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Barylski M.,Medical University of Lódz | Nikolic D.,University of Palermo | Rizzo M.,University of Palermo | Rizzo M.,Euro Mediterranean Institute of Science and Technology | And 2 more authors.
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2014

The first observations linking a low serum level of HDL-C to increased risk for cardiovascular disease were made over 50 years ago. High serum levels of HDL-C appear to protect against the development of atherosclerotic disease, while low serum levels of this lipoprotein are among the most important predictors of atherosclerotic disease in both men and women and people of all racial and ethnic groups throughout the world. It has long been assumed that therapeutic interventions targeted at raising HDL-C levels would lower risk for such cardiovascular events as myocardial infarction, ischemic stroke, and death. Even after five decades of intensive investigation, evidence to support this assumption has been fleeting. A number of post hoc analyses of randomized controlled trials and meta-analyses suggest that HDL-C raising, particularly when coupled with aggressive LDL-C reduction, impacts risk for cardiovascular events and rates of progression of atherosclerotic disease. Unfortunately, four recent prospective trials performed with the intent of testing the "HDL hypothesis" (ILLUMINATE, dal-OUTCOMES, AIM-HIGH, and HPS2-THRIVE) failed to meet their primary composite endpoints. These results have lead many clinicians and investigators to question the validity of the assumption that HDL-C raising reduces risk for cardiovascular events. Additional trials with other drugs are underway. In the meantime, HDL-C cannot be considered a target of therapy. Given the complexity of the HDL proteome and lipidome, there is biological plausibility for how HDL particles might exert atheroprotection. We explore the evidence supporting the inverse relationship between HDL-C and cardiovascular disease risk, documented mechanisms by which HDL particles may exert atheroprotection, and the findings either supporting or negating specific therapeutic interventions in patients afflicted with low HDL-C. © 2013 Elsevier Ltd. All rights reserved.


Barylski M.,Medical University of Lódz | Nikolic D.,University of Palermo | Banach M.,Medical University of Lódz | Rizzo M.,University of Palermo | And 2 more authors.
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2014

High-density lipoprotein (HDL) particles are highly complex polymolecular aggregates capable of performing a remarkable range of atheroprotective functions. Considerable research is being performed throughout the world to develop novel pharmacologic approaches to: (1) promote apoprotein A-I and HDL particle biosynthesis; (2) augment capacity for reverse cholesterol transport so as to reduce risk for the development and progression of atherosclerotic disease; and (3) modulate the functionality of HDL particles in order to increase their capacity to antagonize oxidation, inflammation, thrombosis, endothelial dysfunction, insulin resistance, and other processes that participate in arterial wall injury. HDL metabolism and the molecular constitution of HDL particles are highly complex and can change in response to both acute and chronic alterations in the metabolic milieu. To date, some of these interventions have been shown to positively impact rates of coronary artery disease progression. However, none of them have as yet been shown to significantly reduce risk for cardiovascular events. In the next 3-5 years a variety of pharmacologic interventions for modulating HDL metabolism and functionality will be tested in large, randomized, prospective outcomes trials. It is hoped that one or more of these therapeutic approaches will result in the ability to further reduce risk for cardiovascular events once low-density lipoprotein cholesterol and non-HDL-cholesterol targets have been attained. © 2013 Elsevier Ltd. All rights reserved.


Rizzo M.,University of Palermo | Rizzo M.,Euro Mediterranean Institute of Science and Technology | Otvos J.,LipoScience | Nikolic D.,University of Palermo | And 4 more authors.
Current Medicinal Chemistry | Year: 2014

High-density lipoproteins (HDL) are classified as atheroprotective because they are involved in transport of cholesterol to the liver, known as "reverse cholesterol transport (RCT)" exerting antioxidant and anti-inflammatory activities. There is also evidence for cytoprotective, vasodilatory, antithrombotic, and anti-infectious activities for these lipoproteins. HDLs are known by structural, metabolic and biologic heterogeneity. Thus, different methods are able to distinguish several subclasses of HDL. Different separation techniques appear to support different HDL fractions as being atheroprotective or related with lower cardiovascular (CV) risk. However, HDL particles are not always protective. Modification of constituents of HDL particles (primarily in proteins and lipids) can lead to the decrease in their activity and induce proatherogenic properties, especially when isolated from patients with augmented systemic inflammation. According to available studies, it seems that HDL functionality may be a better therapeutic target than HDL cholesterol quantity; however, it is still disputable which subfractions are most beneficial. There is mounting evidence supporting HDL subclasses as an important biomarker to predict and/or reduce CV risk. In this review we discuss recent notices on atheroprotective and functional characteristic of different HDL subfractions. Also, we provide a brief overview of the different methods used by clinicians and researchers to separate HDL subfractions. Ongoing and future investigations will yield important new information if any given separation method might represent a 'gold standard', and which subfractions are reliable markers of CV risk and/or potential targets of novel, more focused, and effective therapies. © 2014 Bentham Science Publishers.


Nikolic D.,University of Palermo | Katsiki N.,Aristotle University of Thessaloniki | Montalto G.,University of Palermo | Isenovic E.R.,University of Belgrade | And 2 more authors.
Nutrients | Year: 2013

Small, dense low density lipoprotein (sdLDL) represents an emerging cardiovascular risk factor, since these particles can be associated with cardiovascular disease (CVD) independently of established risk factors, including plasma lipids. Obese subjects frequently have atherogenic dyslipidaemia, including elevated sdLDL levels, in addition to elevated triglycerides (TG), very low density lipoprotein (VLDL) and apolipoprotein-B, as well as decreased high density lipoprotein cholesterol (HDL-C) levels. Obesity-related co-morbidities, such as metabolic syndrome (MetS) are also characterized by dyslipidaemia. Therefore, agents that favourably modulate LDL subclasses may be of clinical value in these subjects. Statins are the lipid-lowering drug of choice. Also, anti-obesity and lipid lowering drugs other than statins could be useful in these patients. However, the effects of anti-obesity drugs on CVD risk factors remain unclear. We review the clinical significance of sdLDL in being overweight and obesity, as well as the efficacy of anti-obesity drugs on LDL subfractions in these individuals; a short comment on HDL subclasses is also included. Our literature search was based on PubMed and Scopus listings. Further research is required to fully explore both the significance of sdLDL and the efficacy of anti-obesity drugs on LDL subfractions in being overweight, obesity and MetS. Improving the lipoprotein profile in these patients may represent an efficient approach for reducing cardiovascular risk. © 2013 by the authors; licensee MDPI, Basel, Switzerland.


Banerjee Y.,Sultan Qaboos University | Santos R.D.,University of Sao Paulo | Al-Rasadi K.,Sultan Qaboos University | Rizzo M.,University of Palermo | Rizzo M.,Euro Mediterranean Institute of Science and Technology
Atherosclerosis | Year: 2016

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates the expression of low-density lipoprotein (LDL)-receptors, through reducing their recycling by binding to the receptor along with LDL and targeting it for lysosomal destruction. PCSK9 also enhances the degradation of very-low-density-lipoprotein receptor (VLDLR) and lipoprotein receptor-related protein 1 (LRP-1) in a LDL-receptor independent manner. This role in lipid homeostasis presents PCSK9 as an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidaemias. However, PCSK9 mediates multifarious functions independent of its role in lipid homeostasis, which can be grouped under "pleiotropic functions" of the protein. This includes PCSK9's role in: trafficking of epithelial sodium channel; hepatic regeneration; pancreatic integrity and glucose homeostasis; antiviral activity; antimalarial activity; regulation of different cell signalling pathways; cortical neural differentiation; neuronal apoptosis and Alzheimer's disease. The question that needs to be investigated in depth is "How will the pleotropic functions of PCSK9, be affected by the therapeutic intervention of the protease's LDL-receptor lowering activity?" In this review, we appraise the different lipid lowering strategies targeting PCSK9 in light of the protein's different pleiotropic functions. Additionally, we delineate the key areas that require further examination, to ensure the long-term safety of the above lipid-lowering strategies. © 2016 Elsevier Ireland Ltd.


Nibali L.,University College London | Tatarakis N.,University College London | Needleman I.,University College London | Tu Y.-K.,National Taiwan University | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Background: Several epidemiological studies have reported an association between metabolic syndrome (MetS) and periodontal diseases (PDs). The aim of this systematic review was to investigate the existence and magnitude of this association. Materials and Methods: A systematic search of the literature was conducted looking for casecontrol, cross-sectional, cohort studies and population surveys including patients with measures of MetS and PD. Ovid MEDLINE, EMBASE, LILACS, and Cochrane library databases were used for the search by 2 independent reviewers. A meta-analysis was conducted to investigate the association for coexistence of MetS and PD. Results: A total of 20 studies were included in the review, from an initial search of 3486 titles. Only 1 study reported longitudinal data on the onset of MetS components in association with periodontal measures. However, several studies investigated coexistence. A random effects meta-analysis showed that the presence of MetS is associated with the presence of periodontitis in a total of 36 337 subjects (odds ratio=1.71;95%confidence interval=1.42 to 2.03). When only studies with "secure" diagnoses wereincluded (n=16 405), themagnitudeof association increased (odds ratio=2.09;95%confidence interval = 1.28 to 3.44). Moderate heterogeneity was detected (I2 = 53.6%; P = .004). Conclusions: This review presents clear evidence for an association between MetS and periodontitis. The direction of the association and factors influencing it should be investigated by longitudinal and treatment studies. Periodontal diagnostic procedures should be routinely carried out in MetS patients. Copyright © 2013 by The Endocrine Society.


Tevy M.F.,Barcelona Institute for Research in Biomedicine | Giebultowicz J.,Oregon State University | Pincus Z.,Yale University | Mazzoccoli G.,IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | And 2 more authors.
Trends in Endocrinology and Metabolism | Year: 2013

The circadian clock machinery orchestrates organism metabolism to ensure that development, survival, and reproduction are attuned to diurnal environmental variations. For unknown reasons, there is a decline in circadian rhythms with age, concomitant with declines in the overall metabolic tissue homeostasis and changes in the feeding behavior of aged organisms. This disruption of the relationship between the clock and the nutrient-sensing networks might underlie age-related diseases; overall, greater knowledge of the molecular mediators of and variations in clock networks during lifespan may shed light on the aging process and how it may be delayed. In this review we address the complex links between the circadian clock, metabolic (dys)functions, and aging in different model organisms. © 2012 Elsevier Ltd.


Rizzo M.,University of Palermo | Rizzo M.,Euro Mediterranean Institute of Science and Technology | Rizzo M.,University of South Carolina | Chandalia M.,University of Texas Medical Branch | And 5 more authors.
Cardiovascular Diabetology | Year: 2014

Background: Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown.Methods: A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound.Results: After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholesterol increased by 18% (p < 0.01 for all lipid changes). Carotid IMT decreased from 1.19 ± 0.47 to 0.94 ± 0.21 mm (p < 0.01). Yet, changes in carotid IMT did not correlate with changes in any other variable studied.Conclusions: Liraglutide decreases carotid IMT after 8 months treatment independently of its effect on plasma glucose and lipids concentrations.Trial registration: ClinicalTrials.gov: NCT01715428. © 2014 Rizzo et al.; licensee BioMed Central Ltd.


Rizzo M.,University of Palermo | Rizzo M.,Euro Mediterranean Institute of Science and Technology | Rizzo M.,University of South Carolina | Avogaro A.,University of Padua | And 2 more authors.
Expert Opinion on Therapeutic Targets | Year: 2013

Atherosclerosis and cardiovascular events are highly prevalent and represent the major cause of mortality in patients with type 2 diabetes. Therefore, there is significant interest in the non-glycemic properties of anti-diabetic agents, particularly on those that are effective on cardiovascular risk factors. Thiazolidinediones and incretin-based therapies (IBTs) represent some of the most recent treatment options approved for the management of type 2 diabetes; these agents have shown important glycemic effects, as well as a number of non-glycemic effects. The latter include those on body weight, inflammation, hypertension and dyslipidemia, thus impacting the different components of the metabolic syndrome. Pioglitazone has been shown to significantly reduce cardiovascular adverse outcomes, while preliminary data on IBTs are very encouraging as well. Although highlighting the non-glycemic effects of pioglitazone and incretin-based therapies is of potential significance, clinical practice and patient care must be based largely on evidence-based medicine. Therefore, definitive opinions will await additional data from ongoing studies evaluating the effects of both GLP-1 agonists and DPP-4 inhibitors on cardiovascular morbidity and mortality. © Informa UK, Ltd.


Nikolic D.,University of Palermo | Mikhailidis D.P.,University College London | Davidson M.H.,University of Chicago | Rizzo M.,University of Palermo | And 2 more authors.
Atherosclerosis | Year: 2014

ETC-1002 is a new investigational low density lipoprotein cholesterol (LDL-C)-lowering agent (Esperion Therapeutics, Inc.). ETC-1002 is a dicarboxylic acid derivative with a novel mechanism of action targeting two hepatic enzymes - adenosine triphosphate-citrate lyase (ACL) and adenosine monophosphate-activated protein kinase (AMPK), inhibiting sterol and fatty acid synthesis and promoting mitochondrial long-chain fatty acid oxidation. This agent is currently in phase II clinical research. Available data report that ETC-1002 significantly decreased LDL-C levels (up to 32%) in both patients with normal and elevated baseline levels of triglycerides. Such beneficial effect is superior to currently approved non-statin lipid lowering agents. The levels of apolipoprotein B (apoB) and non-high density lipoprotein cholesterol (non-HDL-C) were also reduced with beneficial effect on other cardiometabolic factors such as inflammatory markers, blood pressure and body weight. Although, the safety and tolerability of ETC-1002 needs to be confirmed in ongoing and future, larger studies, this agent has, so far, been generally safe and well tolerated. This novel, oral, once-daily, small molecule may lead to effective LDL-C lowering treatment in hypercholesterolaemic subjects who are statin intolerant or as add-on therapy in those who are unable to reach the LDL-C goals despite being on statin therapy. This agent might not only exert lipid-lowering related benefits, but also favourable cardiometabolic effects. © 2014 Elsevier Ireland Ltd.

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