Cardiovascular disease and PPARdelta: targeting the risk factors

Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle). It enhances glucose tolerance, insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux and oxygen consumption. These effects positively influence the blood-lipid profile. Furthermore, PPARdelta activation produces a predominant type I/slow twitch/oxidative muscle fiber phenotype that leads to increased endurance, insulin sensitivity and resistance to obesity. PPARdelta has rapidly emerged as a potential target in the battle against dyslipidemia, insulin insensitivity, type II diabetes and obesity, with therapeutic efficacy in the treatment of cardiovascular disease risk factors. GW-501516 is currently undergoing phase II safety and efficacy trials in human volunteers for the treatment of dyslipidemia. The outcome of these clinical trials are eagerly awaited against a background of conflicting reports about cancer risks in genetically predisposed animal models. This review focuses on the potential pharmacological utility of selective PPARdelta agonists in the context of risk factors associated with metabolic and cardiovascular disease.     

Pharmacogenetics of the PPAR genes and cardiovascular disease

The goal of pharmacogenetics is to define the genetic determinants of individual drug responsiveness, and thereby provide personalized treatment to each individual. The peroxisome proliferator-activated receptors (PPARs) are polypeptide products of a set of related genes functioning to regulate several cellular processes that are central to cardiovascular health and disease. Given their pleiotropic roles in lipid and glucose homeostasis, cardiac energy balance and regulation of adipocyte release of circulating inflammatory factors, it is not surprising that PPARs represent an attractive target for clinical investigation and intervention in disease states, such as diabetes, obesity, atherosclerosis, cardiomyopathy, cardiac hypertrophy and heart failure. Research into the manipulation of PPAR function by pharmacologic agents has already resulted in important advances in the treatment of diabetes mellitus and cardiovascular disease. It follows that PPAR pharmacogenetics promises important advances in the personalized treatment of cardiovascular disease.     

Measuring biomarkers to assess the therapeutic effects of PPAR agonists?

The metabolic syndrome is defined as a clustering of cardiovascular risk factors with insulin resistance, including dyslipidemia, coagulation disturbances and hypertension. Activators of the peroxisome proliferator-activated receptors (PPARs) modulate several of the metabolic risk factors predisposing to atherosclerosis. Fibrates are hypolipidemic drugs acting through activation of PPARalpha, whereas glitazones are insulin sensitizers activating PPARgamma. In addition, these drugs exert pleiotropic anti-inflammatory actions. In this review, we will focus on the effects of fibrates and glitazones on biomarker modulation and their usefulness in the treatment of cardiovascular disease.     

Therapeutic Potential of Aleglitazar,a New Dual PPAR-α/γ Agonist

Preventing morbidity and mortality from diabetes mellitus is of paramount importance as the incidence of this disease is increasing across the world. While microvascular complications of diabetes such as nephropathy, retinopathy, and neuropathy are reduced with intensive glycemic control, treatment of hyperglycemia has not been consistently shown to have effects on the macrovascular complications of diabetes such as coronary artery, cerebrovascular, and peripheral vascular disease. Preventive efforts have accordingly shifted toward the modification of other cardiovascular risk factors in diabetic patients. Agonism of the peroxisome proliferator-activated receptors (PPARs) has long been an attractive target for antidiabetic therapy due to the role of PPARs in glycemic control and lipid metabolism. PPAR-γ agonists such as rosiglitazone and pioglitazone are used in clinical practice for the treatment of diabetes, and there is some evidence that pioglitazone may have positive effects on cardiovascular complications by virtue of its favorable effects on lipid profiles. However, they have not been shown to reduce macrovascular events. PPAR-α agonism is the mechanism of action in the fibrate class of medications; these agents have been shown to increase high-density lipoprotein cholesterol (HDL-C) levels, reduce triglyceride levels, and improve cardiovascular outcomes. Given the prevalence of lipid abnormalities in patients with diabetes, dual PPAR-α/γ agonists (glitazars) could potentially benefit patients with diabetes. A phase II trial examining a novel dual PPAR agonist, aleglitazar, showed that therapy with this agent reduced hyperglycemia and favorably modified levels of HDL-C and triglycerides with an acceptable safety profile. Aleglitazar is currently being studied in large-scale clinical trials to assess whether it will reduce the risk of major cardiovascular endpoints (death, myocardial infarction, or stroke) among patients with diabetes and coronary artery disease. If ongoing studies confirm the theoretical benefit and safety of dual PPAR-α/γ agonism, aleglitazar may become the first therapy demonstrated to reduce macrovascular complications in patients with diabetes.     

Mechanism of antiplatelet action of hypolipidemic,antidiabetic and antihypertensive drugs by PPAR activation: PPAR agonists: New antiplatelet agents

Given the prevalence of cardiovascular disease in patients with cardiovascular risk factors (i.e., hypertension, diabetes, smoking and obesity) and that platelet activation plays an important pathogenic role in cardiovascular diseases, it is very important to identify the drugs that have multiple targets. In this sense, the present article describes the mechanism of antiplatelet action of hypolipidemic (statins and fibrates), antidiabetic (thiazolidinediones) and antihypertensive (nifedipine) drugs via peroxisome proliferator-activated receptor (PPAR) activation. The mechanism of antiplatelet action of the drugs is by direct activation of PPARs with the inhibition of cyclooxygenase-1, protein kinase C-alpha, calcium mobilization, thromboxane A2, sCD40L, platelet microparticles and cAMP-phosphodiesterase, and the stimulation of proteins kinase G and A. Thus, these observations highlight PPARs as a novel therapeutic target for the treatment and prevention of cardiovascular diseases.     

Muraglitazar: an agent for the treatment of type 2 diabetes and associated dyslipidemia

Many studies indicate that postprandial metabolic abnormalities, such as hyperglycemia and dyslipidemia, which are exaggerated and prolonged in type 2 diabetes, are important risk factors for cardiovascular disease. Different pharmacotherapies have been developed to specifically target these risk factors associated with type 2 diabetes. The peroxisome proliferator-activated receptor (PPAR) agonists, which are potent insulin sensitizers, have been the focus of much research during the past decade. Since their development, PPAR agonists have emerged as an important target for the treatment of insulin resistance and dyslipidemia. The more recent development of agonists that selectively target both the alpha and gamma PPARs has provided a potential treatment of global risk in patients with the metabolic syndrome or type 2 diabetes. Muraglitazar is a non-thiazolidinedione, oxybenzylglycine dual PPARalpha/gamma agonist that is in advanced clinical development for the treatment of type 2 diabetes and its associated dyslipidemia. This article summarizes the available clinical data on the efficacy and safety of muraglitazar in patients with type 2 diabetes.     

Role of PPAR in cardiovascular diseases

Cardiovascular disease (CVD) is the most critical global health threat, which contributes more than one third of global morbidity. CVD includes heart disease, vascular disease, atherosclerosis, stroke and hypertension. The most important independent risk factors for CVD include dyslipidemia along with hypertension, obesity, sedentary lifestyle, diabetes and chronic inflammation. These factors are directly regulated by diet, metabolism and physical activity. Diets rich in fat and carbohydrate coupled to sedentary lifestyles have contributed to the increase in dyslipidemia, type 2 diabetes, obesity and CVD in the world. Discovery of Peroxisome Proliferator Activated Receptors (PPARs) as a key regulator of metabolic pathways has led to significant insight into the mechanisms regulating these processes. Three PPAR subtypes, encoded by distinct genes, are designated as PPAR-alpha, PPAR-delta (also know as beta) and PPAR-gamma. PPARs act as nutritional sensors that regulate a variety of homeostatic functions including metabolism, inflammation and development. PPAR-alpha is the main metabolic regulator for catabolism whereas PPAR-gamma regulates anabolism or storage. PPARs are expressed in the cardiovascular system such as endothelial cells, vascular smooth muscle cells and monocytes/macrophages. It has been shown that they play an important role in the modulation of inflammatory, fibrotic and hypertrophic responses. In 1997, a Glaxo patent described that Troglitazone (first PPAR-gamma ligand to reach market) reduced TNF-induced VCAM1 expression in HUVECs indicating the potential benefit in atherosclerosis. A series of patents from Eli Lilly and Dr. Reddy's Laboratories Ltd. between 1999 and 2005 described a variety of PPAR-alpha and -alpha,gamma dual ligands in a number of patents having glucose, triglyceride, cholesterol lowering, HDL elevating and body weight reducing activity. Patents from Metabolex and Tularik in 2001 and 2002 described the beneficial effects of SPPARM molecules for insulin resistance and diabetes, without showing concern on PPAR-gamma related side effects such as edema and body weight. GSK and Takeda described the potential effects of PPAR-delta modulators during 2001 to 2004 in few patents. Several clinical and preclinical studies have demonstrated the beneficial effects of PPAR ligands on various cardiovascular risk factors. This review intends to capture some of the key studies in this area as is described in some recent patents and literature.     

PPARs as therapeutic targets in cardiovascular disease

Importance of the field: The role of peroxisome proliferator-activated receptors PPARα, PPARδ and PPARγ in cardiovascular disease is receiving widespread attention. As ligand-activated nuclear receptors, they play a role in regulation of lipid and glucose metabolism. This feature of the PPARs has been successfully exploited to treat systemic metabolic diseases, like hyperlipidemia and type-2 diabetes. Indirectly, their lipid lowering effect also leads to a reduction of the risk for cardiovascular diseases, primarily atherosclerosis.

Areas covered in this review: The pleiotropic effects of each of the PPAR isotypes on vascular and cardiac disease are discussed, with special emphasis on the molecular mechanism of action and on preclinical observations. The mechanism underlying the beneficial effect of PPARs is not confined to whole body metabolism, but also includes modulation of other vital processes, such as inflammation and cell fate (proliferation, differentiation, apoptosis).

What the reader will gain: A large body of preclinical studies indicates that, in addition to their effect on atherogenesis, PPAR ligands also impact on ischemic heart disease and the development of cardiac failure. It remains to be established to what extent these intriguing observations can be translated into clinical practice.

Take home message: The versatile mechanism of action extends the potential therapeutic profile of the PPARs enormously. Conversely, this versatility makes it harder to attain a specific therapeutic effect, without increasing the risk of undesirable side effects. The future challenge will be to design PPAR-based therapeutic strategies that minimize the detrimental side effects.     

PPARs激动剂在心脑血管疾病中的研究进展

PPARs是一类由配体激活的转录因子,属于Ⅱ型核受体超家族成员。PPARs被激活后,能够改善胰岛素抵抗(IR)、纠正脂质代谢紊乱、逆转心肌肥厚、抑制血管平滑肌细胞(VSMCs)和内皮细胞的增殖与迁移,从而改善心脑血管的病理性重构,并具有降压效应。因此,PPARs激动剂的研究在心脑血管疾病的防治中具有重要的理论意义和临床应用价值。本文对近几年的PPARs激动剂进行综述。     

Hypertriglyceridemia

Accumulating evidence indicates that hypertriglyceridemia (HTG) is a risk factor for cardiovascular disease. This increased risk is probably substantially mediated through the metabolic interrelationships between serum triglyceride (TG) levels and other risk factors, such as the atherogenic lipid profile (low high density lipoprotein-cholesterol levels and elevated small dense low density lipoprotein levels), insulin resistance, a prothrombotic propensity and low grade systemic inflammation. TG-lowering strategy in patients with HTG encompasses dietary modification and pharmacological agents, such as fibric acid derivatives, fish-oil and hydroxymethylglutaryl coenzyme A reductase inhibitors, which have, besides their known effects on the atherogenic lipid profile, beneficial effects on other determinants of cardiovascular disease. However, in spite of data from trials investigating fibric acid derivative-induced reduction in coronary events in patients with distinct types of hyperlipidemia, no specific trials have been performed that investigated this risk reduction in patients with HTG, in whom other cardiovascular risk factors are clustered as well. Small-scale studies on determinants of cardiovascular disease in patients with HTG and post-hoc analyses of the Helsinki Heart, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial and Bezafibrate Infarction Prevention trials in patients with high serum TG levels suggest a drug-induced reduction in cardiovascular events. However, a specific trial should be conducted to investigate the effects of lipid-lowering therapy on clinical end-points in patients with HTG of defined types.     

Cardiovascular risk screening program in Australian community pharmacies

Objective To assess the suitability of Australian community pharmacies as cardiovascular disease risk profile screening centres and evaluate whether community pharmacists can play an important role in detecting, educating and referring screened individuals at high risk of cardiovascular disease. Setting 14 Australian community pharmacies. Method Opportunistic cardiovascular disease risk profiling for members of the public aged greater than 30 years with no existing cardiovascular diseases was performed. All major cardiovascular risk factors were measured. Exercise habits, existing conditions and therapy, and family history were also assessed. The results were used to calculate each subject’s 10-year risk of developing cardiovascular events, based on Framingham Risk Equations (New Zealand tables). Each subject’s knowledge of cardiovascular risk factors was assessed using a multiple-choice questionnaire. Written educational materials and verbal counselling were provided. Referral to a doctor for further assessment was recommended as appropriate. The screened individuals were followed up via mailed out questionnaire. A random sample of individuals at elevated risk was phoned to assess for outcomes of the screening and referral process. Main outcome measures Risk of developing cardiovascular disease and knowledge of cardiovascular risk factors. Results A total of 655 individuals (71.4% female) were screened for cardiovascular disease risk factors. Ages ranged from 30 to 90 years (median: 54 years) and 14.2% were smokers. Of the individuals screened, 28.1% had a 10-year risk of developing cardiovascular disease greater than 15%, including 6.9% who had a 10-year risk above 30%. The median calculated 10-year risk of developing cardiovascular disease was 9.5%. Approximately one-third of the individuals had elevated blood pressure, and almost two-thirds were either overweight or obese. The mean total serum cholesterol was 5.31 mmol/l, with 40% of individuals having a level above 5.5 mmol/l and 20% having a high-density lipoprotein cholesterol level below 1.0 mmol/l. There was a statistically significant improvement in the knowledge of cardiovascular disease risk factors at follow-up. Almost half of the contacted high-risk subjects reported lifestyle changes or started drug therapy following re-testing by their general practitioner. Conclusion A pharmacy-based cardiovascular disease risk profile screening and education program has the potential to identify and refer many undiagnosed individuals at high risk of cardiovascular events, and help contain the burden of heart disease.     

Traditional risk factors for coronary atherosclerosis in Indo Asians: the need for a reappraisal

Our ability to assess individual patient cardiovascular risk is based on "traditional" risk factors including patient's characteristics (age, sex and body mass index), hypertension, diabetes, smoking, lipid profile and family history of premature coronary disease. These factors are important for the clinician in order to calculate risk and initiate treatment in both primary and secondary settings. As the morbidity and mortality from vascular disease in United Kingdom migrant populations of Indo Asian origin is significantly higher (approximately 50%) than the Western Europeans, an accurate assessment of risk and preventative therapies can reduce cardiovascular risk and improve clinical outcome. Indeed, scoring systems like the Framingham consistently underestimate risk in Indo Asians. This review assesses differences between traditional risk factors in Indo Asians and summarizes the relevance of more novel factors in a more comprehensive evaluation of cardiovascular risk in the Indo Asian population. Greater appreciation of these traditional risk factors for coronary atherosclerosis in Indo Asians--including hypertension and metabolic syndrome (of which hypertension is a key component)--suggests the need for a reappraisal to put these data in context of current management strategies.