Nutraceutical approaches to non-alcoholic fatty liver disease (NAFLD): A position paper from the International Lipid Expert Panel (ILEP).

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety.

Effects of statins on specialized pro-resolving mediators: An additional pathway leading to resolution of inflammation.

Statins are a class of cholesterol-lowering drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Anti-inflammatory and antioxidant properties, as well as improvement of endothelial function and plaque stabilization have also been proposed as parts of the pleiotropic effects of statins. Specialized pro-resolving mediators (SPMs) are endogenous lipid-derived molecules originating from ω-6 and ω-3 polyunsaturated fatty acids, such as arachidonic, docosahexaenoic and eicosapentaenoic acid that trigger and modulate the resolution of inflammation. Impaired SPM biosynthesis can lead to excessive or chronic inflammation and is implicated in the pathogenesis of several diseases. Exogenous administration of SPMs, including lipoxin, maresin, protectin, have been shown to improve both bacterial and viral infections, mainly in preclinical models, thus minimizing inflammation. Statin-triggered-SPM production in several in vitro and in vivo models may represent another anti-inflammatory pathway involving these drugs. This commentary discusses scientific publications on the effects of statins on SPMs and the resolution of inflammation process.

Non-alcoholic fatty liver disease and steatohepatitis: State of the art on effective therapeutics based on the gold standard method for diagnosis.

OBJECTIVE: The prevalence of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH) is increasing. NAFLD/NASH may progress to cirrhosis and hepatocellular carcinoma. However, most patients with NAFLD/NASH will die from a vascular cause. There are no approved pharmacological treatments for NASH/NAFLD. Many clinical trials have been, or are being, undertaken; however, the challenge is the assessment of the clinical endpoint. The main objective of this narrative review was to evaluate the efficacy of drugs used in clinical trials for the treatment of NAFLD/NASH that included a liver biopsy as the gold standard. METHODS: A literature search was conducted using 3 databases (PubMed, Scopus, and Google Scholar) to identify the clinical trials that included liver biopsy assessment before and after treatment. RESULTS: Interventional clinical trials (n = 33) involving 18 different agents, alone and in combination, were identified. Pioglitazone is the only agent that has shown consistent benefit and efficacy in clinical trials. Pentoxifylline, rosiglitazone, and ursodeoxycholic acid had both positive and negative results from clinical trials. There is also evidence for vitamin E and metformin. Other drugs, including bicyclol, cysteamine bitartrate, l-carnitine, liraglutide, obeticholic acid, oligofructose, selonsertib, silymarin, and statins, each had a single clinical study. CONCLUSIONS: In summary, the available molecules demonstrated a significant improvement in NASH and/or liver fibrosis in a minority of patients; thus, other drugs should be identified, possibly those acting on alternative pathophysiological pathways, and tested for their safety and efficacy.

Association of types of dietary fats and all-cause and cause-specific mortality: A prospective cohort study and meta-analysis of prospective studies with 1,164,029 participants.

BACKGROUND: Associations between dietary fats and mortality are unclear. METHODS: We evaluated the relationship between quartiles of total fat, mono-unsaturated (MUFA), polyunsaturated (PUFA) and saturated fatty acid (SFA) consumption, and all-cause, coronary heart disease (CHD), stroke, and type 2 diabetes (T2D)-associated mortality in 24,144 participants from the National Health and Nutrition Examination Surveys (NHANES) 1999-2010. We added our results to a meta-analysis based on searches until November 2018. RESULTS: In fully adjusted Cox-proportional hazard models in our prospective study, there was an inverse association between total fat (HR: 0.90, 95% confidence interval 0.82, 0.99, Q4 vs Q1) and PUFA (0.81, 0.78-0.84) consumption and all-cause mortality, whereas SFA were associated with the increased mortality (1.08, 1.04-1.11). In the meta-analysis of 29 prospective cohorts (n = 1,164,029) we found a significant inverse association between total fat (0.89, 0.82-0.97), MUFA (0.94, 0.89-0.99) and PUFA (0.89, 0.84-0.94) consumption and all-cause mortality. No association was observed between total fat and CVD (0.93, 0.80-1.08) or CHD mortality (1.03 0.99-1.09). A significant association between SFA intake and CHD mortality (1.10, 1.01-1.21) was observed. Neither MUFA nor PUFA were associated with CVD or CHD mortality. Inverse associations were observed between MUFA (0.80, 0.67-0.96) and PUFA (0.84, 0.80-0.90) intakes and stroke mortality. CONCLUSIONS: We showed differential associations of total fat, MUFA and PUFA with all-cause mortality, but not CVD or CHD mortalities. SFA was associated with higher all-cause mortality in NHANES and with CHD mortality in our meta-analysis. The type of fat intake appears to be associated with important health outcomes.

Nutraceutical support in heart failure: a position paper of the International Lipid Expert Panel (ILEP).

Heart failure (HF) is a complex clinical syndrome that represents a major cause of morbidity and mortality in Western countries. Several nutraceuticals have shown interesting clinical results in HF prevention as well as in the treatment of the early stages of the disease, alone or in combination with pharmacological therapy. The aim of the present expert opinion position paper is to summarise the available clinical evidence on the role of phytochemicals in HF prevention and/or treatment that might be considered in those patients not treated optimally as well as in those with low therapy adherence. The level of evidence and the strength of recommendation of particular HF treatment options were weighed up and graded according to predefined scales. A systematic search strategy was developed to identify trials in PubMed (January 1970 to June 2019). The terms 'nutraceuticals', 'dietary supplements', 'herbal drug' and 'heart failure' or 'left verntricular dysfunction' were used in the literature search. The experts discussed and agreed on the recommendation levels. Available clinical trials reported that the intake of some nutraceuticals (hawthorn, coenzyme Q10, l-carnitine, d-ribose, carnosine, vitamin D, probiotics, n-3 PUFA and beet nitrates) might be associated with improvements in self-perceived quality of life and/or functional parameters such as left ventricular ejection fraction, stroke volume and cardiac output in HF patients, with minimal or no side effects. Those benefits tended to be greater in earlier HF stages. Available clinical evidence supports the usefulness of supplementation with some nutraceuticals to improve HF management in addition to evidence-based pharmacological therapy.

The Role of n-3 Fatty Acids in Cardiovascular Disease: Back to the Future.

Cardiovascular disease (CVD) remains the major cause of death and disability worldwide, and residual risk after implementing all current therapies is still high. In this context, the latest (2016) European Cardiology Society/European Atherosclerosis Society guidelines recommend that triglyceride (TG)-lowering drugs should be used in high-risk patients with TGs levels >2.3 mmol/L (200 mg/dL), after lifestyle measures fail to lower them. After several neutral CVD outcome trials with n-3 fatty acids, the Reduction of Cardiovascular Events with EPA-Intervention Trial met its primary end point, that is, among patients with elevated TGs levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower in those who received 4 g of icosapent ethyl daily. In this review, we comment on the findings of previous and recently published randomized controlled CVD outcome trials assessing n-3 fatty acids supplementation. Both efficacy and safety, as well as future perspectives, are discussed.

Endothelial Dysfunction in Dyslipidaemia: Molecular Mechanisms and Clinical Implications.

The endothelium consists of a monolayer of Endothelial Cells (ECs) which form the inner cellular lining of veins, arteries, capillaries and lymphatic vessels. ECs interact with the blood and lymph. The endothelium fulfils functions such as vasodilatation, regulation of adhesion, infiltration of leukocytes, inhibition of platelet adhesion, vessel remodeling and lipoprotein metabolism. ECs synthesize and release compounds such as Nitric Oxide (NO), metabolites of arachidonic acid, Reactive Oxygen Species (ROS) and enzymes that degrade the extracellular matrix. Endothelial dysfunction represents a phenotype prone to atherogenesis and may be used as a marker of atherosclerotic risk. Such dysfunction includes impaired synthesis and availability of NO and an imbalance in the relative contribution of endothelialderived relaxing factors and contracting factors such as endothelin-1 and angiotensin. This dysfunction appears before the earliest anatomic evidence of atherosclerosis and could be an important initial step in further development of atherosclerosis. Endothelial dysfunction was historically treated with vitamin C supplementation and L-arginine supplementation. Short term improvement of the expression of adhesion molecule and endothelial function during antioxidant therapy has been observed. Statins are used in the treatment of hyperlipidaemia, a risk factor for cardiovascular disease. Future studies should focus on identifying the mechanisms involved in the beneficial effects of statins on the endothelium. This may help develop drugs specifically aimed at endothelial dysfunction.

Lipid-lowering agents for concurrent cardiovascular and chronic kidney disease.

Introduction: Cardiovascular disease (CVD) frequently co-exists with chronic kidney disease (CKD). Patients with concomitant CVD and CKD are at very high risk of CVD events. Areas covered: This narrative review discusses the use of hypolipidaemic drugs in patients with both CVD and CKD. Current guidelines are considered together with the evidence from randomised controlled clinical trials. Expert opinion: Statins are the first-line lipid-lowering therapy in patients with CVD and CKD. Some statins require dose adjustments based on renal function, whereas atorvastatin does not. Ezetimibe can be prescribed in patients with CVD and CKD, usually combined with a statin. According to current guidelines, statin±ezetimibe therapy should not be initiated, but should be continued, in dialysis-treated CKD patients. Fenofibrate (dose adjusted or contra-indicated according to renal function) and omega 3 fatty acids lower triglyceride levels; whether they also exert cardiorenal benefits in patients with CVD and CKD remains to be established. The use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, cholesterol-reducing nutraceuticals, bempedoic acid and apabetalone in such patients should be investigated. Patients with concomitant CVD and CKD should be treated, in terms of lipid-lowering therapy, early and intensively to minimize their very high risk and possibly, progression of CKD.

Safety of red yeast rice supplementation: A systematic review and meta-analysis of randomized controlled trials.

Recently, concerns regarding the safety of red yeast rice (RYR) have been raised after the publication of some case reports claiming toxicity. Since the previous meta-analyses on the effects of RYR were mainly focused on its efficacy to improve lipid profile and other cardiovascular parameters, we carried out a meta-analysis on safety data derived from the available randomized controlled clinical trials (RCTs). Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). Subgroups analyses were carried out considering the intervention (RYR alone or in association with other nutraceutical compounds), monacolin K administered daily dose (≤3, 3.1-5 or >5 mg/day), follow-up (>12 or ≤12 weeks), with statin therapy or statin-intolerance and type of control treatment (placebo or statin treatment). Data were pooled from 53 RCTs comprising 112 treatment arms, which included 8535 subjects, with 4437 in the RYR arm and 4303 in the control one. Monacolin K administration was not associated with increased risk of MuD (odds ratio (OR) = 0.94, 95% confidence interval (CI) 0.53,1.65). Moreover, we showed reduced risk of Non-MuD (OR = 0.59, 95%CI 0.50, 0.69) and SAE (OR = 0.54, 95%CI 0.46, 0.64) vs. control. Subgroups analyses confirmed the high tolerability profile of RYR. Furthermore, increasing daily doses of monacolin K were negatively associated with increasing risk of Non-MuD (slope: -0.10; 95%CI: -0.17, -0.03; two-tailed p < 0.01). Based on our data, RYR use as lipid-lowering dietary supplement seems to be overall tolerable and safe in a large kind of moderately hypercolesterolaemic subjects.

Effect of omega-3 supplements on plasma apolipoprotein C-III concentrations: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Apolipoprotein C-III (apo C-III) is a key regulator of triglycerides metabolism. The aim of this meta-analysis was to assess the effect of fish omega-3 polyunsaturated fatty acids (PUFAs) on apo C-III levels. METHODS: Randomized placebo-controlled trials investigating the impact of omega-3 on apo C-III levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters. RESULTS: This meta-analysis comprising 2062 subjects showed a significant reduction of apo C-III concentrations following treatment with omega-3 (WMD: -22.18 mg/L, 95% confidence interval: -31.61, -12.75, p < .001; I2: 88.24%). Subgroup analysis showed a significant reduction of plasma apo C-III concentrations by eicosapentaenoic acid (EPA) ethyl esters but not omega-3 carboxylic acids or omega-3 ethyl esters. There was a greater apo C-III reduction with only EPA as compared with supplements containing EPA and docosahexaenoic acid (DHA) or only DHA. A positive association between the apo C-III-lowering effect of omega-3 with baseline apo C-III concentrations and treatment duration was found. CONCLUSIONS: This meta-analysis has shown that omega-3 PUFAs might significantly decrease apo C-III. Key messages Omega-3 PUFA supplements significantly reduce apo C-III plasma levels, particularly in hypertriglyceridemic patients when applied in appropriate dose (more than 2 g/day) Triglyceride (TG)-lowering effect is achieved via peroxisome proliferator-activated receptors α Further studies should address the effect of omega-3 PUFAs alone or with other lipid-lowering drugs in order to provide a final answer whether apo C-III could be an important target for prevention of cardiovascular disease New apo C-III antisense oligonucleotide drug (Volanesorsen) showed to be promising in decreasing elevated TGs by reducing levels of apo C-III mRNA.

The Role of Nutraceuticals in Statin Intolerant Patients.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction.

Lipid-lowering activity of artichoke extracts: A systematic review and meta-analysis.

Artichoke is a component of the Mediterranean diet. Therefore, the aim of this meta-analysis was to determine if artichoke extract supplementation affected human lipid parameters. The search included PubMed-Medline, Scopus, Web of Science and Google Scholar databases up to March 28, 2017, to identify RCTs investigating the impact of artichoke extracts on plasma lipid levels. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. Meta-analysis of data from 9 trials including 702 subjects suggested a significant decrease in plasma concentrations of total cholesterol (WMD: -17.6 mg/dL, 95%CI: -22.0, -13.3, p < 0.001), Low Density Lipoprotein-Cholesterol (LDL-C; WMD: -14.9 mg/dL, 95%CI: -20.4, -9.5, p = 0.011) and triglycerides (WMD: -9.2 mg/dL, 95%CI: -16.2, -2.1, p = 0.011). No significant alteration in plasma High Density Lipoprotein-Cholesterol (HDL-C) concentrations was observed (WMD: 1.0 mg/dL, 95%CI: -1.1, 3.1, p = 0.333). A significant association between the LDL-lowering effect of artichoke and baseline LDL-C concentrations (slope: -0.170; 95%CI: -0.288, 0.051; p = 0.005) was observed. Thus, supplementation with artichoke extract was associated with a significant reduction in both total and LDL-C, and triglycerides, suggesting that supplementation may be synergistic with lipid-lowering therapy in patients with hyperlipidemia.

Dietary patterns, plasma vitamins and Trans fatty acids are associated with peripheral artery disease.

BACKGROUND: To investigate the association between dietary patterns (DP), plasma vitamins and trans fatty acids (TFAs) with the likelihood of peripheral artery disease (PAD). METHODS: National Health and Nutrition Examination Survey (NHANES) data for the years 1999-2002 were used. PAD was diagnosed by ankle brachial index assessment. Plasma concentrations of vitamins were measured using high performance liquid chromatography. Vitamin D levels were measured by radioimmunoassay. Analysis of covariance, principal components analysis (PCA) and adjusted logistic regression were applied, accounting for the survey design and sample weights. RESULTS: Of the 4864 eligible participants, 2482 (51.0%) were men and 269 (5.5%) had prevalent PAD. PCA uncovered three DPs which accounted for 56.8% of the variance in dietary nutrients consumption including DP1 (fatty acids and cholesterol), DP2 (minerals, vitamins and fiber), and DP3 (polyunsaturated fatty acids [PUFA]). PAD patients had a significantly higher serum concentrations of trans 9-octadecenoic acid and trans 9, trans 12-octadienoic acid as well as lower plasma levels of vitamin D, retinol, retinyl stearate and retinyl palmitate (p < 0.001 for all comparisons). In models adjusted for age, race, diabetes, cholesterol, hypertension, smoking and energy intake, individuals in the highest quartile of the DP1 had higher odds for PAD compared with those in the lowest quartile [(odds ratio (OR): 6.43, 95% confidence interval (CI): 2.00-20.63 p < 0.001], while those in the highest quartile of DP2 and DP3 had lower odds of PAD relative to those in the lowest quartile (OR:0.28, OR:0.44, respectively; p < 0.001 for both comparisons). CONCLUSION: We found that quality of diet, plasma vitamins and TFAs are associated with the likelihood of PAD. If confirmed in prospective studies, the possibility that dietary factors, plasma vitamins and TFAs might be valuable for preventing or delaying the clinical progression of PAD, should be investigated in intervention trials.

Dietary food patterns and glucose/insulin homeostasis: a cross-sectional study involving 24,182 adult Americans.

AIM: To investigate the association of major dietary patterns with glucose and insulin homeostasis parameters in a large American sample. The association between dietary patterns (DP) derived via principal components analysis (PCA), with glucose/insulin homeostasis parameters was assessed. The likelihood of insulin resistance (IR) across the DPs quarters was also explored. METHOD: The United States National Health and Nutrition Examination Survey (NHANES) participants during 2005-2012 were included if they underwent measurement of dietary intake as well as glucose and insulin homeostasis parameters. Analysis of covariance (ANCOVA) and adjusted logistic and linear regression models were employed to account for the complex survey design and sample weights. RESULTS: A total of 24,182 participants were included; 48.9% (n = 11,815) were men. Applying PCA revealed three DP (56.8% of variance): the first was comprised mainly of saturated fat (SFA), total fat, mono-unsaturated fatty acids (MUFA) and carbohydrate (CHO); the second is highly enriched with vitamins, trace elements and dietary fiber; and the third was composed of polyunsaturated fatty acids (PUFA), cholesterol and protein. Among the total population, after adjustment for age, sex, race, C-reactive protein, smoking, and physical activity, glucose homeostasis factors, visceral adiposity index and lipid accumulation product improved across the quarters of the first and third DP; and a reverse pattern with the second DP. The same trend was observed for the non-diabetic subjects. Moreover, subjects with higher adherence to the first and third DP had higher likelihood for developing IR, whereas there was a lower likelihood for the second DP. CONCLUSION: This study shows that the DP heavily loaded with CHO, SFA, PUFA, protein, total fat and MUFA as well as high-cholesterol-load foods is associated with impaired glucose tolerance; in contrast, the healthy pattern which is high in vitamins, minerals and fiber may have favourable effects on insulin sensitivity and glucose tolerance.

Lipid-lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel.

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting.

Lipid-modifying effects of krill oil in humans: systematic review and meta-analysis of randomized controlled trials.

Context: Some experimental and clinical trials have shown that krill oil, extracted from small red crustaceans, might be an effective lipid-modifying agent, but the evidence is not conclusive. Objective: The effect of krill oil supplements on plasma lipid concentrations was assessed through a systematic review of the literature and a meta-analysis of available randomized controlled trials. Data sources: PubMed and Scopus were searched up to March 25, 2016, to identify RCTs investigating the effect of krill oil supplements on plasma lipids. Study selection: Randomized controlled trials that investigated the impact of at least 2 weeks of supplementation with krill oil on plasma/serum concentrations of at least one of the main lipid parameters (ie, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides) and that reported sufficient information on plasma/serum lipid levels at baseline and at the end of study in both krill oil and control groups were eligible for inclusion. Data extraction: Two reviewers independently extracted the following data: first author's name, year of publication, study location, study design, number of participants in the krill oil and control groups, dosage of krill oil, type of control allocation, treatment duration, demographic characteristics of study participants, and baseline and follow-up plasma concentrations of lipids. Effect size was expressed as the weighted mean difference (WMD) and 95% confidence interval (95%CI). Results: Meta-analysis of data from 7 eligible trials (14 treatment arms) with 662 participants showed a significant reduction in plasma concentrations of low-density lipoprotein cholesterol (WMD, -15.52 mg/dL; 95%CI, -28.43 to -2.61; P = 0.018) and triglycerides (WMD, -14.03 mg/dL; 95%CI, -21.38 to -6.67; P < 0.001) following supplementation with krill oil. A significant elevation in plasma concentrations of high-density lipoprotein cholesterol was also observed (WMD, 6.65 mg/dL; 95%CI, 2.30 to 10.99; P = 0.003), while a reduction in plasma concentrations of total cholesterol did not reach statistical significance (WMD, -7.50 mg/dL; 95%CI, -17.94 to 2.93; P = 0.159). Conclusion: Krill oil supplementation can reduce low-density lipoprotein cholesterol and triglycerides. Additional clinical studies with more participants are needed to assess the impact of krill oil supplementation on other indices of cardiometabolic risk and on the risk of cardiovascular outcomes.

Homocysteine and Non-Cardiac Vascular Disease.

Elevated homocysteine (Hcy) levels are predictors of cardiovascular disease (CVD). Hyperhomocysteinemia has also been associated with total and CVD mortality. However, whether Hcy is just a marker or plays a causal role in CVD remains to be elucidated. In this narrative review, we discuss the associations between Hcy and non-cardiac vascular diseases, namely stroke, peripheral artery disease (PAD), carotid artery disease, chronic kidney disease (CKD), atherosclerotic renal artery stenosis (ARAS), abdominal aortic aneurysm (AAA) and erectile dysfunction (ED). The effects of several drugs on Hcy levels are also considered. Folic acid, vitamin B6 and B12 supplementation can significantly decrease circulating Hcy concentrations but their effects on CVD risk reduction are conflicting. No current guidelines recommend the routine screening of Hcy levels in patients with non-cardiac vascular diseases. Therefore, further research is needed to elucidate the use of Hcy in the clinical practice.

Lipid-modifying effects of nutraceuticals: An evidence-based approach.

The present review provides an up-to-date summary of the findings on the lipid-lowering effects of the most important nutraceuticals and functional foods. Based on current knowledge, nutraceuticals might exert significant lipid-lowering, and their use has several advantages: A number of important questions remain to be addressed, including whether longer durations of therapy would result in a better response and the exact safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. Additionally, data regarding the effects of nutraceutical supplementation on the incidence of cardiovascular outcomes are lacking, and it is not clear whether additional lipid lowering by nutraceuticals can modify the residual cardiovascular risk that remains after statin therapy.