An insight on the future therapeutic application potential of Stevia rebaudiana Bertoni for atherosclerosis and cardiovascular diseases.

Stevia rebaudiana Bertoni is a native plant to Paraguay. The extracts have been used as a famous sweetening agent, and the bioactive components derived from stevia possess a broad spectrum of therapeutical potential for various illnesses. Among its medicinal benefits are anti-hypertensive, anti-tumorigenic, anti-diabetic, and anti-hyperlipidemia. Statins (3-hydro-3-methylglutaryl-coenzyme A reductase inhibitor) are a class of drugs used to treat atherosclerosis. Statins are explicitly targeting the HMG-CoA reductase, an enzyme in the rate-limiting step of cholesterol biosynthesis. Despite being widely used in regulating plasma cholesterol levels, the adverse effects of the drug are a significant concern among clinicians and patients. Hence, steviol glycosides derived from stevia have been proposed as an alternative in replacing statins. Diterpene glycosides from stevia, such as stevioside and rebaudioside A have been evaluated for their efficacy in alleviating cholesterol levels. These glycosides are a potential candidate in treating and preventing atherosclerosis provoked by circulating lipid retention in the sub-endothelial lining of the artery. The present review is an effort to integrate the pathogenesis of atherosclerosis, involvement of lipid droplets biogenesis and its associated proteins in atherogenesis, current approaches to treat atherosclerosis, and pharmacological potential of stevia in treating the disease.

Therapeutic potential of targeting intestinal bitter taste receptors in diabetes associated with dyslipidemia.

Intestinal release of incretin hormones after food intake promotes glucose-dependent insulin secretion and regulates glucose homeostasis. The impaired incretin effects observed in the pathophysiologic abnormality of type 2 diabetes have triggered the pharmacological development of incretin-based therapy through the activation of glucagon-like peptide-1 (GLP-1) receptor, including GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 (DPP4) inhibitors. In the light of the mechanisms involved in the stimulation of GLP-1 secretion, it is a fundamental question to explore whether glucose and lipid homeostasis can be manipulated by the digestive system in response to nutrient ingestion and taste perception along the gastrointestinal tract. While glucose is a potent stimulant of GLP-1 secretion, emerging evidence highlights the importance of bitter tastants in the enteroendocrine secretion of gut hormones through activation of bitter taste receptors. This review summarizes bitter chemosensation in the intestines for GLP-1 secretion and metabolic regulation based on recent advances in biological research of bitter taste receptors and preclinical and clinical investigation of bitter medicinal plants, including bitter melon, hops strobile, and berberine-containing herbs (e.g. coptis rhizome and barberry root). Multiple mechanisms of action of relevant bitter phytochemicals are discussed with the consideration of pharmacokinetic studies. Current evidence suggests that specific agonists targeting bitter taste receptors, such as human TAS2R1 and TAS2R38, may provide both metabolic benefits and anti-inflammatory effects with the modulation of the enteroendocrine hormone secretion and bile acid turnover in metabolic syndrome individuals or diabetic patients with dyslipidemia-related comorbidities.

Clinical study of Dendrobium Nobile Lindl intervention on patients with metabolic syndrome.

BACKGROUND: Metabolic syndrome (MS) is a common chronic disease in modern society, and the etiology and pathogenesis of it is still unknown. For its main symptoms: disorder of glucose and lipid metabolism, the usual treatment is applying statin and hypoglycemic drugs. Comparing to the long-term application of these drugs which may cost great side effects, Dendrobium Nobile Lindl (DN) has been proved for its hypoglycemic and lipid-lowering effects without obvious side effects. So this trial is aim to evaluate the efficacy and safety of DN-powder in intervention of MS, and to explore the mechanism of action of DN through multi-group correlation analysis. METHODS: This clinical trial is a single-arm, non-randomized, open, exploratory trial. A total of 30 participants who are suffering from MS will be assigned into therapy group (n = 30). The treatment course will last for 8 weeks, and a follow-up period for 4 weeks. The participants will receive DN-powder for 6 g, twice a day during the study period. The primary outcome will be the change of lipid and glucose metabolism. Other outcomes will be the body weight and body mass index (BMI) which will be assessments record in every 2 weeks. Participants who quit the trial due to untolerable reactions or uncontrollable conditions will enter into a follow-up period after the last treatment. All participants will enter into a follow-up period for 4 weeks after the last treatment. Adverse events will be recorded during the whole study. DISCUSSION: The results of the trial are aim to provide evidence of the safety and efficacy of DN-powder in intervention of MS which may be potential to become an important alternative therapy for certain patients. TRIAL REGISTRATION: It has been registered at http://www.chictr.org.cn/showprojen.aspx?proj=55914. (Identifier: ChiCTR2000034550), Registered 9 July 2020.

Effect of DLT-SML on Chronic Stable Angina Through Ameliorating Inflammation, Correcting Dyslipidemia, and Regulating Gut Microbiota.

ABSTRACT: Chronic stable angina (CSA) is caused by coronary atherosclerosis. The gut microbiota (GM) and their metabolite trimethylamine-N-oxide (TMAO) levels are associated with atherosclerosis. Danlou tablet (DLT) combined with Salvia miltiorrhiza ligustrazine (SML) injection has been used to treat CSA. This study aims to investigate how DLT combined with SML (DLT-SML) regulates serum lipids, inflammatory cytokines, GM community, and microbial metabolite in patients with CSA. In this study, 30 patients with CSA were enrolled in the DLT-SML group, and 10 healthy volunteers were included in the healthy control group. The patients in the DLT-SML group were subdivided as the normal total cholesterol (TC) group and high-TC group according to their serum TC level before treatment. Blood samples were collected to investigate the (1) lipid content, including triglyceride (TG), TC, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, (2) fasting blood glucose (Glu), (3) inflammatory cytokines, including interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α), and (4) gut-derived metabolite, including lipopolysaccharides and TMAO level. GM composition was analyzed by sequencing 16S rRNA of fecal samples. Results showed that DLT-SML significantly decreased serum TG, TC, low-density lipoprotein cholesterol, IL-1ß, TNF-α, and TMAO levels of patients with CSA. DLT-SML increased the abundance of Firmicutes and decreased Proteobacteria, which were significantly lower or higher in patients with CSA, respectively, compared with the healthy control group. In particular, DLT-SML increased the microbial diversity and decreased Firmicutes/Bacteroidetes ratio of patients with high-TC. The abundance of Sarcina, Anaerostipes, Streptococcus, Weissella, and Erysipelatoclostridium was decreased, whereas Romboutsia, Faecalibacterium, and Subdoligranulum were increased by DLT-SML treatment in patients with CSA. These findings indicated that DLT-SML improved patients with CSA by ameliorating dyslipidemia profile, decreasing the circulating inflammatory cytokines, and regulating the GM composition and their metabolites.

Personalized medicine in lipid-modifying therapy.

The choice of lipid-modifying treatment is largely based on the absolute level of cardiovascular risk and baseline lipid profile. Statins are the first-line treatment for most patients requiring reduction of low-density-lipoprotein cholesterol (LDL-C) and ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors can be added to reach LDL-C targets. Statins have some adverse effects that are somewhat predictable based on phenotypic and genetic factors. Fibrates or omega-3 fatty acids can be added if triglyceride levels remain elevated. The RNA-targeted therapeutics in development offer the possibility of selective liver targeting for specific lipoproteins such as lipoprotein(a) and long-term reduction of LDL-C with infrequent administration of a small-interfering RNA may help to overcome the problem of adherence to therapy.

Effectiveness and safety of Hwangryunhaedok-Tang (Huang-Lian-Jie-Du-Tang, Oren-Gedoku-to) for dyslipidemia: A protocol for a PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Recent experimental and clinical studies have suggested that Hwangryunhaedok-tang (HHT), an herbal formula, could improve the lipid profiles in patients with dyslipidemia. This systematic review aimed to evaluate the effectiveness and safety of HHT monotherapy or adjunctive HHT therapy with conventional lipid-lowering drugs in managing dyslipidemia. METHODS: Twelve English, Korean, Chinese, and Japanese databases were comprehensively searched from their inception to January 2020. Randomized controlled trials (RCTs) using HHT monotherapy or adjunctive HHT therapy for dyslipidemic patients were included. The primary outcome was the low-density lipoprotein cholesterol (LDL-C) level. Descriptive analyses of participant details, interventions, and outcomes were conducted and where appropriate data were available, a meta-analysis was performed and presented as a risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). The risk of bias was assessed using the Cochrane risk of bias tool and the quality of evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Nine RCTs with 536 participants were included. In comparison with lipid-lowering drugs alone, HHT as an adjunctive therapy to lipid-lowering drugs or as a monotherapy showed significantly superior (MD -1.15 mmol/L, 95% CI -1.25 to -1.05) or inferior results (MD 0.23 mmol/L, 95% CI 0.09 to 0.38), respectively, for LDL-C levels. The incidence of adverse events was significantly lower when HHT was used in addition to lipid-lowering drugs, in comparison to that with lipid-lowering drugs alone. No serious adverse events were reported in the HHT group. Most included studies showed a high risk of performance bias and the quality of evidence was rated generally "low" because of the high risk of bias and inconsistency or imprecision of the meta-analysis results. CONCLUSION: Current evidence suggests that HHT may be beneficial for patients with dyslipidemia and may reduce the adverse events associated with lipid-lowering drugs. However, due to the high risk of bias of the included studies and low quality of evidence for the main findings, no definitive conclusion could be reached. Further rigorous, high-quality, and placebo-controlled RCTs should be conducted to assess the efficacy of HHT. TRIAL REGISTRATION NUMBER: PROSPERO CRD42020164563.

Lipid-lowering nutraceuticals update on scientific evidence.

: Cardiovascular diseases (CVDs) are the main cause of mortality worldwide. Risk factors of CVD can be classified into modifiable (smoking, hypertension, diabetes, hypercholesterolemia) through lifestyle changes or taking drug therapy and not modifiable (age, ethnicity, sex and family history). Elevated total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels have a lead role in the development of coronary heart disease (CHD), while high levels of high-density lipoprotein-cholesterol (HDL-C) seem to have a protective role.The current treatment for dyslipidemia consists of lifestyle modification or drug therapy even if not pharmacological treatment should be always considered in addition to lipid-lowering medications.The use of lipid-lowering nutraceuticals alone or in association with drug therapy may be considered when the atherogenic cholesterol goal was not achieved.These substances can be classified according to their mechanisms of action into natural inhibitors of intestinal cholesterol absorption, inhibitors of hepatic cholesterol synthesis and enhancers of the excretion of LDL-C. Nevertheless, many of them are characterized by mixed or unclear mechanisms of action.The use of these nutraceuticals is suggested in individuals with borderline lipid profile levels or with drug intolerance, but cannot replace standard lipid-lowering treatment in patients at high, or very high CVD risk.Nutraceuticals can also have vascular effects, including improvement in endothelial dysfunction and arterial stiffness, as well as antioxidative properties. Moreover, epidemiological and clinical studies reported that in patients intolerant of statins, many nutraceuticals with demonstrated hypolipidemic effect are well tolerated.

Effects of dehydroepiandrosterone (DHEA) supplementation on the lipid profile: A systematic review and dose-response meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Dehydroepiandrosterone (DHEA) supplementation has gained attention in individuals with adrenal insufficiency, and as a tool for increasing androgens and estrogens whereby is proposed to improve the accretion of muscle and bone mass. However, DHEA supplementation has demonstrated negative effects on the lipid profile and, thus, we aimed to analyze the body of evidence in this regard. METHODS AND RESULTS: A systematic review and dose-response meta-analysis of randomized controlled trials (RCTs) was performed employing in Scopus, PubMed/Medline, Web of Science, Embase and Google Scholar, then including relevant articles that addressed the effects of DHEA supplementation on the lipid profile, up to February 2020. Combined findings were generated from 23 eligible articles. Hence, total cholesterol (TC) (weighted mean difference (WMD): -3.5 mg/dl, 95% confidence interval (CI): -8.5 to 1.6)), low-density lipoprotein-cholesterol (LDL-C) (WMD: 0.34 mg/dl, 95% CI: -3 to 3.7) and triglycerides (TG) levels (WMD: -2.85 mg/dl, 95% CI: -9.3 to 3.6) did not alter in DHEA group compared to the control, but HDL-C levels significantly reduced in DHEA group (WMD: -3.1 mg/dl, 95% CI: -4.9 to -1.3). In addition, a significant reduction in HDL-C values was observed in studies comprising women (WMD: -5.1 mg/dl, 95% CI: -7.2 to -3) but not in males (WMD: 0.13 mg/dl, 95% CI: -1.4 to 1.7). CONCLUSIONS: Overall, supplementation with DHEA did not change circulating values of TC, LDL-C and TG, whereas it may decrease HDL-C levels. Further long-term RCTs are required to investigate the effects of DHEA particularly on major adverse cardiac events.

A review of saponin intervention in metabolic syndrome suggests further study on intestinal microbiota.

Metabolic syndrome (MetS) is a series of symptoms including insulin resistance, obesity, dyslipidemia, elevated fasting blood glucose levels, and hepatic steatosis. As a key criterion in MetS, the onset of insulin resistance is related to abnormal levels of circulating free fatty acids and adipokines. It has been discovered in recent years that metabolites and pathogen-associated molecular patterns of intestinal/gut microbiota are also important factors that cause insulin resistance and MetS. Saponins are the main components of many botanicals and traditional Chinese medicines (TCMs), such as ginseng, platycodon, licorice, and alfalfa. They have poor bioavailability, but can be transformed into secondary glycosides and aglycones by intestinal microbiota, further being absorbed. Based on in vivo and in vitro data, we found that saponins and their secondary metabolites have a preventive effect on MetS, and the effective targets are distributed in the intestine and other organs in human body. Intestinal targets involve pancreatic lipase, dietary cholesterol, and intestinal microbiota. Other targets include central appetite, nuclear receptors such as PPAR and LXR, AMPK signaling pathway and adipokines levels, etc. In view of the poor bioavailability of saponins, it is inferred that targets for prototype-saponins to interfere with MetS is mainly located in the intestine, and the activation of other targets may be related to secondary glycosides and aglycones transformed from saponins by intestinal flora. We suggest that the role of intestinal microbiota in saponin intervention in MetS should be further investigated.

Short-Term Efficacy (at 12 Weeks) and Long-Term Safety (up to 52 Weeks) of Omega-3 Free Fatty Acids (AZD0585) for the Treatment of Japanese Patients With Dyslipidemia　- A Randomized, Double-Blind, Placebo-Controlled, Phase III Study.

BACKGROUND: This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia.Methods and Results:In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P<0.0001 for both AZD0585 doses vs. placebo). No clinically significant changes from baseline to the 12-week endpoint in total cholesterol, LDL-C, and LDL-C/apolipoprotein (Apo) B were found with AZD0585. High-density lipoprotein cholesterol (HDL-C) was slightly increased and very low-density lipoprotein cholesterol, non-HDL-C, ApoC-II, and ApoC-III were decreased with AZD0585 compared with placebo at the 12-week endpoint. Lipid profiles up to Week 52 were consistent with those up to the 12-week endpoint. No clinically important safety concerns were raised. CONCLUSIONS: AZD0585 significantly decreased serum triglyceride levels compared with placebo at the 12-week endpoint and was generally safe and well tolerated in Japanese patients with dyslipidemia.

An overview of statin-induced myopathy and perspectives for the future.

Introduction: Statins remain the most commonly prescribed lipid-lowering drug class for the treatment of atherosclerotic cardiovascular disease. Their well-recognized side effects are known as statin-associated muscle symptom (SAMS). Some advances in this field have been made in recent years, but the understanding of the mechanisms has lagged. Investigating the specific role of the anti-HMGCR autoantibody, pharmacokinetic genetic variants, characterization of the known phenotypes of statin toxicity, in relation to clinical markers of disease, is of high importance.Areas covered: We summarized currently available findings (on PubMed) related to SAMS and discussed the therapeutic approaches, risk factors, drug interactions, potential novel systems, algorithms and biomarkers for SAMS detection. CoQ10 supplementation has been suggested as a complementary approach to manage SAMS, while vitamin D levels may be useful for both the diagnosis and management.Expert Opinion/Commentary: Further studies might help to understand the easiest way to diagnose SAMS, suitable prevention and an effective non-statin therapy. This review sheds new light on the future directions in both research and clinical practice, which will help with rapid risk assessment, identification of the SAMS risk factors in order to decrease the incidence of statins' adverse effects, and the most effective therapy.

Effects of Xuezhitong in Patients with Hypertriglyceridemia: a Multicentre, Randomized, Double-Blind, Double Simulation, Positive Drug and Placebo Parallel Control Study.

BACKGROUD: Xuezhitong (XZT) is an extract of Allium macrostemon Bunge that has lipid-lowering properties. OBJECTIVE: To evaluate the effects of XZT on lipids in subjects with hypertriglyceridemia (HTG) without severe dyslipidaemia. METHODS: A total of 358 subjects with HTG were enrolled and randomly assigned to receive XZT (2700 mg daily), xuezhikang (XZK) (1200 mg daily) or placebo. The primary endpoint was the reduction or percent reduction in the TG level over 12 weeks of treatment. RESULTS: At the 12-week follow-up, a reduction in the TG level from baseline was observed in both groups, but the XZT and XZK groups demonstrated a significantly greater reduction than the placebo group (30.77%, 24.02% vs 11.59%, P < 0.0167); 70.54% of subjects in the XZT group and 62.30% of subjects in the XZK group demonstrated reductions in TG levels of at least 20%, compared with 41.67% of the subjects in the placebo group (P < 0.0167). Treatment with XZT capsules also demonstrated superior performance compared with the placebo with respect to the control of lipids (17.97% vs 5.00%), total cholesterol (TC) (14.18% vs 3.89%), low-density lipoprotein cholesterol (LDL-C) (17.98% vs 2.95%), and high-density lipoprotein cholesterol (HDL-C) (21.47% vs 2.16%). Daily use of XZT for 12 weeks resulted in statistically significant (65.22% vs 38.30%, 25.00%; P < 0.0167) and clinically meaningful increases in HDL-C levels by ≥4 mg/dl compared with XZK and placebo. XZT was safe and well tolerated; the safety and tolerability profiles were similar across treatment groups. No subject experienced myopathy or markedly elevated liver transaminases or creatine kinase. CONCLUSIONS: XZT significantly reduced TG levels and was well tolerated. Longer-term studies in more diverse patient populations are needed to corroborate these findings. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn Identifier: ChiCTR1900025854.

Emerging Mechanisms of Cardiovascular Protection for the Omega-3 Fatty Acid Eicosapentaenoic Acid.

Patients with well-controlled LDL (low-density lipoprotein) levels still have residual cardiovascular risk associated with elevated triglycerides. Epidemiological studies have shown that elevated fasting triglyceride levels associate independently with incident cardiovascular events, and abundant recent human genetic data support the causality of TGRLs (triglyceride-rich lipoproteins) in atherothrombosis. Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), lower blood triglyceride concentrations but likely exert additional atheroprotective properties at higher doses. Omega-3 fatty acids modulate T-cell differentiation and give rise to various prostaglandins and specialized proresolving lipid mediators that promote resolution of tissue injury and inflammation. The REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) with an EPA-only formulation lowered a composite of cardiovascular events by 25% in patients with established cardiovascular disease or diabetes mellitus and other cardiovascular risk factors. This clinical benefit likely arises from multiple molecular mechanisms discussed in this review. Indeed, human plaques readily incorporate EPA, which may render them less likely to trigger clinical events. EPA and DHA differ in their effects on membrane structure, rates of lipid oxidation, inflammatory biomarkers, and endothelial function as well as tissue distributions. Trials that have evaluated DHA-containing high-dose omega-3 fatty acids have thus far not shown the benefits of EPA alone demonstrated in REDUCE-IT. This review will consider the mechanistic evidence that helps to understand the potential mechanisms of benefit of EPA.

Effects of spirulina on weight loss and blood lipids: a review.

Spirulina, a cyanobacteria commonly referred to as a blue-green algae, is one of the oldest lifeforms on Earth. Spirulina grows in both fresh and saltwater sources and is known for its high protein and micronutrient content. This review paper will cover the effects of spirulina on weight loss and blood lipids. The currently literature supports the benefits of spirulina for reducing body fat, waist circumference, body mass index and appetite and shows that spirulina has significant benefits for improving blood lipids.

Effects of Lipid Lowering Drugs on Arterial Stiffness: One More Way to Reduce Cardiovascular Risk?

Arterial stiffness (AS) is considered an independent predictor of cardiovascular disease (CVD) events. Among lipid lowering drugs, statins have a beneficial effect on AS, independent of their hypolipidaemic effect. Based on 3 meta-analyses and other studies, this effect is compound- and doserelated. Potent statins at high doses are more effective than less powerful statins. Ezetimibe (± statin) also seems to decrease AS in patients with dyslipidaemia. Fibrates have no effect on AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have data that beneficially affect all AS risk factors, suggesting a beneficial effect on artery compliance. However, there is no direct measurement of their effect on AS indices. In patients with dyslipidaemia, prescribing high dose statins (± ezetimibe) will not only decrease low-density lipoprotein cholesterol levels but also improve AS (in addition to other effects). This effect on AS may contribute to the observed reduction in vascular events.

Randomized Study of Providing Evidence Context to Mitigate Physician Misinterpretation Arising From Off-Label Drug Promotion.

BACKGROUND: Recent court decisions have thrown into question the Food and Drug Administration's rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians' beliefs about drug efficacy. METHODS AND RESULTS: In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%, P<0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, -6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, -24% to 7%]). CONCLUSIONS: Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers' knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.

Impact of phytosterol supplementation on plasma lipoprotein(a) and free fatty acid (FFA) concentrations: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Although some earlier studies have indicated the effect of phytosterol (PS) supplementation on serum lipoprotein(a) (Lp(a)) and free fatty acid (FFA) concentration, findings are still conflicting. We aimed to assess the impact of PS supplementation on serum Lp(a) and FFA concentration through a systematic review and meta-analysis of available RCTs. METHODS AND RESULTS: We performed a systematic search of all available RCTs conducted up to 21 February 2019 in the following databases: PubMed, Scopus, and Cochrane. The choice of fixed- or random-effect model for analysis was determined according to the I2 statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). Pooling of 12 effect sizes from seven articles revealed a significant reduction of Lp(a) levels following PS supplementation (MD: -0.025 mg/dl, 95% CI: -0.045, -0.004, p = 0.017) without significant heterogeneity among the studies (I2 = 0.0%, p = 0.599). Also, PS supplementation significantly lowered FFA (MD: -0.138 mg/dl, 95% CI: -0.195, -0.081, p = 0.000) without significant heterogeneity among the studies (I2 = 0.0%, p = 0.911). The results for meta-regression and sensitivity analysis were not significant. CONCLUSION: The meta-analysis suggests that oral PS supplementation could cause a significant reduction in serum Lp(a) and FFA.

Efficacy of l-carnitine supplementation for management of blood lipids: A systematic review and dose-response meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: l-carnitine has an important role in fatty acid metabolism and could therefore act as an adjuvant agent in the improvement of dyslipidemia. The purpose of present systematic review and meta-analysis was to critically assess the efficacy of l-carnitine supplementation on lipid profiles. METHODS AND RESULTS: We performed a systematic search of all available randomized controlled trials (RCTs) in the following databases: Scopus, PubMed, ISI Web of Science, The Cochrane Library. Mean difference (MD) of any effect was calculated using a random-effects model. In total, there were 55 eligible RCTs included with 58 arms, and meta-analysis revealed that l-carnitine supplementation significantly reduced total cholesterol (TC) (56 arms-MD: -8.53 mg/dl, 95% CI: -13.46, -3.6, I2: 93%), low-density lipoprotein-cholesterol (LDL-C) (47 arms-MD: -5.48 mg/dl, 95% CI: -8.49, -2.47, I2: 94.5) and triglyceride (TG) (56 arms-MD: -9.44 mg/dl, 95% CI: -16.02, -2.87, I2: 91.8). It also increased high density lipoprotein-cholesterol (HDL-C) (51 arms-MD:1.64 mg/dl, 95% CI:0.54, 2.75, I2: 92.2). l-carnitine supplementation reduced TC in non-linear fashion based on dosage (r = 21.11). Meta-regression analysis indicated a linear relationship between dose of l-carnitine and absolute change in TC (p = 0.029) and LDL-C (p = 0.013). Subgroup analyses showed that l-carnitine supplementation did not change TC, LDL-C and TG in patients under hemodialysis treatment. Intravenous l-carnitine and lower doses (>2 g/day) had no effect on TC, LDL-C and triglycerides. CONCLUSION: l-carnitine supplementation at doses above 2 g/d has favorable effects on patients' lipid profiles, but is modulated on participant health and route of administration.

The Effects of a New Generation of Nutraceutical Compounds on Lipid Profile and Glycaemia in Subjects with Pre-hypertension.

INTRODUCION: Treatment strategies for patients with pre-hypertension and low-moderate cardiovascular (CV) risk may include nutraceutical compounds (NCs). AIM: To investigate the efficacy and safety of a new-generation of NC in lowering BP values and improving metabolic profile, in a group of hyper-cholesterolemic subjects with pre-hypertension. METHODS: 131 subjects with pre-hypertension (systolic BP 130-139 mmHg and/or diastolic BP 85-89 mmHg) without organ damage and history of CV diseases were enrolled. 66 subjects were treated with a once-daily oral formulation of a NC (red yeast rice, Berberine, Coenzyme Q10, folic acid and chrome) added to diet for 3 months, while 65 patients followed a diet only. Differences in serum total cholesterol (TC), low- and high-density lipoprotein cholesterol (LDLC and HDLC), triglycerides (TG), glycemia, creatine phosphokinase (CPK), aspartate aminotransferase (AST) alanine aminotransferase (ALT) and body mass index (BMI) were evaluated. RESULTS: At the end of treatment, significant reductions of TC, LDLC, TG glucose levels were observed in both treatment groups, while HDLC values increased in the active treatment group only. A greater reduction of TC, LDLC and glycemia was observed in the treatment group. TG levels were not different within the two groups. BP and BMI levels remained unchanged, as well AST, ALT; CPK slightly increased in both groups, but it remained in the normal range. CONCLUSIONS: In patients with pre-hypertension, NC supplementation was safe, well tolerated and effective in improving lipid pattern and glucose levels and in preventing the progression to overt hypertension.