a decade ago, only six large randomized trials assessing the efficacy and safety of this innovative concept have been completed (one is still ongoing). The results demonstrate that the polypill therapy significantly improved adherence, lowered systolic blood pressure, and low-density lipoprotein cholesterol, compared with usual care, in patients at high risk for CVD, especially among those who were undertreated at baseline. Correspondingly, further studies showed that the strengths of the polypill include better adherence, equivalent or better risk factor control, and improved quality of life among polypill users, as compared with usual care. However, the long-term outcome of the polypill on CVD events and mortality are unavailable and are currently being studied in clinical trials.     

Utility of Biomarkers and Imaging in the Development of Drugs for the Treatment of Coronary Atherosclerosis

Biomarkers and imaging trials have often been used as guideposts in the development of drugs for atherosclerosis. This article explores the role of biomarkers and imaging trials in the development of 4 drugs: rimonabant, torcetrapib, ezetimibe, and niacin. Rimonabant, a selective cannabinoid-1 receptor, causes weight loss and exerts favourable effects on lipid biomarkers. An intracoronary ultrasound study showed no effect for the primary but significant benefit for the secondary end point. A large clinical outcomes trial was halted when it became apparent that the drug caused serious psychiatric side effects, including suicide. Torcetrapib, a cholesteryl ester transfer protein inhibitor, lowers low-density lipoprotein (LDL) cholesterol and induces a marked increase in high-density lipoprotein (HDL) cholesterol. However, a large clinical outcomes trial was halted very prematurely due to a 58% increase in all-cause mortality. Neutral imaging studies were reported later. Ezetimibe lowers low density lipoprotein cholesterol but did not reduce carotid intima-media thickness, and there is as yet no clinical trial evidence that it reduces cardiovascular events after a decade on the market. Niacin exerts favourable effects on lipid biomarkers and has shown regression of atherosclerosis in small carotid imaging trials, but did not reduce events in a recent clinical trial that was stopped early due to a lack of efficacy. In summary, favourable effects on lipid biomarkers often do not translate into clinical benefit, and imaging trials, which focus on a narrow measurement of atherosclerosis, are also often not helpful.     

Rheumatoid Arthritis Pharmacotherapies: Do They Have Anti-Atherosclerotic Activity?

Rheumatoid arthritis (RA) is associated with a heightened risk of cardiovascular disease (CVD) events, presumably related to a greater burden of atherosclerosis, as well as atherosclerotic plaques that tend to be inflamed and rupture prone. Many of the inflammatory pathways underlying the pathobiology of RA are also recognized contributors to atherosclerosis. Immunomodulation is the mainstay for RA therapy, and a variety of biologic and non-biologic pharmacotherapies are used either singly or in combination to control articular and systemic inflammation and prevent joint destruction. Almost all of these agents have theoretical potential to favorably affect atherogenesis and atherothrombosis, but mechanisms by which they exert effects have been incompletely studied, to date. However, whether clinical control of RA disease activity is associated with a reduction in CVD events regardless of agent used or whether the potency of anti-atherogenic effects varies between disease-modifying anti-rheumatic drugs (DMARDs) is an area of current interest in RA research. More broadly, RA immunotherapies are currently being tested in high-CVD-risk patients in proof-of-concept clinical trials that could alter the paradigm for CVD treatment and prevention in the general population. In this review, we will summarize the current evidence ascribing atheroprotective effects to RA pharmacotherapies.     

Strategies to reverse atherosclerosis: An imaging perspective

Several treatment strategies, including lowering low-density lipoprotein cholesterol with intensive statin therapy, reducing triglycerides with fibrates, and raising high-density lipoprotein cholesterol with nicotinic acid, have the potential to induce atherosclerosis regression. Atherosclerosis imaging techniques including intravascular ultrasound, carotid ultrasound to measure carotid intima-media thickness, and cardiovascular MRI are established modalities for describing longitudinal changes in the quantity and quality of atherosclerotic plaque. An increasing number of clinical trials are using radiologic measures of subclinical atherosclerosis as surrogate end points in lieu of the traditional "hard" end points of myocardial infarction and death. This approach has great appeal, as improvements in atherosclerosis imaging now enable the characterization of early atheromas and positive remodeling within the vessel wall before the plaque becomes obstructive. Additional prospective data correlating these surrogate end points with hard outcomes are needed to determine whether atherosclerosis regression will be the major determinant of future treatment strategies.     

Novel lipid-modifying therapies addressing unmet needs in cardiovascular disease

Cardiovascular disease(CVD) remains a major cause of morbidity and mortality worldwide. Currently, it is well established that dyslipidemia is one of the major risk factors leading to the development of atherosclerosis and CVD. Statins remain the standard-of-care in the treatment of hypercholesterolemia and their use has significantly reduced cardiovascular morbidity and mortality. In addition, recent advances in lipid-modifying therapies, such as the development of proprotein convertase subtilisin/kexin type 9 inhibitors, have further improved cardiovascular outcomes in patients with hypercholesterolemia.However, despite significant progress in the treatment of dyslipidemia, there is still considerable residual risk of recurring cardiovascular events. Furthermore, in some cases, an effective therapy for the identified primary cause of a specific dyslipidemia has not been found up to date. Thus, a number of novel pharmacological interventions are under early human trials, targeting different molecular pathways of lipid formation, regulation and metabolism. This editorial aims to discuss the current clinical and scientific data on new promising lipidmodifying therapies addressing unmet needs in CVD, which may prove beneficial in the near future.     

Postmenopausal hormone replacement therapy and the vascular wall: epidemiology and clinical studies

The clinical relevance of estrogen's multiple acute and more delayed effects on vascular wall structure and function is incompletely understood. This review attempts to reevaluate epidemiological findings and clinical studies concerning the vascular actions of estrogens and gives implications for strategies in postmenopausal hormone replacement therapy (HRT). There is large evidence from observational studies that HRT reduces the risk of cardiovascular mortality and morbidity in postmenopausal women. However, according to the only large randomized, placebo-controlled, secondary prevention Heart and Estrogen/progestin Replacement Study (HERS), women with prevalent cardiovascular disease (CVD) have increased CVD events within the first year after onset of HRT. The net effects of HRT on atherosclerosis, coagulation, fibrinolysis or the inflammatory response are unproven. Randomized trials of intermediate outcomes reveal that HRT has favorable effects on isolated cardiovascular risk factors, e.g. lipoproteins, carbohydrate metabolism and vasodilatation, but the impact of this effects on clinical endpoints is still not clear. The basis of "evidenced based medicine" is currently not sufficient to provide exact recommendation who will benefit from HRT and who might not. Therefore, the decision about hormone use should consider individual benefit-risk profiles.     

Mineralocorticoids and Cardiovascular Disease in Females with Insulin Resistance and Obesity

Purpose of the Review

In the present review, we will discuss the evidence and the mechanisms underlying the complex interplay between obesity, mineralocorticoid receptor activation, and cardiovascular dysfunction with special emphasis on the pathogenesis of cardiovascular disease (CVD) in obese and insulin-resistant females.

Recent Findings

Since the initial isolation of aldosterone in 1953 and the cloning of the mineralocorticoid receptor (MR) decades later, our understanding has expanded tremendously regarding their involvement in the pathogenesis of CVD. Recent results from both pre-clinical and clinical studies support a close correlation between increase adiposity and enhanced aldosterone production (MR activation).

Summary

Importantly, insulin resistance and obese females are more prone to the deleterious cardiovascular effects of MR activation, and enhanced MR activation in females has emerged as an important causative event in the genesis of a more severe CVD in diabetic women. Different clinical trials have been completed examining the effect of MR blockade in subjects with CVD. Despite its important beneficial mortality impact, side effects are frequent and a newer MR antagonist, finerenone, with less risk of hyperkalemia is currently being tested in large clinical trials.

     

What Are We Learning from the FDA-Mandated Cardiovascular Outcome Studies for New Pharmacological Antidiabetic Agents?

Cardiovascular disease (CVD) is common in patients with diabetes. For these patients, clinicians should seek diabetes treatment that is beneficial rather than harmful in relation to CVD. Until recently, there have been many treatments for hyperglycemia, whose impact on CVD has been controversial. The aims of this review are to evaluate the effectiveness of antihyperglycemic medications on risk factors for CVD and to examine the impact of these drugs on CVD in cardiovascular (CV) outcome trials. In this article, we summarize current knowledge about the impacts of these drugs on various risk factors as well as CV outcomes. We identify the recent emergence of trials with antihyperglycemic agents showing newly discovered CV benefits as well as past trials with antihyperglycemic agents not showing much benefit on CV events. Rather than focusing on treatment strategies, we review the effects of individual drug classes on CV outcomes. We also briefly review goal-driven glycemia reduction and its impact on CVD. We conclude that antihyperglycemic agents are associated with improvement in CV risk factors in patients with diabetes and insulin resistance; in fact, a few drugs reduced CV events in randomized CV outcome trials. Therefore, the use of these drugs is appropriate for reducing glucose and decreasing CV event risk in a select subpopulation.     

Niacin and statin combination therapy for atherosclerosis regression and prevention of cardiovascular disease events: reconciling the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial with previous surrogate endpoint trials

Despite substantial risk reductions targeting low-density lipoprotein cholesterol with statins, there remains significant residual risk as evidenced by incident and recurrent cardiovascular disease (CVD) events among statin-treated patients. Observational studies have shown that low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased CVD risk. It remains unclear whether strategies aimed at increasing HDL-C in addition to background statin therapy will further reduce risk. The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, which compared combined niacin/simvastatin with simvastatin alone, failed to demonstrate an incremental benefit of niacin among patients with atherosclerotic CVD and on-treatment low-density lipoprotein cholesterol values <70 mg/dl, but this study had some limitations. Previously, small randomized, clinical trials of niacin plus statins showed that modest regression of carotid atherosclerosis is possible in individuals with CVD, CVD risk equivalents, or atherosclerosis. This viewpoint summarizes these imaging trials studying niacin and places them in the context of the failure of AIM-HIGH to support the HDL-C-increasing hypothesis.     

Effects of the Thiazolidinedione Medications on Micro- and Macrovascular Complications in Patients with Diabetes—Update 2008

Introduction

The thiazolidinedione (TZD) drugs, including pioglitazone (Actos®) and rosiglitazone (Avandia®), are commonly prescribed in patients with type 2 diabetes mellitus (T2DM), largely due to their favorable effects on hyperglycemia, insulin sensitivity, and cardiometabolic profile. However, the data are sparse assessing the effects of TZDs on micro- and macrovascular disease risk.

Discussion

Although no studies have been published on microvascular clinical outcomes, both TZDs significantly reduce the urine albumin-to-creatinine ratio. TZDs have consistently been associated with favorable effects on atherosclerosis and cardiovascular disease (CVD) risk. Only one study has been published to date specifically designed to assess the effects of a TZD (pioglitazone) on macrovascular outcomes, the PROactive trial. In this trial, pioglitazone versus placebo was associated with a non-significant 10% reduction in the combined primary endpoint of mortality, coronary and peripheral vascular events, and revascularizations. No individual trial has been published specifically assessing the CVD effects of rosiglitazone, but several meta-analyses and a published interim report from an ongoing trial (RECORD) point to safety concerns regarding rosiglitazone use and the risk of myocardial infarctions (MI), leading to amplified warnings in the product labeling for rosiglitazone to reflect these concerns.

Conclusion

All published trials and meta-analyses of TZDs have consistently shown increased risk of heart failure (HF) with both TZDs, though the actual placebo-subtracted incidence of HF is low (<0.5% per year). The initiation of either TZD is contraindicated in patients with NHYA class III or IV HF, and cautions exist for their use in any patient with heart failure. Much uncertainty remains regarding the aggregate CVD effects of the TZDs, and several trials are presently underway to further address these issues.     

Women and Peripheral Arterial Disease: A Review of Sex Differences in Epidemiology,Clinical Manifestations,and Outcomes

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in women. Peripheral arterial disease (PAD), a manifestation of CVD and a marker for other adverse CVD outcomes such as ischemic heart disease and stroke, remains underrecognized and undertreated in women. Contrary to the previous belief that PAD is mainly a disease of white men, contemporary data suggest equal, if not higher, prevalence rates in nonwhite women. Women often present with asymptomatic or atypical disease and seek medical attention with more advanced disease. Cardiovascular morbidity and mortality rates, as well as procedural mortality rates, remain elevated in women compared with men. There are sex-specific markers and comorbidities with a higher female prevalence that are associated with PAD. Greater focus on PAD in cardiovascular trials, equivalent enrollment of women in large trials, and focused prevention strategies may help reduce the economic burden and adverse outcomes associated with PAD in women.     

Cardiovascular Disease in Systemic Lupus Erythematosus: The Role of Traditional and Lupus Related Risk Factors

Atherosclerosis is a chronic inflammatory disorder characterized by immune cell activation, inflammation driven plaque formation and subsequent destabilization. In other disorders of an inflammatory nature, the chronic inflammatory state per se has been linked to acceleration of the atherosclerotic process which is underlined by an increased incidence of cardiovascular disease (CVD) in disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and antiphopholipid (Hughes) syndrome (APS). SLE is an autoimmune disease that may affect any organ. Premature coronary heart disease has emerged as a major cause of morbidity and mortality in SLE. In addition to mortality, cardiovascular morbidity is also markedly increased in these patients, compared with the general population. The increased cardiovascular risk can be explained only partially by an increased prevalence of classical risk factors for cardiovascular disease; it also appears to be related to inflammation. Inflammation is increasingly being considered central to the pathogenesis of atherosclerosis and an important risk factor for vascular disease. Recent epidemiologic and pathogenesis studies have suggested a great deal in common between the pathogenesis of prototypic autoimmune disease such as SLE and that of atherosclerosis.We will review traditional risk factors for CVD in SLE. We will also discuss the role of inflammation in atherosclerosis, as well as possible treatment strategies in these patients.Key Words: Cardiovascular disease, systemic lupus erythematosus, atherosclerosis.     

Potential Anti-Atherosclerotic Effects of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Mellitus

Cardiovascular disease (CVD) is the leading cause of mortality in patients with diabetes. Pharmacotherapy that can reduce hyperglycemia and also exhibit pleiotropic effects that can result in a reduction in cardiovascular disease will be a major advance. Recently, the dipeptidyl-peptidase-4 inhibitors were introduced as ant-hyperglycemic therapy. Studies from numerous groups have reported effects that could potentially result in a reduction in CVD. Some of the drugs in this class, especially vildagliptin and sitagliptin, have been shown to reduce postprandial hyperlipidemia following a fat load, improve endothelial function as evidenced by increased forearm blood flow, and also display anti-inflammatory effects. Their effects on platelet function, blood pressure, and oxidative stress are very preliminary and need to be confirmed. Finally, they have been shown to reduce subclinical atherosclerosis by reducing carotid intimal-medial thickness. However, the final arbiter with respect to a reduction in CVD will be the ongoing clinical trials.     

Intravascular ultrasound for the evaluation of therapies targeting coronary atherosclerosis

Many cardiovascular events are clinical manifestations of underlying atherosclerotic disease. The progression of atherosclerosis, traditionally measured by angiography, is predictive of future clinical events and is a valid surrogate marker of cardiovascular (CV) disease. There is growing interest in using novel surrogate end points in clinical trials to expedite the development of new CV therapies. Innovative imaging technologies, such as intravascular ultrasound (IVUS), may carry advantages for the evaluation of coronary atherosclerotic burden and disease progression. Unlike angiography, which displays only the opacified luminal "silhouette," IVUS provides transmural imaging of the entire arterial wall and permits both detection of early-stage atherosclerosis and accurate cross-sectional and even 3-dimensional quantification of plaques. Intravascular ultrasound is now used to guide therapeutic interventions and for diagnostic purposes, primarily for the evaluation of ambiguous lesions and left main coronary artery disease. In addition, clinical studies are using IVUS serially to measure plaque progression, which appears to be related to future CV events. Although the probative force of clinical end point studies still is stronger, IVUS is catching up. Currently, several trials of CV therapies use IVUS-determined plaque progression as the end point. The rationale for using IVUS-based surrogate end points in clinical trials is discussed in the present review. Key advantages of using IVUS-based surrogate end points versus clinical outcome include smaller patient numbers and substantially shorter trial durations; this reduces costs and may expedite the development and testing of new drugs. We expect in the near future a further increase of the use of IVUS-based surrogate end points in trials that evaluate novel CV therapies targeting on coronary atherosclerosis.     

Intravascular ultrasound for the evaluation of therapies targeting coronary atherosclerosis.

Many cardiovascular events are clinical manifestations of underlying atherosclerotic disease. The progression of atherosclerosis, traditionally measured by angiography, is predictive of future clinical events and is a valid surrogate marker of cardiovascular (CV) disease. There is growing interest in using novel surrogate end points in clinical trials to expedite the development of new CV therapies. Innovative imaging technologies, such as intravascular ultrasound (IVUS), may carry advantages for the evaluation of coronary atherosclerotic burden and disease progression. Unlike angiography, which displays only the opacified luminal "silhouette," IVUS provides transmural imaging of the entire arterial wall and permits both detection of early-stage atherosclerosis and accurate cross-sectional and even 3-dimensional quantification of plaques. Intravascular ultrasound is now used to guide therapeutic interventions and for diagnostic purposes, primarily for the evaluation of ambiguous lesions and left main coronary artery disease. In addition, clinical studies are using IVUS serially to measure plaque progression, which appears to be related to future CV events. Although the probative force of clinical end point studies still is stronger, IVUS is catching up. Currently, several trials of CV therapies use IVUS-determined plaque progression as the end point. The rationale for using IVUS-based surrogate end points in clinical trials is discussed in the present review. Key advantages of using IVUS-based surrogate end points versus clinical outcome include smaller patient numbers and substantially shorter trial durations; this reduces costs and may expedite the development and testing of new drugs. We expect in the near future a further increase of the use of IVUS-based surrogate end points in trials that evaluate novel CV therapies targeting on coronary atherosclerosis.     

Importance of medication adherence in cardiovascular disease and the value of once-daily treatment regimens

An estimated 71 million individuals in the United States are currently diagnosed with cardiovascular disease (CVD). If untreated, CVD conditions such as systemic hypertension, coronary artery disease, and heart failure will have potentially serious and often fatal outcomes. Numerous clinical trials have established a variety of evidence-based medications that are efficacious in the treatment of CVD. These drugs will be ineffective, however, if patients have trouble adhering to their prescribed regimens. In patients with hypertension or heart failure, or in those who have suffered a myocardial infarction, poor adherence to therapies has been linked to a variety of problems, including poor blood pressure control, rehospitalization, and increased healthcare resource utilization. Both the asymptomatic nature of some forms of CVD and the high pill burden associated with certain therapies have been linked to poor adherence. Reducing pill burden through the use of once-daily formulations has proven valuable in improving adherence to evidence-based therapies. This review will discuss the impact of adherence to prescribed therapies for CVD, outline common barriers to adherence, and demonstrate the value of once-daily dosing regimens for improved patient adherence.     

Do we need to consider inflammatory markers when we treat atherosclerotic disease?

This review considers the value of monitoring inflammatory markers as a guide to selecting appropriate drugs in patients at high risk of cardiovascular disease (CVD). Clinical and experimental studies investigated inflammation in patients with acute coronary syndromes (ACS), stable coronary artery disease (CAD) and diabetes mellitus (DM) or metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) or systemic autoimmune diseases (SAD). Evidence suggests that in these high risk groups inflammation plays a role in the extent and severity of atherosclerosis. Simple inflammatory markers (e.g. C-reactive protein and fibrinogen) can be monitored cost effectively and may influence the selection of drugs that can normalize both traditional CVD risk factors and inflammation. However, this concept requires proof in appropriately designed trials that include clinically relevant end points.     

Marital status and outcomes in patients with cardiovascular disease

The national burden of cardiovascular disease (CVD) continues to impose significant risk of morbidity, mortality and increased costs. While traditional risk factors have been well-established, the evolving role of non-traditional risk factors, including socioeconomic and psychosocial factors, is increasingly being recognized. Several studies have acknowledged an association between marital status and the presence of CVD and its associated adverse outcomes. Across multiple U.S. and international cohorts, patients who are unmarried, including those who are divorced, separated, widowed, or never married, have an increased rate of adverse cardiovascular events when compared to their married counterparts. Some studies suggest that marriage may have a more protective role for men compared to women. Furthermore, dissatisfaction in a marriage and marriage quality have significant impact on cardiovascular risk. Psychosocial and socioeconomic factors, as well as other acute stressors, may contribute to the association between marital status and CVD outcomes, but the underlying mechanisms are not completely clear. Further investigation is required to identify potential targets for intervention and to determine whether more aggressive targeting of standard anti-atherosclerotic therapies can favorably impact CVD risk in unmarried patients.     

Inflammation and Cardiovascular Disease: From Pathogenesis to Therapeutic Target

Atherosclerosis represents the most common pathological substrate of coronary heart disease (CHD), and the characterization of the disease as a chronic low-grade inflammatory condition is now largely accepted. A number of mediators of inflammation have been widely studied, both as surrogate biomarkers and as causal agents, in the pathophysiological network of atherogenesis and plaque vulnerability. The epidemiological observation that biomarkers of inflammation are associated with clinical cardiovascular risk supports the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk on the background of traditional medical therapy. A large number of randomized controlled trials have shown that drugs commonly used in cardiovascular disease (CVD), such as statins, may be effective in the primary and secondary prevention of cardiovascular events through an anti-inflammatory effect. Moreover, several anti-inflammatory drugs are being tested for their potential to reduce residual cardiovascular risk on the background of validated medical therapy for atherosclerotic disease. In this paper, we review relevant evidence with regard to the relationship between inflammation and CVD, from pathogenesis to therapeutic strategies.     

The Protective Role of Positive Well-Being in Cardiovascular Disease: Review of Current Evidence,Mechanisms, and Clinical Implications

Positive psychological aspects of well-being—including positive emotions, optimism, and life satisfaction—are increasingly considered to have protective roles for cardiovascular disease (CVD) and longevity. A rapidly-growing body of literature has linked positive well-being with better cardiovascular health, lower incidence of CVD in healthy populations, and reduced risk of adverse outcomes in patients with existing CVD. This review first examines evidence on the associations of positive well-being with CVD and mortality, focusing on recent epidemiological research as well as inconsistent findings. Next, an overview is provided of putative biological, behavioral, and stress-buffering mechanisms that may underlie the relationship between positive well-being and cardiovascular health. Key areas for future inquiry are discussed, in addition to emerging developments that capitalize on technological and methodological advancements. Promising initial results from randomized controlled trials suggest that efforts to target positive well-being may serve as valuable components of broader CVD management programs.