Plant Sterols/Stanols: Do they have a Role in Current Cardiovascular Disease Prevention?

Plant sterols/stanols inhibit cholesterol absorption in the gastrointestinal tract. The daily consumption of 2 g/day of plant sterols/stanols decreases low-density lipoprotein cholesterol (LDL-C) levels by approximately 10%. Plant sterols/stanols also reduce LDL-C levels when co-administered with statins, a fact useful for patients intolerable to high-dose statins. However, no randomized, controlled clinical trials have examined the clinical benefit of daily consumption of plant sterols/stanols. Furthermore, concerns regarding a possible atherogenic effect of plant sterols have been expressed. The use of plant sterols/stanols-enriched foods is a useful adjunct for hypercholesterolemic patients to achieve their LDL-C target, but we need more data to establish if this hypolipidemic effect results to reduced cardiovascular risk

LDL cholesterol estimation in patients with the metabolic syndrome

BACKGROUND: The Friedewald formula (LDL-F) for the estimation of low-density lipoprotein (LDL) cholesterol concentrations is the most often used formula in clinical trials and clinical practice. However, much concern has been raised as to whether this formula is applicable in all patient populations such as the presence of chylomicronaemia and/or hypertriglyceridaemia. The aim of the present study was to evaluate various LDL cholesterol calculation formulas as well as LDL cholesterol levels provided by the Lipoprint LDL System (LDL-L) in patients with the metabolic syndrome (MetSyn). RESULTS: LDL-F showed significant differences from other formulas in the total cohort, as well as in MetSyn individuals. This was not the case in nonMetSyn subjects, where LDL-F did not differ with other formulas, with the exception of one formula (LDL by Planella, LDL-P). The bias between LDL-F and other LDL estimation formulas were significantly higher in MetSyn subjects compared to nonMetSyn individuals, except for LDL-L which produced similar bias with LDL-F in both study groups. CONCLUSION: LDL-F seems to exhibit some limitations as far as the calculation of LDL-C levels in patients with the MetSyn is concerned. LDL-L might be more accurate in MetSyn subjects, but so far its use is limited for the estimation of small, dense LDL (sdLDL) cholesterol levels and mean LDL particle size for research purposes only

A Review of Time Courses and Predictors of Lipid Changes with Fenofibric Acid-Statin Combination

Fibrates activate peroxisome proliferator activated receptor α and exert beneficial effects on triglycerides, high-density lipoprotein cholesterol, and low density lipoprotein subspecies. Fenofibric acid (FA) has been studied in a large number of patients with mixed dyslipidemia, combined with a low- or moderate-dose statin. The combination of FA with simvastatin, atorvastatin and rosuvastatin resulted in greater improvement of the overall lipid profile compared with the corresponding statin dose. The long-term efficacy of FA combined with low- or moderate- dose statin has been demonstrated in a wide range of patients, including patients with type 2 diabetes mellitus, metabolic syndrome, or elderly subjects. The FA and statin combination seems to be a reasonable option to further reduce cardiovascular risk in high-risk populations, although trials examining cardiovascular disease events are missing

Modeling anthropometric indices in relation to 10-year (2002-2012) incidence of cardiovascular disease, among apparently healthy individuals:the ATTICA study

Aims: Body fat accumulation is implicated in the development of cardiovascular disease (CVD). Our objective was to explore potential associations between anthropometric indices and the 10-year CVD incidence in Greek adults without previous CVD. Methods: During 2001–2, we enrolled 3042 adults without CVD from the general population of Attica, Greece. In 2011–2, the 10-year study follow-up was performed, recording the CVD incidence in 1958 participants with baseline body mass index (BMI) ≥18.5 kg/m2. Results: The study 10-year CVD incidence was 15.8%, exhibiting a gradual increase according to the baseline body mass index (BMI) category. Baseline BMI ≥30 kg/m2 was related with significantly higher 10-year CVD risk compared to BMI <25 kg/m2, even after adjustment for age and other known CVD risk factors. Baseline BMI, waist circumference, waist-to-hip ratio, waist-to-height ratio and waist-to-hip-to-height ratio were independently associated with the 10-year CVD risk in multi-adjusted models. Gender-specific analyses showed that these associations were more evident in men compared to women, with baseline BMI exhibiting an independent association with the 10-year CVD incidence in men. Conclusions: Our results indicate that even simple anthropometric indices exhibit independent associations with CVD risk in a representative sample of the Greek general population without previous CVD

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome

Background: Obesity is a chronic condition, which constitutes an independent risk factor for themetabolic syndrome (MetS). The MetS increases the risk for cardiovascular disease (CVD).Objective: The present open-label randomized study evaluated the long-term effects of orlistat, fenofibrate and orlistat plus fenofibrate treatment on anthropometric variables, lipid profile, and carbohydrate metabolism, as well as on LDL and HDL phenotype and activities of atherosclerosis related enzymes, in overweight and obese patients [body mass index (BMI)>28 kg/m²] with MetS (defined by NCEP-ATPIII). Methods: Eighty-nine overweight and obese patients with MetS participated in the study. Patients were prescribed a low-calorie diet and randomized to receive for 6 months orlistat 120 mg TID (O group), micronized fenofibrate 200 mg/d (F group), or orlistat 120 mg TID plus micronized fenofibrate 200 mg/d (OF group). Results: Six patients dropped out, whereas eighty three patients completed the study, without any evidence of increased rate of adverse events in the combination group. After the first 3 months 43.5% of patients in the O group, 47.6% in the F group and 50% in the OF group no longer met the MetS diagnostic criteria (p28 kg/m²] με ΜετΣ (σύμφωνα με τον ορισμό της NCEP-ATPIII] η επίδραση της ορλιστάτης, της φαινοφιμπράτης και του συνδυασμού ορλιστάτης με φαινοφιμπράτη στις ανθρωπομετρικές και μεταβολικές παραμέτρους του ορού, το φαινότυπο των LDL και HDL σωματιδίων και τις ενεργότητες ενζύμων που συμμετέχουν στις διαδικασίες της αθηροσκλήρωσης. Υλικό-Μέθοδοι: Στη μελέτη συμμετείχαν 89 ασθενείς. Οι ασθενείς έλαβαν υποθερμιδική δίαιτα και στη συνέχεια τυχαιοποιήθηκαν σε φαινοφιμπράτη (Φ) 200 mg την ημέρα (29 ασθενείς) ή σε ορλιστάτη (O) 120 mg τρεις φορές την ημέρα (30 ασθενείς) ή σε συνδυασμό ορλιστάτης με φαινοφιμπράτη (ΟΦ) στις δόσεις που προαναφέρθηκαν (30 ασθενείς). Πριν την έναρξη της αγωγής και μετά από 6 μήνες θεραπείας εκτιμήθηκαν τα σωματομετρικά στοιχεία και προσδιορίσθηκαν οι μεταβολικές παράμετροι στον ορό των ασθενών. Αποτελέσματα: Από τους 89 ασθενείς που συμμετείχαν, έξι δεν ολοκλήρωσαν τη μελέτη. Έπειτα από 3 μήνες θεραπείας το 43.5% των ασθενών στην ομάδα Ο, το 47,6% στην ομάδα Φ και το 50% στην ομάδα ΟΦ δεν πληρούσε πλέον τα κριτήρια για τη διάγνωση του ΜετΣ. Η αρτηριακή πίεση, o δείκτης μάζας σώματος, το σωματικό βάρος, η περίμετρος μέσης, η ολική χοληστερόλη, η LDL χοληστερόλη, τα τριγλυκερίδια, η ινσουλίνη και ο δείκτης HOMA (homeostasis model assessment) μειώθηκαν σημαντικά σε όλες τις ομάδες μετά από έξι μήνες αγωγής. Οι μειώσεις του BMI, του σωματικού βάρους και της περιμέτρου μέσης ήταν σημαντικά μεγαλύτερες στις ομάδες Ο και ΟΦ σε σύγκριση με την ομάδα Φ (p<0.05). Στην ομάδα ΟΦ παρατηρήθηκε μεγαλύτερη ελάττωση της ολικής και της LDL χοληστερόλης σε σύγκριση με τις ομάδες Φ και Ο, καθώς και μεγαλύτερη μείωση των τριγλυκεριδίων σε σύγκριση με την ομάδα Ο (p<0.05). Η βελτίωση των παραμέτρων του μεταβολισμού των υδατανθράκων ήταν σημαντικά μεγαλύτερη στις ομάδες Ο και ΟΦ σε σύγκριση με την ομάδα Φ (p<0.05). Στο τέλος της εξάμηνης θεραπείας παρατηρήθηκε σημαντική μείωση του ποσοστού των ασθενών με φαινότυπο nonA, που χαρακτηρίζεται από την παρουσία sdLDL σωματιδίων. Η μείωση αυτή του ποσοστού των ασθενών με φαινότυπο nonA ήταν σημαντικά μεγαλύτερη μετά τη χορήγηση της Φ και του συνδυασμού ΟΦ σε σύγκριση με τη χορήγηση της Ο (p<0.05). Η χοληστερόλη των μικρών πυκνών LDL σωματιδίων (sdLDL) μειώθηκε σημαντικά σε όλες τις ομάδες. Παρατηρήθηκε ότι η μείωση της χοληστερόλης των sdLDL, καθώς και η αύξηση της μέσης και μέγιστης διαμέτρου των LDL σωματιδίων, ήταν σημαντικά μεγαλύτερες με τη χορήγηση της Φ και του συνδυασμού ΟΦ σε σύγκριση με τη χορήγηση της Ο (p<0.05). Επίσης, στις ομάδες Φ και ΟΦ παρατηρήθηκε σημαντικά μεγαλύτερη μείωση της ποσοστιαίας αναλογίας της χοληστερόλης των sdLDL στο σύνολο της LDL χοληστερόλης σε σύγκριση με την ομάδα Ο (p<0.05). Η συγκέντρωση της HDL-C μεταβλήθηκε σημαντικά μόνο στην ομάδα Φ (p<0.05). Στην ομάδα Ο αυξήθηκαν τα επίπεδα της χοληστερόλης των μεγάλων HDL σωματιδίων και μειώθηκαν τα επίπεδα της χοληστερόλης των μικρών HDL σωματιδίων. Στην ομάδα Φ παρατηρήθηκε αύξηση των επιπέδων της χοληστερόλης των μικρών HDL σωματιδίων, ενώ δεν παρατηρήθηκε καμία μεταβολή στα επίπεδα της χοληστερόλης των μικρών ή μεγάλων HDL σωματιδίων στην ομάδα του συνδυασμού. Τα επίπεδα της pre-beta1-HDL αυξήθηκαν σημαντικά σε όλες τις ομάδες της μελέτης, όμως αυτή η αύξηση ήταν σημαντικά μεγαλύτερη στην ομάδα ΟΦ. Η ενεργότητα του ενζύμου lipoprotein-associated phospholipase A₂ (LpPLA₂) στο πλάσμα μειώθηκε σημαντικά σε όλες τις ομάδες της μελέτης. H ενεργότητα του ενζύμου που συσχετίζεται με τα HDL σωματίδια (HDL-LpPLA₂) και έχει αντιαθηρογόνες ιδιότητες ελαττώθηκε στις ομάδες Φ και ΟΦ. Η ενεργότητα της PON1 δεν μεταβλήθηκε σημαντικά σε καμία ομάδα, όμως ο λόγος PON1/LDL-C αυξήθηκε σημαντικά περισσότερο στην ομάδα ΟΦ σε σύγκριση με τις ομάδες Ο και Φ. Η συγκέντρωση των τριγλυκεριδίων στο πλάσμα ελαττώθηκε σημαντικά σε όλες τις ομάδες της μελέτης. Τα επίπεδα στο πλάσμα της apoC-III μειώθηκαν σημαντικά σε όλες τις ομάδες (p<0.05), ενώ τα επίπεδα της apoC-II μειώθηκαν μόνο στις ομάδες Φ και ΟΦ. Η χορήγηση του συνδυασμού είχε αθροιστική επίδραση στα επίπεδα της apoC-II και της apoC-III. Η πολυπαραγοντική ανάλυση έδειξε ότι η μεταβολή των επιπέδων των τριγλυκεριδίων στην ομάδα Ο συσχετιζόταν θετικά με τα αρχικά επίπεδα των τριγλυκεριδίων και αρνητικά με τα αρχικά επίπεδα της apoC-II. Στην ομάδα Φ η μεταβολή των τριγλυκεριδίων συσχετιζόταν με τα αρχικά τους επίπεδα στο πλάσμα, καθώς και με τη μεταβολή των επιπέδων της apoC-III. Στην ομάδα ΟΦ η μεταβολή των τριγλυκεριδίων συσχετιζόταν θετικά με τα αρχικά τους επίπεδα στο πλάσμα και με τη μεταβολή των επιπέδων της apoC-III, ενώ συσχετιζόταν αρνητικά με τα αρχικά επίπεδα της apoC-II. Η υψηλής ευαισθησίας C-αντιδρώσα πρωτεΐνη (hsCRP) μειώθηκε σε όλες τις ομάδες, χωρίς όμως να παρατηρηθεί σημαντική διαφορά μεταξύ τους. Όσον αφορά τα επίπεδα της βισφατίνης στο πλάσμα, αυτά δεν μεταβλήθηκαν σε καμία από τις ομάδες της μελέτης. Συμπεράσματα: Ο συνδυασμός ορλιστάτης με φαινοφιμπράτη, σε σύγκριση με τη μονοθεραπεία, είχε ως αποτέλεσμα σημαντική βελτίωση των ανθρωπομετρικών καιμεταβολικών παραμέτρων σε υπέρβαρους και παχύσαρκους ασθενείς με μεταβολικό σύνδρομο

Combination drug treatment in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) includes simple steatosis, a benign condition, and non-alcoholic steatohepatitis, a condition that beyond TG accumulation also includes necroinflammation and fibrosis. An association between NAFLD and cardiovascular disease (CVD) has been recently suggested. NAFLD patients usually have an increased CVD risk profile. NAFLD is also associated with metabolic syndrome (MetS) and is considered as the hepatic component of MetS by some authors. Currently, the only established treatment of NAFLD is gradual weight loss. However, multifactorial treatment of NAFLD risk factors may be needed to reduce the increased CVD risk of NALFD patients. Drug combinations that include antiobesity drugs (such as orlistat and sibutramine) and target CVD risk factors may be a good approach to NAFLD patients. Our group has investigated the orlistat-fenofibrate combination treatment in obese patients with MetS and the orlistat-ezetimibe and sibutramine-antihypertensive combination treatment in obese patients with hyperlipidaemia with promising results in CVD risk factor reduction and improvement of liver function tests. Small studies give promising results but double-blind, randomized trials examining the effects of such multifactorial treatment in hard CVD endpoints in NAFLD patients are missing

Role of ezetimibe in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. Ezetimibe inhibits cholesterol absorption from the intestinal lumen into enterocytes. The molecular target of ezetimibe is the sterol transporter Niemann-Pick C1-like 1 protein (NPC1L1). Human NPC1L1 is abundantly expressed in the liver and may facilitate the hepatic accumulation of cholesterol. Ezetimibe exerts beneficial effects on several metabolic variables. Ezetimibe treatment attenuates hepatic steatosis and is beneficial in terms of NAFLD biochemical markers. The combination of ezetimibe with other interventions may also be beneficial in NAFLD patients. Our group investigated the ezetimibe-orlistat combination treatment in overweight and obese patients with hypercholesterolemia, with beneficial effects on NAFLD biochemical markers. These results are promising for patients with NAFLD, who usually have increased cardiovascular disease risk and need a multifactorial treatment. However, it should be mentioned that most results are from animal studies and, although modest elevation of liver function tests may raise the suspicion of NAFLD, none of these tests are sensitive to establish the diagnosis of NAFLD with great accuracy

Residual Cardiovascular Risk in Diabetic Patients: The Role of Fibrate Statin Combination

Patients with Type 2 diabetes mellitus (T2DM) have increased cardiovascular disease (CVD) risk. The use of statins significantly reduces the rate of CVD events but many T2DM patients, especially those with mixed dyslipidaemia (MD), have residual CVD risk. The use of fibrates, which improve triglyceride and high-density lipoprotein cholesterol levels, is beneficial for the treatment of patients with MD. Evidence from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study showed a possible beneficial effect on CVD events of the addition of fenofibrate (FF) to statin treatment in patients with T2DM and atherogenic MD. Furthermore, FF has been associated with slowing of the progression of early diabetic retinopathy. The combination of statin with a fibrate may improve the residual CVD risk and microvascular complications of patients with T2DM. However, trials specifically designed to assess the effects of fibrate-statin combination on cardiovascular outcomes in patients with T2DM are missing