Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group

Introduction The effects of omega-6 PUFAs on the CV risk factors are still controversial. Thus, we performed a systematic review and meta-analysis of RCTs as well as a Mendelian Randomization analysis to evaluate the links and possible causality between omega-6 PUFA, CVD and cardiometabolic risk factors. Material and methods Selected databases were searched until September 2019 to identify prospective studies investigating the effects of omega-6 PUFAs supplementation on CVD events/mortality. Random-effects model meta-analysis was performed for quantitative data synthesis. Trial sequential analysis (TSA) was used to evaluate the optimal sample size to detect a 20% reduction in outcomes after administration of omega-6 PUFAs. Inverse variance weighted method (IVW), weighted median-based method, MR-Egger and MR-PRESSO were applied for MR. Results The pooled estimate risk ratio (RR) of omega-6 PUFAs supplementation was 0.94 for any CVD event (95%CI:0.77-1.15, I2=66.2%), 1.06 for CVD death (95%CI:0.73-1.55, I2=66.2%), 0.84 for coronary heart disease (CHD) events (95%CI:0.61-1.16, I2=79.4%), 0.87 for myocardial infarction (MI) (95%CI:0.74-1.01, I2=2.3%) and 1.36 for stroke (95%CI:0.45-4.07, I2=55.3%). In contrast, MR showed that individuals with higher serum adrenic acid (AA) levels had a greater risk for CHD events (IVW=Beta:0.526), MI (IVW=Beta:0.606) and large artery stroke (IVW=Beta:1.694), as well as increased levels of FBG (IVW=Beta:0.417), LDL-C (IVW=Beta:0.806,) HDL-C (IVW=Beta:0.820), and lower levels of triglycerides (TG) (IVW=Beta:-1.064) and total cholesterol (TC) (IVW=Beta:-1.064). Conclusions Omega-6 PUFAs supplementation did not affect the risk for CVD morbidity and mortality. Additionally, in MR analysis we showed that higher AA levels might even significantly increase with the risk of CHD, MI and large artery stroke.

Comparative efficacy and safety of renal denervation (RDN) interventions for uncontrolled (UH) and resistant hypertension (RH) is unknown. We assessed the comparative efficacy and safety of existing RDN interventions for UH and RH. Six search engines were searched up to 1 May 2020. Primary outcomes were mean 24-h ambulatory and office systolic blood pressure (SBP). Secondary outcomes were mean 24-h ambulatory and office diastolic blood pressure (DBP), clinical outcomes, and serious adverse events. Frequentist random-effects network meta-analyses were used to evaluate effects of RDN interventions. Twenty randomized controlled trials (RCTs) (n = 2152) were included, 15 in RH (n = 1544) and five in UH (n = 608). Intervention arms included radiofrequency (RF) in main renal artery (MRA) (n = 10), RF in MRA and branches (n = 4), RF in MRA+ antihypertensive therapy (AHT) (n = 5), ultrasound (US) in MRA (n = 3), sham (n = 8), and AHT (n = 9). RF in MRA and branches ranked as the best treatment to reduce 24-h ambulatory, daytime, and nighttime SBP and DBP versus other interventions (p-scores: 0.83 to 0.97); significant blood pressure effects were found versus sham or AHT. RF in MRA+AHT was the best treatment to reduce office SBP and DBP (p-scores: 0.84 and 0.90, respectively). RF in MRA and branches was the most efficacious versus other interventions to reduce 24-h ambulatory SBP and DBP in UH or RH.

Background Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. Methods and findings We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD −14.94%; 95% CI −17.31%, −12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD −18.17%; 95% CI −21.14%, −15.19%; p < 0.001), low-density lipoprotein cholesterol (MD −22.94%; 95% CI −26.63%, −19.25%; p < 0.001), low-density lipoprotein particle number (MD −20.67%; 95% CI −23.84%, −17.48%; p < 0.001), apolipoprotein B (MD −15.18%; 95% CI −17.41%, −12.95%; p < 0.001), high-density lipoprotein cholesterol (MD −5.83%; 95% CI −6.14%, −5.52%; p < 0.001), high-density lipoprotein particle number (MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049), and hsCRP (MD −27.03%; 95% CI −31.42%, −22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. Conclusions Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.

Introduction: The long-term effect of potato consumption on mortality and cardiovascular (CV) and cardiometabolic risk factors is still largely unknown. Using the National Health and Nutrition Examination Surveys (NHANES) 1999-2010, we evaluted the long-term impact of potato intake on total and cause-specific (cardiovascular disease [CVD], cerebrovascular disease and cancer] mortality, and the results were next validated in the systematic review and meta-analysis of cohort studies investigating pooled associations of potato consumption with all-cause and cause-specific death. Material and methods: Vital status through December 31, 2011 was ascertained in NHANHES. Cox proportional hazards were applied to determine the hazard ratios (HRs) and 95% confidence intervals (95% CIs) of mortality for each quartile of the potato intake, with the lowest quartile (Q1 – with the lowest intake) used as reference. In the meta-analysis we used adjusted Cox regression to determine the risk ratio (RR) and 95%CI, as well as random effects models and generic inverse variance methods to synthesize quantitative and pooled data, followed by a leave-one-out method for sensitivity analysis. RESULTS: Among 24,856 participants included, 3433 deaths occurred during the mean follow-up of 6.4 years. In multivariate adjusted models, total (42%), CVD (65%), cerebrovascular (26%) and cancer (52%) mortality risk was greater in individuals with higher potato consumption than those with the lowest intake (p<0.001 for all comparisons). However, this link disappeared after adjustment for confounding factors. Results from pooling current prospective studies revealed a non-significant association between total (RR: 1.25, 0.98-1.60, p=0.066), CVD (RR: 0.99, 0.90-1.08, p=0.845) and stroke mortality (RR: 0.94, 0.85-1.03, p=0.214) with potato consumption. Individuals with a higher potato intake had a less favorable profile of cardiometabolic factors, including greater waist circumference (97.2 vs. 99.5 cm, p<0.001) and a less favorable profile of systolic and diastolic blood pressure, levels of triglycerides (TGs), high-density lipoprotein-cholesterol (HDL-C) and TG/HDL-C ratio (p<0.001 for all comparisons). CONCLUSIONS: Our results highlighted insignificant effects of potato intake on long-term mortalities; whereas potato consumption was adversely related to cardiometabolic risk factors. These findings should be taken into consideration for public health strategies, establishing the position for potatoes in the food pyramid. Keywords: Mortality, Potato, Stroke, Cardiovascular Disease, Cardiometabolic, and Meta-Analysis.

The incidence of diabetes mellitus, as well as its complications, is rapidly growing. Diabetic nephropathy is one of the most prevalent disorders induced by chronic uncontrolled hyperglycemia and is accompanied by a reduction in renal sufficiency with microstructural tissue damage in the kidneys. Many therapeutic protocols have been designed to address the treatment and prevention of diabetic nephropathy. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a newly introduced class of glucose-lowering agents that reduce blood glucose by inhibition of urinary glucose reabsorption in renal proximal tubules and so induce glycosuria. Also, these hypoglycemic agents may provide protective effects in different tissues such as cardiovascular, brain, and kidneys. In recent years, accumulating evidence has indicated that SGLT2i possess potent renal protective properties in the setting of diabetes. In the current study, we present the latest findings regarding the renoprotective effects of SGLT2 inhibition and discuss the molecular mechanisms involved.

Abstract Background The role of statins in patients with heart failure (HF) of different levels of left ventricular ejection fraction (LVEF) remains unclear especially in the light of the absence of prospective data from randomized controlled trials (RCTs) in non-ischemic HF, and taking into account potential statins’ prosarcopenic effects. We assessed the association of statin use with clinical outcomes in patients with HF. Methods We searched PubMed, EMBASE, Scopus, Google Scholar and Cochrane Central until August 2018 for RCTs and prospective cohorts comparing clinical outcomes with statin vs non-statin use in patients with HF at different LVEF levels. We followed the guidelines of the 2009 PRISMA statement for reporting and applied independent extraction by multiple observers. Meta-analyses of hazard ratios (HRs) of effects of statins on clinical outcomes used generic inverse variance method and random model effects. Clinical outcomes were all-cause mortality, cardiovascular (CV) mortality and CV hospitalization. Results Finally we included 17 studies (n = 88,100; 2 RCTs and 15 cohorts) comparing statin vs non-statin users (mean follow-up 36 months). Compared with non-statin use, statin use was associated with lower risk of all-cause mortality (HR 0.77, 95% confidence interval [CI], 0.72–0.83, P

Background: Maternal vitamin D deficiency has been associated with an increased risk for preeclampsia. Despite this, the current evidence regarding the efficacy of vitamin D supplementation in preventing preeclampsia is controversial. To assess the impact of vitamin D supplementation on the risk of preeclampsia, we performed a systematic review of the literature and a meta-analysis of the available randomized clinical trials (RCTs). Methods: The primary outcome was preeclampsia. Subgroup analyses were carried out considering the timing of the supplementation, type of intervention and the study design. Meta-regression analysis, including the amount of vitamin D and maternal age, were planned to explore heterogeneity. Results: Data were pooled from 29 RCTs comprising 65 arms, which included overall 5297 participants, of whom 2833 were in the vitamin D-treated arm and 2464 in the control arm. Vitamin D administration in pregnancy was associated with a reduced risk of preeclampsia (odd ratio [OR] 0.37, 95% confidence interval [CI]: 0.26, 0.52; I2=0%). If the vitamin D supplementation was started up to 20 weeks’ gestation, the odds was a little lower (OR 0.35, 95%CI: 0.24, 0.50, p<0.001). The effect was largely independent of the supplementation cessation (until delivery or not), type of intervention (vitamin D alone or in association with calcium), and study design. Increasing dose of vitamin D was associated with reduced incidence of preeclampsia (slope of log OR: -1.1, 95%CI: -1.73, -0.46; p<0.001). Conclusions: Results suggest that vitamin D supplementation may be useful in preventing preeclampsia. These data are especially useful for health-care providers who engage in the management of pregnant women at risk for preeclampsia. Our findings are a call for action to definitively address vitamin D supplementation as a possible intervention strategy in preventing preeclampsia in pregnancy.

Aims. To assess the effect of fibrates on circulating cystatin C levels. Materials and methods. Clinical studies evaluating the effect of a fibrate on circulating cystatin C levels were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases. A random-effect model and generic inverse variance method were used for quantitative data synthesis, sensitivity analysis conducted using the leave-one-out method, and weighted random-effects meta-regression performed to evaluate potential confounders on cystatin C levels. Results. This meta-analysis of data from 9 published studies (16 treatment arms) involved a total of 2195 subjects. In a single-arm analysis of clinical trials (without control group; 8 studies comprising 14 treatment arms), fibrate therapy increased circulating cystatin C concentrations (WMD: 0.07 mg/dL, 95% CI: 0.04, 0.10, p <0.001; I² = 82.66%). When the analysis was restricted to randomized controlled trials (4 studies comprising 6 treatment arms), again elevation of circulating cystatin C levels was observed (WMD: 0.06 mg/L, 95% CI: 0.03, 0.09, p <0.001; I² = 42.98%). Elevated cystatin C levels were only seen with fenofibrate, not other fibrates. Conclusion. The results suggest that fenofibrate treatment adversely affects cystatin C levels and might partially explain the limited efficacy of fenofibrate in reducing cardiovascular events.

Background and aims There is considerable controversy regarding the link between serum uric acid (SUA) and mortality. We prospectively evaluated the association between SUA and risk of total and cause specific (coronary heart disease [CHD], cerebrovascular and cancer) mortality by using the National Health and Nutrition Examination Surveys (NHANES, 1999–2010). Furthermore, a systematic review and meta-analysis of cohort studies was performed to investigate pooled associations of SUA with all-cause and cause-specific mortality. Methods Vital status through December 31, 2011 was ascertained. PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched (up to April 2018). Adjusted Cox proportional hazard regression models were used to determine the association between SUA and mortality. The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis. Results Overall, 21,025 individuals were included (mean age = 47.6 years, 48.7% men) and 3520 deaths occurred during the 144 months of follow-up. In adjusted models, individuals in the highest quartile of SUA had 10 and 8% greater risk of CHD and stroke mortality, whereas there was no link between SUA, all-cause and cancer mortality. The associations of CHD and stroke mortality with SUA were more pronounced in women and, among women, in those aged >50 years. Furthermore, all-cause mortality was positively and significantly related to SUA concentrations only in women. In the meta-analysis, SUA was shown to predict the risk of total (21%), CHD (24%) and stroke (29%) mortality. Furthermore, participants with a higher level of central adiposity had a greater risk of mortality from CHD and stroke for the same level of SUA. Conclusions Our results highlight the adverse impact of SUA on mortality, particularity in older (>50 years) women. The clinical implications of these findings remain to be established in future trials.

Introduction: The present study aimed to assess the prevalence and association of various bacterial infections with cardiovascular disease (CVD) in Iran. Material and methods: An electronic search was performed using related keywords in the national and international databases up to June 30, 2017. Out of the 1807 articles found on the associations between bacterial infections and CVD, 20 relevant studies were selected for the meta-analysis. Results: The prevalence of bacterial infections was higher in case groups compared with the control groups. Odds ratios for assessing the association between Chlamydia pneumonia infection and CVD based on PCR, IgG and IgA tests were 7.420 (95% CI: 3.088–17.827), 3.710 (95% CI: 1.361–10.115) and 2.492 (95% CI: 1.305–4.756), respectively. Moreover, the calculated odds ratio for Mycoplasma pneumonia infection was 1.815 (95% CI: 0.973–3.386). For Helicobacter pylori infection, odds ratios based on IgG and IgA tests were 3.160 (95% CI: 1.957–5.102) and 0.643 (95% CI: 0.414–0.999), respectively. Conclusions: The present meta-analysis suggested that there was a significant association between H. pylori, C. pneumonia and M. pneumonia infections and CVD in Iran. These findings confirm the potential role of bacterial infections as predisposing factors for CVD.

INTRODUCTION: The aim of this meta-analysis was to establish whether vascular pulse wave velocity (PWV) as a measure of arterial stiffness is changed in patients with familial hypercholesterolemia (FH). METHODS: Studies comparing PWV between patients with FH and controls were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (up to November 26, 2017). A meta-analysis was conducted using Comprehensive Meta-Analys V2 software. A random-effects model (using DerSimonian-Laird method) and the generic inverse variance method were used to compensate for the heterogeneity of studies concerning demographic characteristics and differences in the studies design. RESULTS: This meta-analysis of 8 studies involving 317 patients with FH and 244 non-FH individuals did not suggest a significantly altered PWV in FH patients versus controls (weighted mean difference [WMD]: 0.17 m/s, 95% confidence interval [CI]:-0.31, 0.65, p=0.489; I2 = 80.15%). The result was robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies from the meta-analysis. Subanalysis of 6 of these studies which had data on intima-media thickness (IMT) indicated an increased IMT in FH patients when compared with controls (WMD: 0.03 mm, 95%CI: 0.003, 0.06, p=0.034; I2 = 48.95%). However, the effect size was sensitive to some of the included studies. CONCLUSIONS: This meta-analysis suggests that FH patients do not have significantly altered PWV when compared with normocholesterolemic individuals. However, a subanalysis of studies in which IMT was measured indicated that IMT is increased in FH patients compared with controls.

Purpose of review: Acute decompensated heart failure (ADHF) is one of the biggest challenges in the management of chronic heart failure. Despite several advances in medical and device therapy, high readmission and mortality rates continue to be a burden on healthcare systems worldwide. The aim of the current review is to provide an overview on current as well as future approaches in cardiorenal interactions in patients with ADHF. Recent findings: One of the strongest predictors of adverse outcomes in ADHF is renal dysfunction, referred to as cardiorenal syndromes (CRS) or cardiorenal interactions. Patients with ADHF frequently develop worsening of renal function (WRF) and/or acute kidney injury (AKI). Recent studies brought new information about biomarkers in diagnosing and predicting prognosis of CRS. Among others, dry weight at hospital discharge is considered a surrogate marker of successful treatment in ADHF patients with/without renal dysfunction. The etiology of WRF appears to be an important factor for determining risk related to WRF as well as clinical management. The hypertonic saline used as adjunctive therapy for intravenous loop diuretics and/or induction of aquaresis (e.g., using tolvaptan) may be promising and efficient approaches in the future.

Introduction: Raised blood pressure (BP) is the biggest contributor to mortality and disease burden worldwide and fewer than half of those with hypertension are aware of it. May Measurement Month (MMM) is a global campaign set up in 2017, to raise awareness of high BP and as a pragmatic solution to a lack of formal screening worldwide. The 2018 campaign was expanded, aiming to include more participants and countries. Methods and results: Eighty-nine countries participated in MMM 2018. Volunteers (>_18 years) were recruited through opportunistic sampling at a variety of screening sites. Each participant had three BP measurements and completed a questionnaire on demographic, lifestyle, and environmental factors. Hypertension was defined as a systolic BP >_140mmHg or diastolic BP >_90 mmHg, or taking antihypertensive medication. In total, 74.9% of screenees provided three BP readings. Multiple imputation using chained equations was used to impute missing readings. 1 504 963 individuals (mean age 45.3 years; 52.4% female) were screened. After multiple imputation, 502 079 (33.4%) individuals had hypertension, of whom 59.5% were aware of their diagnosis and 55.3% were taking antihypertensive medication. Of those on medication, 60.0% were controlled and of all hypertensives, 33.2% were controlled. We detected 224 285 individuals with untreated hypertension and 111 214 individuals with inadequately treated (systolic BP >_ 140mmHg or diastolic BP >_ 90 mmHg) hypertension. Conclusions: May Measurement Month expanded significantly compared with 2017, including more participants in more countries.The campaign identified over 335 000 adults with untreated or inadequately treated hypertension. In the absence of systematic screening programmes, MMM was effective at raising awareness at least among these individuals at risk.

Background How long one lives, how many years of life are spent in good and poor health, and how the population's state of health and leading causes of disability change over time all have implications for policy, planning, and provision of services. We comparatively assessed the patterns and trends of healthy life expectancy (HALE), which quantifies the number of years of life expected to be lived in good health, and the complementary measure of disability-adjusted life-years (DALYs), a composite measure of disease burden capturing both premature mortality and prevalence and severity of ill health, for 359 diseases and injuries for 195 countries and territories over the past 28 years. Methods We used data for age-specific mortality rates, years of life lost (YLLs) due to premature mortality, and years lived with disability (YLDs) from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to calculate HALE and DALYs from 1990 to 2017. We calculated HALE using age-specific mortality rates and YLDs per capita for each location, age, sex, and year. We calculated DALYs for 359 causes as the sum of YLLs and YLDs. We assessed how observed HALE and DALYs differed by country and sex from expected trends based on Socio-demographic Index (SDI). We also analysed HALE by decomposing years of life gained into years spent in good health and in poor health, between 1990 and 2017, and extra years lived by females compared with males. Findings Globally, from 1990 to 2017, life expectancy at birth increased by 7·4 years (95% uncertainty interval 7·1–7·8), from 65·6 years (65·3–65·8) in 1990 to 73·0 years (72·7–73·3) in 2017. The increase in years of life varied from 5·1 years (5·0–5·3) in high SDI countries to 12·0 years (11·3–12·8) in low SDI countries. Of the additional years of life expected at birth, 26·3% (20·1–33·1) were expected to be spent in poor health in high SDI countries compared with 11·7% (8·8–15·1) in low-middle SDI countries. HALE at birth increased by 6·3 years (5·9–6·7), from 57·0 years (54·6–59·1) in 1990 to 63·3 years (60·5–65·7) in 2017. The increase varied from 3·8 years (3·4–4·1) in high SDI countries to 10·5 years (9·8–11·2) in low SDI countries. Even larger variations in HALE than these were observed between countries, ranging from 1·0 year (0·4–1·7) in Saint Vincent and the Grenadines (62·4 years [59·9–64·7] in 1990 to 63·5 years [60·9–65·8] in 2017) to 23·7 years (21·9–25·6) in Eritrea (30·7 years [28·9–32·2] in 1990 to 54·4 years [51·5–57·1] in 2017). In most countries, the increase in HALE was smaller than the increase in overall life expectancy, indicating more years lived in poor health. In 180 of 195 countries and territories, females were expected to live longer than males in 2017, with extra years lived varying from 1·4 years (0·6–2·3) in Algeria to 11·9 years (10·9–12·9) in Ukraine. Of the extra years gained, the proportion spent in poor health varied largely across countries, with less than 20% of additional years spent in poor health in Bosnia and Herzegovina, Burundi, and Slovakia, whereas in Bahrain all the extra years were spent in poor health. In 2017, the highest estimate of HALE at birth was in Singapore for both females (75·8 years [72·4–78·7]) and males (72·6 years [69·8–75·0]) and the lowest estimates were in Central African Republic (47·0 years [43·7–50·2] for females and 42·8 years [40·1–45·6] for males). Globally, in 2017, the five leading causes of DALYs were neonatal disorders, ischaemic heart disease, stroke, lower respiratory infections, and chronic obstructive pulmonary disease. Between 1990 and 2017, age-standardised DALY rates decreased by 41·3% (38·8–43·5) for communicable diseases and by 49·8% (47·9–51·6) for neonatal disorders. For non-communicable diseases, global DALYs increased by 40·1% (36·8–43·0), although age-standardised DALY rates decreased by 18·1% (16·0–20·2). Interpretation With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures. Despite the progress made in reducing the burden of communicable diseases and neonatal disorders in low SDI countries, the speed of this progress could be increased by scaling up proven interventions. The global trends among non-communicable diseases indicate that more effort is needed to maximise HALE, such as risk prevention and attention to upstream determinants of health.

Elevated blood pressure (BP) is a worldwide burden, leading to over 10 million deaths yearly. May Measurement Month (MMM) is a global initiative organized by the International Society of Hypertension aimed at raising awareness of hypertension and the need for BP screening. An opportunistic cross-sectional survey of volunteers aged ≥18 was carried out in May 2017. BP measurement, the definition of hypertension and statistical analysis followed the globally approved MMM17 Study Protocol. In Poland 5834 (98.9%, Caucasian) individuals were screened. After multiple imputation, 2601 (35.3%) had hypertension. Of individuals not receiving anti-hypertensive medication, 976 (20.6%) were hypertensive. Of individuals receiving anti-hypertensive medication, 532 (49.1%) had uncontrolled BP. In the crude screened group, 81.4% declared to not receive any anti-hypertensive treatment, while the remaining 18.6% were on such medications. In overweight and obese patients both systolic and diastolic BP were significantly higher than in normal weight and underweight subjects. In addition, BP measured on Sundays was significantly lower than on Mondays. MMM17 was one of the largest recent BP screening campaigns in Poland. We found that over 1/3 of participants were hypertensive. Almost half of the treated subjects had uncontrolled BP. These results suggest that opportunistic screening can identify substantial numbers with raised BP.

Objective The aim of this meta-analysis of randomized placebo-controlled trials was to examine whether ursodeoxycholic acid treatment is an effective lipid-lowering agent. Methods PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases were searched in order to find randomized controlled trials evaluating the effect of ursodeoxycholic acid on lipid profile. A random-effect model and the generic inverse variance weighting method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A random-effects meta-regression model was performed to explore the association between potential confounders and the estimated effect size on plasma lipid concentrations. Results Meta-analysis of 20 treatment arms revealed a significant reduction of total cholesterol following ursodeoxycholic acid treatment (WMD: − 13.85 mg/dL, 95% CI: -21.45, − 6.25, p < 0.001). Nonetheless, LDL-C (WMD: -6.66 mg/dL, 95% CI: -13.99, 0.67, p = 0.075), triglycerides (WMD: − 1.42 mg/dL, 95% CI: -7.51, 4.67, p = 0.648) and HDL-C (WMD: -0.18 mg/dL, 95% CI: -5.23, 4.87, p = 0.944) were not found to be significantly altered by ursodeoxycholic acid administration. In the subgroup of patients with primary biliary cirrhosis, ursodeoxycholic acid reduced total cholesterol (WMD: − 29.86 mg/dL, 95% CI: -47.39, − 12.33, p = 0.001) and LDL-C (WMD: -37.27 mg/dL, 95% CI: -54.16, − 20.38, p < 0.001) concentrations without affecting TG and HDL-C. Conclusion This meta-analysis suggests that ursodeoxycholic acid therapy might be associated with significant total cholesterol lowering particularly in patients with primary biliary cirrhosis.

Objective: The associations of egg consumption with total, coronary heart disease (CHD), and stroke mortality are poorly understood. We prospectively evaluated the link between total, CHD, and stroke mortality with egg consumption using a randomly selected sample of U.S. adults. Next we validated these results within a meta-analysis and systematic review of all available prospective results. We assessed the mean of cardiometabolic risk factors across the intake of eggs. Method: We made the analysis based on data from the National Health and Nutrition Examination Surveys (NHANES; 1999-2010). In NHANES, vital status through December 31, 2011, was ascertained. Cox proportional hazard regression models were used to relate baseline egg consumption with all-cause and cause-specific mortality. PubMed, Scopus, Web of Science, and Google Scholar databases were also searched (up to December 2017). The DerSimonian-Laird method and generic inverse variance methods were used for quantitative data synthesis. Results: Overall, 23,524 participants from NHANES were included (mean age of 47.7 years; 48.7% were men). Across increasing the intake of eggs, adjusted mean levels of cardiometabolic risk factors worsened. Adjusted logistic regression showed that participants in the highest category of egg intake had a greater risk of diabetes (T2DM; 30%) and hypertension (HTN; 48%). With regard to total and CHD mortality, multivariable Cox regression in a fully adjusted model showed no link in males and females. In males, egg intake had a reverse (66%) association with stroke mortality, while this link was not significant among females. The results of pooling data from published prospective studies also showed no link between CHD and total mortality with egg consumption, whereas we observed a reverse (28%) association between egg intake and stroke mortality. These findings were robust after sensitivity analysis. Conclusions: According to our findings, egg intake had no significant impact on CHD and total mortality, whereas it had a beneficial effect on mortality from stroke. However, egg consumption was associated with T2DM, HTN, C-reactive protein, and markers of glucose/insulin homeostasis. If confirmed in clinical trials (causation), this information may have applications for population-wide health measures.

Aim. To evaluate by meta-analysis of interventional studies the effect of statin therapy on arterial wall inflammation. Background. Arterial exposure to low-density lipoprotein (LDL) cholesterol levels is responsible for initiation and progression of atherosclerosis and arterial wall inflammation. 18F-fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (18F-FDG PET/CT) has been used to detect arterial wall inflammation and monitor the vascular anti-inflammatory effects of lipid-lowering therapy. Despite a number of statin-based interventional studies exploring 18F-FDG uptake, these trials have produced inconsistent results. Methods. Trials with at least one statin treatment arm were searched in PubMed-Medline, SCOPUS, ISI Web of Knowledge, and Google Scholar databases. Target-to-background ratio (TBR), an indicator of blood-corrected 18F-FDG uptake, was used as the target variable of the statin anti-inflammatory activity. Evaluation of studies biases, a random-effects model with generic inverse variance weighting, and sensitivity analysis were performed for qualitative and quantitative data assessment and synthesis. Subgroup and meta-regression analyses were also performed. Results. Meta-analysis of seven eligible studies, comprising 10 treatment arms with 287 subjects showed a significant reduction of TBR following statin treatment (Weighted Mean Difference (WMD): −0.104, p = 0.002), which was consistent both in high-intensity (WMD: −0.132, p = 0.019) and low-to-moderate intensity statin trials (WMD: −0.069, p = 0.037). Statin dose/duration, plasma cholesterol and C-reactive protein level changes, and baseline TBR did not affect the TBR treatment response to statins. Conclusions. Statins were effective in reducing arterial wall inflammation, as assessed by 18F-FDG PET/CT imaging. Larger clinical trials should clarify whether either cholesterol-lowering or other pleiotropic mechanisms were responsible for this effect.

Introduction: Many experimental and clinical trials have suggested that flax-seed might be a potent antihypertensive, but the evidence concerning the effects of flaxseed supplements on plasma C-reactive protein (CRP) concentrations has not been fully conclusive. We assessed the impact of the effects of flaxseed supplementation on plasma CRP concentrations through a systematic review of literature and meta-analysis of available randomised controlled trials (RCTs). Material and methods: The literature search included EMBASE, ProQuest, CINAHL, and PUBMED databases up to 1 st February 2016 to identify RCTs investigating the effect of flaxseed supplements on plasma CRP concentrations. Meta-analysis was performed using a random-effects model, and effect size was expressed as weighed mean difference (WMD) and 95% confidence interval (CI). Results: Meta-analysis of 17 selected RCTs with 1256 individuals did not suggest a significant change in plasma CRP concentrations following sup-plementation with flaxseed-containing products (WMD:-0.25 mg/l, 95% CI:-0.53, 0.02, p = 0.074). The effect size was robust in the leave-one-out sensitivity analysis. Subgroup analysis did not suggest any significant difference in terms of changing plasma CRP concentrations among different types of flaxseed supplements used in the included studies, i.e. flaxseed oil (WMD:-0.67 mg/l, 95% CI:-2.00, 0.65, p = 0.320), lignan extract (WMD:-0.32 mg/l, 95% CI:-0.71, 0.06, p = 0.103) and ground powder (WMD:-0.18 mg/l, 95% CI:-0.42, 0.06, p = 0.142). Conclusions: The meta-analysis of RCTs did not show a significant change in plasma CRP concentrations following supplementation with various flaxseed products. Large, well-designed studies should be still performed to validate the current results.

Objectives This meta-analysis of randomised placebo-controlled clinical trials aimed to assess the effect of fenofibrate on apolipoprotein C-III (apo C-III), a key regulator of triglyceride metabolism. Materials and methods Randomised placebo-controlled trials investigating the impact of fenofibrate treatment on apo C-III levels were searched in PubMed-Medline, Scopus, Web of Science and Google Scholar databases from inception to 18 August 2017. Quantitative data synthesis was determined by a random-effects model and generic inverse variance method. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate glycaemic parameter confounders. Results Meta-analysis of 10 clinical trials involving 477 subjects showed fenofibrate therapy decreased apo C-III levels (weighted mean difference (WMD) −4.78 mg/dL, 95% CI −6.95 to –2.61, p<0.001; I ² 66.87%). Subgroup analysis showed that fenofibrate reduced plasma apo C-III concentrations in subgroups of trials with treatment durations of either <12 weeks (WMD −4.50 mg/dL, p=0.001) or ≥12 weeks (WMD: −4.73 mg/dL, p=0.009) and doses of fenofibrate <200 mg/day (WMD −6.33 mg/dL, p<0.001) and >200 mg/day (p=0.006), with no significant difference between the subgroups. Conclusion This meta-analysis found that fenofibrate therapy significantly decreases apo C-III levels, an effect evident with both short-term treatment and doses less than 200 mg/day.

Background The ‘placebo effect’ and ‘nocebo effect’ are phenomena whereby beneficial (placebo) or adverse (nocebo) effects result from the expectation that an inert substance will relieve or cause a particular symptom. These terms are often inappropriately applied to effects experienced on drug therapy. Quantifying the magnitude of placebo and nocebo effects in clinical trials is problematic because it requires a ‘no treatment’ arm. To overcome the difficulties associated with measuring the nocebo effect, and the fact that its definition refers to inert compounds, rather than drugs, we introduce the concept of ‘drucebo’ (a combination of DRUg and plaCEBO or noCEBO) to relate to beneficial or adverse effects of a drug, which result from expectation and are not pharmacologically caused by the drug. As an initial application of the concept, we have estimated the contribution of the drucebo effect to statin discontinuation and statin‐induced muscle symptoms by performing a systematic review of randomized controlled trial of statin therapy. Methods This preferred reporting items for systematic reviews and meta‐analysis‐compliant systematic review was prospectively registered in PROSPERO (CRD42017082700). We searched PubMed and Cochrane Central from inception until 3 January 2018 using a search strategy designed to detect studies including the concepts (Statins AND Placebo AND muscle pain). We included studies that allowed us to quantify the drucebo effect for adverse muscle symptoms of statins by (i) comparing reported rates of muscle symptoms in blinded and unblinded phases of randomized controlled trials and (ii) comparing rates of muscle symptoms at baseline and during blinded therapy in trials that included patients with objectively confirmed statin intolerance at baseline. Extraction was performed by two researchers with disagreements settled by a third reviewer. Results Five studies allowed the estimation of the drucebo effect. All trials demonstrated an excess of side effects under open‐label conditions. The contribution of the drucebo effect to statin‐associated muscle pain ranged between 38% and 78%. The heterogeneity of study methods, outcomes, and reporting did not allow for quantitative synthesis (meta‐analysis) of the results. Conclusions The drucebo effect may be useful in evaluating the safety and efficacy of medicines. Diagnosis of the drucebo effect in patients presenting with statin intolerance will allow restoration of life‐prolonging lipid‐lowering therapy. Our study was limited by heterogeneity of included studies and lack of access to individual patient data. Further studies are necessary to better understand risk factors for and clinical management of the drucebo effect.

Background: To examine the association between serum concentrations of antioxidant and telomere length (TL) in U.S adults. Methods: Participants of the National Health and Nutrition Examination Survey (NHANES) with data available on TL measures from 2001 to 2002 were included. Serum lipophilic antioxidants level was measured using high performance liquid chromatography with photodiode array detection. We used analysis of co-variance and multivariable-adjusted linear regression models, accounting for the survey design and sample weights. Results: Of the 5992 eligible participants, 47.5% (n = 2844) were men. The mean age was 46.9 years overall, 47.2 years in men and 46.6 in women (p = 0.071). In age, sex, race, education, marital status, adiposity, smoking, C-reactive protein adjusted linear regressions, antioxidant, serum α-carotene, trans-β-carotene, cis- β-carotene, β-cryptoxanthin and combined Lutein/zeaxanthin were positively and significantly associated with TL (all p < 0.001). Conclusions: Our findings support a possible positive association between serum concentrations of lipophylic antioxidant and TL. The implications of this association deserve further investigation.

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% CI: -31.61, -12.75, p<0.001; I2: 88.24%). Subgroup analysis showed a significant reduction of plasma apo C-III concentrations by 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 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. Conclusion: This meta-analysis has shown that omega-3 PUFAs might decrease apo C-III.

Introduction: Atrial fibrillation (AF) is one of the most common complication following cardiac surgery AF significantly increases the length of intensive care unit and hospitalization stay and worsens the early and longterm prognosis. The purpose of our study was to apply metaanalysis methodology to find the most important risk factors that predict postoperative atrial fibrillation in patients undergoing isolated surgical revascularization of heart. Material and methods: After a careful review, nine studies met the inclusion criteria for the metaanalysis. A total of 28 786 patients were assessed in the metaanalysis. Results: Postoperative atrial fibrillation appeared in 7019 patients (24.4%), with mean age 67.1±2.9, among which there were 5283 men (75.3%) and 1736 women (24.7%). The age of patients without postoperative atrial fibrillation was lower (62.2±3.3), however the sex distribution was very similar (74.4% men vs. 25.6% women). The following predictors of postoperative atrial fibrillation (AF SCORE) were significant; advanced age (SMD 0.57), preoperative ejection fraction (SMD -0.12), the history of atrial fibrillation (OR 2.07), arterial hypertension (1.27), heart failure (1.47), peripheral vascular disease (1.37), chronic obstructive pulmonary disease (1.31), neurological event (1.44), renal failure (1.46), significant stenosis of left main coronary artery before the surgery (1.14), and postoperative use of inotropic therapy (1.76). Conclusions: The validated AF SCORE for developing postoperative atrial fibrillation may used to stratify patients undergoing surgical revascularization into high-risk and low-risk groups. It might be useful to appropriately target high-risk patients for aggressive prophylactic treatment in the preoperative period.

Objectives: We conducted a systematic review and meta-analysis to estimate the prevalence of overweight and obesity in children (aged 5–12 years) and adolescents (aged 12-19 years) years in Asian countries. Study Design: Systematic review and meta-analysis Methods: We comprehensively searched specialised databases for relevant studies conducted in Asian countries between Jan 1, 1999, and May 30, 2017. Random effects models (using DerSimonian-Laird method) and generic inverse variance methods were used for quantitative data synthesis. Sensitivity analysis was conducted using the ‘leave-one-out’ method. Heterogeneity was quantitatively assessed using the I2 index. Systematic review registration: CRD42016033061. Results: Among 22286 identified citations, 41 studies met the inclusion criteria with n=71,998 and n=353,513 for children and adolescents. The pooled prevalence (overall, boys and girls) was 5.8% (n=4175), 7.0% (n=2631) and 4.8% (n=1651) for obesity in children aged 5-11 years; 8.6% (n=30402), 10.1% (n=17990) and 6.2% (n=10874) for obesity in adolescents age 12-19 years. For overweight in children the values for overall, boys and girls were 11.2% (n=7900), 11.7% (n=4280) and 10.9% (n=3698) respectively; and for overweight in adolescents, 14.6% (n=46886), 15.9% (27183), and 13.7% (20574). These findings were robust in sensitivity analyses. Boys consist the majority of children and adolescent with obesity compared with girls (children=7.0 vs. 4.8%, adolescent= 10.1 vs. 6.2%, p<0.001, respectively), further with regard to overweight, boys consist the higher percentage of children and adolescent compared with girls (children=11.7 vs. 10.9%, adolescent= 15.9 vs. 13.7%, p<0.001, respectively). Conclusion: In view of the number of children who are overweight or obese, the associated detrimental effects on health, and the cost to health-care systems, implementation of programmes to monitor and prevent unhealthy weight gain in children and adolescents is needed throughout Asian countries. Key words: Childhood, Adolescent, Overweight, Obesity

Introduction: The aim of the study was to undertake a systematic review and meta-analysis of prospective studies to determine the effect of magnesium (Mg) supplementation on C-reactive protein (CRP). Design: Systematic review and meta-analysis of randomised controlled trials (RCTs). Material and methods: Data sources: PubMed-Medline, Web of Science, Co-chrane Database, and Google Scholar databases were searched (up until December 2016). Eligibility criteria: Randomized controlled trials evaluating the impact of Mg supplementation on CRP. We used random effects models meta-analysis for quantitative data synthesis. For sensitivity analysis was used the leave-one-out method. Heterogeneity was quantitatively assessed using the I 2 index. Main outcome: Level of CRP after Mg supplementation. Results: From a total of 96 entries identified via searches, eight studies were included in the final selection. The meta-analysis indicated a significant reduction in serum CRP concentrations following Mg supplementation (weighted mean difference (WMD)-1.33 mg/l; 95% CI:-2.63 to-0.02, het-erogeneity p < 0.123; I 2 = 29.1%). The WMD for interleukin 6 was-0.16 pg/dl (95% CI:-3.52 to 3.26, heterogeneity p = 0.802; I 2 = 2.3%), and 0.61 mg/dl (95% CI:-2.72 to 1.48, p = 0.182, heterogeneity p = 0.742; I 2 = 6.1%) for fasting blood glucose. These findings were robust in sensitivity analyses. Random-effects meta-regression revealed that changes in serum CRP levels were independent of the dosage of Mg supplementation (slope:-0.004; 95% CI:-0.03, 0.02; p = 0.720) or duration of follow-up (slope:-0.06; 95% CI:-0.37, 0.24; p = 0.681). Conclusions: This meta-analysis suggests that Mg supplementation significantly reduces serum CRP level. RCTs with a larger sample size and a longer follow-up period should be considered for future investigations to give an unequivocal answer.

INTRODUCTION: Pentoxifylline is a xanthine derivative with several potential cardiovascular (CV) benefits, but the evidence regarding its effects on blood pressure (BP) and inflammatory markers such as tumor necrosis factor (TNF-α), C-reactive protein (CRP) and interleukin-6 (IL-6) is not conclusive. PURPOSE: To evaluate the impact of pentoxifylline on systolic blood pressure (SBP), diastolic blood pressure (DBP), TNF-α, CRP and IL-6 through a systematic review and meta-analysis of available randomized controlled trials (RCTs). METHODS: The search included PUBMED, ProQuest, Scopus, and EMBASE up to September 1st, 2015 to identify randomized controlled trials (RCTs) with both BP and circulating inflammatory markers data measured during pentoxifylline therapy. Quantitative data synthesis was performed using a random-effects model, with weighed mean difference (WMD) and 95% confidence interval (CI) as summary statistics. RESULTS: Meta-analysis of 12 RCTs did not suggest any significant effect of pentoxifylline on either SBP (WMD: 0.69 mmHg, 95% CI: -1.59, 2.97, p = 0.553) or DBP (WMD: 0.19 mmHg, 95% CI: -1.15, 1.54, p = 0.778). Both analyses (SBP and DBP) were robust in the leave-one-out sensitivity analysis. Meta-analysis showed a significant effect of pentoxifylline treatment in reducing plasma concentrations of TNF-α (WMD: -1.03 pg/mL, 95% CI: -1.54, -0.51, p < 0.001) (figure) and CRP (WMD: -1.39 mg/L, 95% CI: -2.68, -0.10, p = 0.034) (figure). However, no significant alteration was observed in plasma IL-6 concentrations following pentoxifylline treatment (WMD: 1.17 pg/mL, 95% CI: -1.28, 3.62, p = 0.350). The impact of pentoxifylline on plasma TNF-α levels was found to be positively associated with treatment duration (slope: 0.031; 95% CI: 0.004, 0.057; p = 0.023) but independent of pentoxifylline dose (slope: -0.0003; 95% CI: -0.002, 0.001; p = 0.687). CONCLUSIONS: Pentoxifylline did not have any effect on BP and plasma IL-6 concentrations, but significantly reduced circulating TNF-α and CRP concentrations, suggesting a potential use for pentoxifylline in systemic inflammatory conditions.

Background: An admission SBP of <120 mm Hg has been shown to be associated with short-term poor outcomes in hospitalized patients with HF (PMID: 17090768). However, this association has not been well studied in hospitalized patients with HFpEF. We examined if a low discharge SBP among hospitalized HFpEF patients with a stable admission-to-discharge SBP was independently associated with poor outcomes. Methods: In the Medicare-linked OPTIMIZE-HF registry, 10482 hospitalized patients with HF had EF >40%. A stable admission-to-discharge SBP was defined as SBP fluctuation of <20 mm Hg between hospital admission and discharge. Of the 4688 patients with stable SBP, 1325 (28%) had a discharge SBP of <120 mm Hg. Propensity scores for discharge SBP of <120 mm Hg, estimated for each of the 4688 patients, were used to assemble a cohort of 1096 pairs of patients, with a discharge SBP <120 vs ≥120 mm Hg, who were balanced on 58 baseline characteristics. The 2192 matched patients had a mean (±SD) age of 79 (±10) years, a mean (±SD) EF of 56 (±4) percent, a mean (±SD) discharge SBP of 122 (±17) mm Hg, 60% were women, and 7% African American. Results: During 2.1 years of median follow-up (max, 5.9 years), all-cause mortality occurred in 75% and 70% of matched patients with a discharge SBP <120 vs ≥120 mm Hg, respectively (HR, 1.19; 95% CI, 1.08–1.31; Figure). A discharge SBP <120 mm Hg was also associated with a higher risk for the combined outcome of all-cause readmission or all-cause mortality (HR 1.10 (95% CI, 1.01–1.20) but not with all-cause readmission (HR, 1.07; 95% CI, 0.98–1.18) or HF readmission (HR, 1.03; 95% CI, 0.90–1.17). These associations remained unchanged when we repeated the above analyses among the 4688 pre-match patients, adjusting for propensity scores. Conclusion: Among hospitalized patients with HFpEF and stable admission-to-discharge SBP, a low discharge SBP was independently associated with higher all-cause mortality but not with all-cause or HF readmissions.

Tissue inhibitors of metalloproteinases (TIMPs) and matrix metalloproteinases (MMPs) are associated with the development of atherosclerosis and cardiovascular disease. Statin therapy has been shown to modulate MMPs and TIMP-1 levels but clinical findings have not been conclusive. This study aimed to systematically review the clinical findings on the impact of statin therapy on plasma MMP-9, MMP-3 and TIMP-1 levels and calculate an effect size for the mentioned effect through a meta-analysis of available data. A total of 10 eligible studies with 11 treatment arms were included in the meta-analysis. Statin therapy had no significant effect on plasma MMP-9 (SMD: -0.23, 95% CI: -0.69, 0.24, p=0.345) nor MMP-3 concentrations (SMD: -0.004, 95% CI: -0.60, 0.59, p=0.990). However, meta-analysis demonstrated that statin therapy significantly decreases plasma TIMP-1 levels (SMD: -0.30, 95% CI: -0.56, -0.03, p=0.029). Random-effects meta-regression indicated that neither treatment duration nor changes in LDL-C levels are associated with changes in plasma MMP-9 levels following statin therapy. The results of the present meta-analysis suggested a significant reduction in plasma concentrations of TIMP-1, but not MMP-9 and MMP-3, following statin therapy.

Background and aims: Ezetimibe reduces plasma low-density lipoprotein cholesterol (LDL-C) levels by up to 20%. However, its effect on plasma lipoprotein(a) [Lp(a)] concentrations in patients with primary hypercholesterolemia has not been defined. Objective: Therefore, we performed a systematic review and meta-analysis to assess this effect based on the available randomized controlled trials (RCTs). Methods: We searched the PubMed and SCOPUS databases from inception until 28 February 2017 to identify RCTs that investigated the effect of ezetimibe monotherapy on plasma Lp(a) concentrations in patients with primary hypercholesterolemia. We pooled mean percentage changes in plasma Lp(a) concentrations as a mean difference (MD) with a 95% confidence interval (CI). Results: Seven RCTs with 2337 patients met the selection criteria and were included in the analysis. Overall pooled analysis suggested that ezetimibe 10 mg significantly reduced plasma Lp(a) concentrations in patients with primary hypercholesterolemia by - 7.06% (95% CI - 11.95 to - 2.18; p = 0.005) compared with placebo. No significant heterogeneity was observed (χ2 = 5.34; p = 0.5). Excluding one study from the analysis resulted in insignificant differences between the two groups (p = 0.2). Meta-regression did not find a significant association between the mean percentage changes in Lp(a) and other potential moderator variables, which included the mean percentage changes of LDL-C concentrations (p = 0.06) and baseline Lp(a) mean values (p = 0.46). Conclusions: Ezetimibe monotherapy (10 mg/day) showed a small (7.06%) but statistically significant reduction in the plasma levels of Lp(a) in patients with primary hypercholesterolemia. According to current literature, this magnitude of reduction seems to have no clinical relevance. However, further studies are warranted to clarify the mechanism mediating this effect of ezetimibe and to investigate its efficacy in combination with other drugs that have shown promise in lowering Lp(a) levels.

Background Statins are well-established low-density lipoprotein cholesterol–lowering drugs. Elevated apolipoprotein CIII (Apo CIII) levels are associated with elevated triglyceride-rich particles, which are also considered to be a possible risk factor for cardiovascular disease. Objective The aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of statins on Apo CIII concentrations. Methods Randomized placebo-controlled trials investigating the impact of statin treatment on cholesterol lowering that include lipoprotein measurement were searched in PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar databases (up to July 31, 2017). 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 Apo CIII concentrations. Results This meta-analysis of data from 6 randomized placebo-controlled clinical trials (10 statin arms) involving 802 subjects showed that statin therapy significantly decreased circulating Apo CIII concentrations (weighted mean difference [WMD]: −2.71, 95% confidence interval [CI]: −3.74 to –1.68, P < .001; I²: 73.83%). The effect size was robust in the leave-one-out sensitivity analysis and not driven by any single study. Subgroup analysis showed a reduction of Apo CIII concentrations by atorvastatin (WMD: –4.74, 95% CI: –3.74 to –1.68, P = .002; I²: 84.02%), rosuvastatin (WMD: –2.68, 95% CI: –4.52 to –0.84, P = .004; I²: 0%), and lovastatin (WMD: –1.64, 95% CI: –2.22 to –1.07, P < .001; I²: 0%). Conclusion This meta-analysis suggests that statin treatment significantly reduces plasma Apo CIII levels.

Aims: The aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of fibrates on glycemic parameters. Materials and methods: Only randomized placebo-controlled trials investigating the impact of fibrate treatment on glucose homeostasis markers were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 11, 2017). 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 of data from 22 randomized placebo-controlled clinical trials involving a total of 11,402 subjects showed that fibrate therapy significantly decreased fasting plasma glucose (WMD: -0.28 mmol/L, 95% CI: -0.42, -0.14, p < 0.001), insulin levels (WMD: -3.87 pmol/L, 95% CI: -4.97, -2.78, p < 0.001) and insulin resistance (HOMA-IR, WMD: -1.09, 95% CI: -1.71, -0.47, p = 0.001), but with no effect on HbA1c (WMD: 0.01%, 95% CI: -0.18, 0.19, p = 0.955). All analyses were robust in the leave-one-out sensitivity analysis except for insulin levels that showed a non-significant result (WMD: -0.84 pmol/L, 95% CI: -6.36, 4.68, p = 0.766) following omission of one of the included trials. Conclusion: This meta-analysis has shown that fibrate treatment significantly decreases fasting plasma glucose, insulin levels, and HOMA-IR indicating additional clinical therapeutic benefits.

Objective: The aim of this systematic review and meta-analysis was to determine and clarify the impact of curcuminoids on serum lipid levels. Methods: Randomized controlled trials (RCTs) investigating the effects of curcuminoids on plasma lipids were searched in PubMed-Medline, Scopus, Web of Science databases (from inception to April 3rd, 2017). 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 lipid concentrations. Results: A meta-analysis of 20 RCTs with 1427 participants suggested a significant decrease in plasma concentrations of triglycerides (WMD: -21.36 mg/dL, 95% CI: -32.18, -10.53, p < 0.001), and an elevation in plasma HDL-C levels (WMD: 1.42 mg/dL, 95% CI: 0.03, 2.81, p = 0.046), while plasma levels of LDL-C (WMD: -5.82 mg/dL, 95% CI: -15.80, 4.16, p = 0.253) and total cholesterol (WMD: -9.57 mg/dL, 95% CI: -20.89, 1.75, p = 0.098) were not altered. The effects of curcuminoids on lipids were not found to be dependent on the duration of supplementation. Conclusion: This meta-analysis has shown that curcuminoid therapy significantly reduces plasma triglycerides and increases HDL-C levels.

Introduction: Uric acid (UA), the final product of purine catabolism, may be associated with an increased risk of cardiovascular disease. Aim: The aim of this meta-analysis of randomized placebo-controlled trials was to evaluate whether lowering serum UA (SUA) levels with allopurinol is associated with improved flow-mediated dilation (FMD), a validated marker of early vascular damage. Methods: A literature search was carried out from inception until 20 June 2017. Meta-analysis was performed using an inverse variance-weighted, random-effects model with standardized mean difference (SMD) as the effect size estimate. Results: Meta-analysis of data from the ten eligible randomized controlled trials (RCTs), with 670 subjects, suggested a significant increase in FMD following allopurinol treatment (weighted mean difference [WMD] 1.79%, 95% confidence interval [CI] 1.01-2.56, p < 0.001; I (2): 86.77%). The effect size was robust and remained significant after omission of each single study. Subgroup analyses of RCTs based on the administered dose or duration of treatment did not reveal any significant impact of these variables on FMD change. Nor was a significant association found between allopurinol-induced changes in SUA levels and FMD (slope 0.46, p = 0.253), whereas baseline FMD significantly influenced the degree of FMD improvement following allopurinol treatment (slope 0.52, p = 0.022). Nitroglycerin-mediated dilation was not altered by allopurinol treatment (WMD 0.88%, 95% CI - 1.15-2.91, p = 0.395; I (2): 80.88%). Conclusion: This meta-analysis of available RCTs suggests a significant benefit from allopurinol intake in increasing FMD in humans, independent of its effect on SUA levels.

The study aims to investigate the effect of argan oil on plasma lipid concentrations through a systematic review of the literature and a meta-analysis of available randomized controlled trials. Randomized controlled trials that investigated the impact of at least 2 weeks of supplementation with argan oil on plasma/serum concentrations of at least 1 of the main lipid parameters were eligible for inclusion. Effect size was expressed as the weighted mean difference (WMD) and 95% confidence interval (95% CI). Meta-analysis of data from 5 eligible trials with 292 participants showed a significant reduction in plasma concentrations of total cholesterol (WMD: −16.85 mg/dl, 95% CI [−25.10, −8.60], p < .001), low-density lipoprotein cholesterol (WMD: −11.67 mg/dl, 95% CI [−17.32, −6.01], p < .001), and triglycerides (WMD: −13.69 mg/dl, 95% CI [−25.80, −1.58], p = .027) after supplementation with argan oil compared with control treatment, and plasma concentrations of high-density lipoprotein cholesterol (WMD: 4.14 mg/dl, 95% CI [0.86, 7.41], p = .013) were found to be increased. Argan oil supplementation reduces total cholesterol, low-density lipoprotein cholesterol, and triglycerides and increases high-density lipoprotein cholesterol levels. Additionally, larger clinical trials are needed to assess the impact of argan oil supplementation on other indices of cardiometabolic risk and on the risk of cardiovascular outcomes.

Objective: Fibrinogen is a key mediator of thrombosis and it has been implicated in the pathogenesis of atherosclerosis. Because metformin has shown a potential protective effect on different atherothrombotic risk factors, we assessed in this meta-analysis its effect on plasma fibrinogen concentrations. Methods: A systematic review and meta-analysis was carried out to identify randomized placebo-controlled trials evaluating the effect of metformin administration on fibrinogen levels. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases (by June 2, 2017) and quality of studies was performed according to Cochrane criteria. Quantitative data synthesis was conducted using a random-effects model and sensitivity analysis by the leave-one-out method. Meta-regression analysis was performed to assess the modifiers of treatment response. Results: Meta-analysis of data from 9 randomized placebo-controlled clinical trials with 2302 patients comprising 10 treatment arms did not suggest a significant change in plasma fibrinogen concentrations following metformin therapy (WMD: -0.25 g/L, 95% CI: -0.53, 0.04, p = 0.092). The effect size was robust in the leave-one-out sensitivity analysis and remained non-significant after omission of each single study from the meta-analysis. Conclusion: No significant effect of metformin on plasma fibrinogen concentrations was demonstrated in the current meta-analysis.

Background: Soy supplementation has been shown to reduce total and low-density lipoprotein cholesterol, while increasing high-density lipoprotein cholesterol. However, contradictory effects of soy isoflavone supplementation on lipoprotein(a) [Lp(a)] have been reported suggesting the need for a meta-analysis to be undertaken. Objective: The aim of the study was to investigate the impact of supplementation with soy isoflavones on plasma Lp(a) levels through a systematic review and meta-analysis of eligible randomized placebo-controlled trials. Methods: The search included PubMed-Medline, Scopus, ISI Web of Knowledge, and Google Scholar databases (by March 26, 2017), and quality of studies was evaluated according to Cochrane criteria. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference and 95% confidence interval as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. Results: Ten eligible studies comprising 11 treatment arms with 973 subjects were selected for the meta-analysis. Meta-analysis did not suggest any significant alteration of plasma Lp(a) levels after supplementation with soy isoflavones (standardized mean difference: 0.08, 95% confidence interval: -0.05, 0.20, P = .228). The effect size was robust in the leave-one-out sensitivity analysis. In meta-regression analysis, neither dose nor duration of supplementation with soy isoflavones was significantly associated with the effect size. Conclusion: This meta-analysis of the 10 available randomized placebo-controlled trials revealed no significant effect of soy isoflavones treatment on plasma Lp(a) concentrations.

The year 2012 has been extremely interesting concerning new findings on diagnosis, management and therapy of dyslipidaemia, hypertension and kidney disease. Looking at recent lipid disorders studies, two issues have seemed to be especially important-searching for new potent biomarkers of lipid disorders (including studies on dysfunctional High Density Lipoprotein [HDL] cholesterol, as well as subfractions/subpopulations of HDL/Low Density Lipoprotein [LDL] cholesterol) and research on new lipid disorders drugs, especially concerning proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which seem to be very potent in LDL-C lowering. Within the past year, there has been also growing clinical and research progress in hypertension management, especially concerning Resistant Hypertension (RH). In 2012, many important studies on Renal denervation (RDN), as a method of RH therapy have been published, including the ones with patients with different concomitant diseases (e.g., Chronic Kidney Disease (CKD)), as well as with longer follow-up. On the basis of the available data RDN has gained an important role in RH treatment and has recently been introduced to clinical practice. November 2012 has been critical for new nephrology data, as the most important trails were presented during American Society of Nephrology (ASN) Congress in San Diego. They concerned among others, the problems of secondary hyperparathyroidism management in CKD patients, new data on transplantations (e.g., glucocorticoid avoidance strategy), nephro cardiology (stepped pharmacotherapy algorithm vs. ultrafiltration in heart failure patients with CKD), as well as acute kidney injury and diabetic nephropathy (new data on bardoxolone methyl).

Purpose of review: Reduction in circulating cholesterol is an important step in lowering cardiovascular risk. Although statins are the most frequently prescribed cholesterol-lowering medication, there remains a significant portion of patients who require alternative treatment options. Nutraceuticals are increasingly popular as cholesterol-lowering agents. Despite the lack of long-term trials evaluating their use on cardiovascular endpoints and mortality, several studies have demonstrated their potential cholesterol-lowering effects. The purpose of this review is to provide an update on the role of nutraceuticals as cholesterol-lowering agents. The present review will focus on individual nutraceutical compounds, which have shown modest cholesterol-lowering abilities, as well as combination nutraceuticals, which may offer potential additive and/or synergistic effects. Recent findings: Berberine, red yeast rice, and plant sterols have moderate potential as cholesterol-lowering agents. Combination nutraceuticals, including the proprietary formulation, Armolipid Plus, appear to confer additional benefit on plasma lipid profiles, even when taken with statins and other agents. Summary: Although robust, long-term clinical trials to examine the effects of nutraceuticals on clinical outcomes are still required, their cholesterol-lowering ability, together with their reported tolerance and safety, offer a pragmatic option for lowering plasma cholesterol levels.

Methods: We conducted an electronic search of PubMed, SCOPUS, Web of Science and Embase databases through to July 24th, 2016 to identify the relevant studies. Relevant outcomes were pooled by RevMan version 5.3. The meta-analysis was registered in PROSPERO (CRD42016043480).

The aim of this systematic review and meta-analysis of prospective interventional studies was to investigate the effects of coenzyme Q10 (CQ10) on plasma C-reactive protein (CRP) levels. PubMed/Medline, Web of Science (WoS), Cochrane Database and Google Scholar databases were searched (up to December 2016) to identify prospective studies evaluating the impact of CQ10 supplementation on CRP. Random effects models meta-analysis was used for quantitative data synthesis. Sensitivity analysis used the leave-one-out method, and heterogeneity was quantitatively assessed using the I(2) index. Systematic review PROSPERO database registration: CRD42016038155. From a total of 119 entries identified via searches, 7 studies were finally included to the analysis. The results of the meta-analysis indicated a non-significant reduction in CRP concentrations following supplementation with CQ10 with a weighted mean difference [WMD] of -0.25mg/l (95% confidence intervals [CI] -0.56 to 0.06, I(2)=42.0%). The WMD for the effects on interleukin 6 (IL6) was -0.72pg/dl, (95% CI -1.24 to -0.24, I(2)=51.8%). These findings were robust in sensitivity analyses. Random-effects meta-regression revealed that changes in plasma CRP levels were independent of the dosage of CQ10 (slope: -0.0005; 95% CI: -0.005, 0.004; p=0.832) while duration of supplementation was the dependent mediator (slope: slope: -0.111; 95% CI: -0.21, -0.004; p=0.042). In conclusion, CQ10 supplementation has a borderline favourable effect on CRP levels, and a significant effect on IL-6 level. This suggests that CQ10 supplementation likely attenuates subclinical inflammation.

Abstract: Background: Cinnamon is a rich botanical source of polyphenols, whose positive effects on blood lipid concentrations have been hypothesized, but have not been conclusively studied. Objective: To systematically review and evaluate the effect of administration of cinnamon on blood lipid concentrations. Methods: We assessed 13 RCTs with 750 participants investigating the effect of cinnamon supplementation on blood lipid concentrations. A meta-analysis was performed using random-effect models, with weighted mean differences (with 95% CI) for endpoints calculated using a random-effects model. Results: No statistically significant effect of cinnamon was observed on blood LDL-C (WMD: -0.16 mmol/L [-6.19 mg/dL], 95% CI: -0.35, 0.03 [-13.53, 1.16], p = 0.10) and HDL-C (WMD: 0.05 mmol/L [1.92 mg/dL], 95% CI: -0.03, 0.12 [-0.03, 4.64], p = 0.21) concentrations. However, a statistically significant reduction in blood triglycerides (WMD: -0.27 mmol/L [-23.91 mg/dL], 95% CI: -0.39, -0.14 [-34.54, -12.40], p < 0.01) and total cholesterol concentrations (WMD: -0.36 mmol/L [-13.92 mg/dL], 95% CI: -0.63, -0.09 [-24.36, -3.48], p < 0.01) was observed. HDL-C was significantly elevated following the omission of one study (WMD: 0.04 mmol/L [1.54 mg/dL], 95% CI: 0.03, 0.06 [1.16, 2.32], p < 0.01) during our sensitivity analysis. A meta-regression analysis was conducted and no significant association was found between changes in lipid parameters and cinnamon dose. In contrast, changes in blood levels of total cholesterol (slope: 0.09; 95% CI: 0.02, 0.16; p < 0.01), LDL-C (slope: 0.05; 95% CI: 0.001, 0.10; p = 0.05) and triglycerides (slope: 0.06; 95% CI: 0.04, 0.09; p < 0.01) were significantly and positively associated with the duration of supplementation. No statistically significant association was found between blood HDL-C changes and duration of supplementation. Conclusion: Cinnamon supplementation significantly reduced blood triglycerides and total cholesterol concentrations without any significant effect on LDL-C and HDL-C.

In recent years there has been a 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 to obtain the theraputic lipid goals and reduce the cardiovascular residual risk. Some nutraceuticals have essential lipid lowering-properties confirmed in studies, some might have also possible positive effects on non-lipid cardiovascular risk factors and have proven to improve early markers of vascular health such as endothelial function and pulse wave velocity. However the clinical evidence supporting the use of single or a combination of lipid-lowering nutraceuticals is largely variable and for many of them very limitted and therefore often debatable. The purpose of this Position Paper is to provide consensus-based recommendations for optimal management of lipid-lowering nutraceuticals in patients with dyslipidemia still not being on statin therapy, on statin or combination therapy without lipid goals achieved, and for those with statin intolerance. This statement is intended for physicians and other health care professional that are engaged in the diagnosis and management of patients with lipid disorders, especially in the setting of primary care. Key words: dyslipidemia, lipid, nutraceuticals, position paper, recommendations.

Tibolone is a synthetic steroid with estrogenic, androgenic and progestogenic activity, but the evidence regarding its effects on fibrinogen and anti-thrombin III (ATIII) has not been conclusive. We assessed the impact of tibolone on fibrinogen and ATIII through a systematic review and meta-analysis of available randomized controlled trials (RCTs). The search included PUBMED, Web of Science, Scopus, and Google Scholar (up to January 31st, 2016) to identify controlled clinical studies investigating the effects of oral tibolone treatment on fibrinogen and ATIII. Overall, the impact of tibolone on plasma fibrinogen concentrations was reported in 10 trials comprising 11 treatment arms. Meta-analysis did not suggest a significant reduction of fibrinogen levels following treatment with tibolone (WMD: −5.38%, 95% CI: −11.92, +1.16, p = 0.107). This result was robust in the sensitivity analysis and not influenced after omitting each of the included studies from meta-analysis. When the studies were categorized according to the duration of treatment, there was no effect in the subsets of trials lasting either <12 months (WMD: −7.64%, 95% CI: −16.58, +1.29, p = 0.094) or ≥12 months (WMD: −0.62%, 95% CI: −8.40, +7.17, p = 0.876). With regard to ATIII, there was no change following treatment with tibolone (WMD: +0.74%, 95% CI: −1.44, +2.93, p = 0.505) and this effect was robust in sensitivity analysis. There was no differential effect of tibolone on plasma ATIII concentrations in trials with either <12 months (WMD: +2.26%, 95% CI: −3.14, +7.66, p = 0.411) or ≥ 12 months (WMD: +0.06%, 95% CI: −1.16, +1.28, p = 0.926) duration. Consistent with the results of subgroup analysis, meta-regression did not suggest any significant association between the changes in plasma concentrations of fibrinogen (slope: +0.40; 95% CI: −0.39, +1.19; p = 0.317) and ATIII (slope: −0.17; 95% CI: −0.54, +0.20; p = 0.374) with duration of treatment. In conclusion, meta-analysis did not suggest a significant reduction of fibrinogen and ATIII levels following treatment with tibolone.

Purpose: We conducted a meta-analysis of randomized controlled trials (RCTs) and quasi-RCTs to synthesize evidence about the efficacy and safety of alternate-day vs daily dosing of statins. Methods: We searched selected databases through January 2, 2017 to identify relevant RCTs and quasi-RCTs. The primary outcome was change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TG), while secondary outcomes included adverse events and adherence. Results: Twelve RCTs and 1 quasi-RCT (n = 1023 patients) were included in the analysis. Pooled analysis revealed no statistically significant difference between alternate-day and daily regimens of atorvastatin and rosuvastatin in terms of change in LDL-C (mean difference [MD] 6.79 mg/dL, 95% confidence interval [CI] -1.59, 15.17, p = 0.11, and 10.51 mg/dL, 95%CI -0.23, 21.26, p = 0.06, respectively) and TG (p > 0.05). Daily regimens of atorvastatin and rosuvastatin were superior to alternate-day regimes in term of change in TC (MD 12.45 mg/L, 95%CI 8.14, 16.76, p < 0.00001, and 15.80 mg/dL, 95%CI 5.66, 25.95, p = 0.002, respectively). For all outcomes, there was no statistically significant difference between alternate-day and daily regimens for both fluvastatin and pravastatin (p > 0.05). Both regimens of statins were generally well tolerated with good adherence. Conclusions: Alternate-day dosing of individual statins (especially atorvastatin and rosuvastatin) is as efficacious as daily dosing on LDL-C and TG.

Background: Compounds and extracts derived from natural sources continue to stand in the spotlight of drug design owing to their versatile interaction with enzymes, receptors and metabolic pathways. Nanomedicine offers an operative tool for the efficient delivery of natural products, in terms of increased bioavailability, targeting, and controlled release while protecting active constituents against physico-chemical alterations. The interest of the scientific community in the field of nanosized delivery of natural compounds is demonstrated by the exponential growth of the publications in this field. Aim: Beyond the presentation of successful examples of nanoscale delivery systems containing natural products, the scope of this review is to point out the yet underexplored capacities of this field with relevance for the pharmaceutical and nutraceutical market. Chapters: Departing from a short presentation of plant-derived natural products and strategies to obtain nanoformulations, the current work reviews nanoparticulate drug delivery systems targeting diseases of various organs and systems: skin, central nevous system, skeletal tissue, cardiovascular apparatus, and diabetes. Conclusions: While notable progress has been achieved in the preparation of nanomedicines containing selected dietary polyphenols, works dealing with crude extracts or standardized fractions are much less frequent. In fact, most of the plants with solidly documented therapeutic properties and registered in pharmacopoeias still wait to benefit from advances in the field of nanotechnology. At least for some of them, adequate nanoformulation shall contribute to their removal from the group of dietary supplements and pharmaceutical preparations with suboptimal bioavailability and efficacy.

The year 2013 proved to be very exciting as far as landmark trials and new guidelines in the field of lipid disorders, blood pressure and kidney diseases. Among these are the International Atherosclerosis Society Global Recommendations for the Management of Dyslipidemia, European Society of Cardiology (ESC)/European Society of Hypertension Guidelines for the Management of Arterial Hypertension, American Diabetes Association Clinical Practice Recommendations, the Kidney Disease: Improving Global Outcomes Clinical Practice Guidelines for Managing Dyslipidemias in Chronic Kidney Disease (CKD) Patients, the American College of Cardiology/American Heart Association Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, the Joint National Committee Expert Panel (JNC 8) Evidence-Based Guideline for the Management of High Blood Pressure in Adults, the American Society of Hypertension/International Society of Hypertension Clinical Practice Guidelines for the Management of Hypertension in the Community, the American College of Physicians Clinical Practice Guideline on Screening, Monitoring, and Treatment of Stage 1-3 CKD and many important trials presented among others during the ESC Annual Congress in Amsterdam and the American Society of Nephrology Annual Meeting-Kidney Week in Atlanta, GA. The paper is an attempt to summarize the most important events and reports in the mentioned areas in the passing year.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is part of the proteinase K subfamily of subtilases and plays a key role in lipid metabolism. It increases degradation of the low-density lipoprotein receptor (LDL-R), modulates cholesterol metabolism and transport, and contributes to the production of apolipoprotein B (apoB) in intestinal cells. Exogenous PCSK9 modifies the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase and enhances secretion of chylomicrons by modulating production of lipids and apoB-48. Statins increase PCSK9 messenger RNA expression and attenuate the capacity to increase LDL-R levels. Therefore, the inhibition of PCSK9 in combination with statins provides a promising approach for lowering low-density lipoprotein cholesterol (LDL-C) concentrations. This review will address new therapeutic strategies targeting PCSK9, including monoclonal antibodies, antisense oligonucleotides, small interfering RNAs, and other small molecule inhibitors. Further studies are still needed to determine the efficacy and safety of the PCSK9 inhibitors not only to decrease LDL-C but also to investigate the potential underlying mechanisms involved and to test whether these compounds actually reduce cardiovascular end points and mortality.

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are muscle-related. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term ‘statin intolerance’. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.

BACKGROUND: Circulating markers relevant to the development of abdominal aortic aneurysm (AAA) are currently required. Lipoprotein(a) (Lp(a)) is considered a candidate marker associated with the presence of AAA. PURPOSE: The present meta-analysis aimed to evaluate the association between circulating Lp(a) levels and the presence of AAA. METHODS: A PubMed-based search was conducted up to April 30, 2015 to identify the studies focusing on Lp(a) levels in patients with AAA and controls. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. RESULTS: Overall, 9 studies with 1564 patients were included. The studies were published between 1988 and 2013, and were conducted in Sweden, USA, UK, Austria, Italy, and New Zealand. The mean age of the patients ranged from 56-73.5 years. The patients with AAA were found to have a significantly higher level of Lp(a) compared with the controls (SMD: 0.87, 95% CI: 0.41, 1.33, p < 0.001). This result remained robust in the sensitivity analysis and its significance was not influenced after omitting each of the included studies. CONCLUSIONS: The present meta-analysis found a higher level of circulating Lp(a) in patients with AAA compared with controls. High Lp(a) levels can be associated with the presence of AAA and Lp(a) may be a marker in screening for AAA. Further studies are needed to establish the clinical utility of measuring Lp(a) in the prevention and management of AAA.

Anthracyclines, especially doxorubicin and daunorubicin, are the drugs of first choice in the treatment of patients with hematologic malignancies, soft-tissue sarcomas, and solid tumors. Unfortunately, the use of anthracyclines is limited by their dose-dependent and cumulative cardiotoxicity. The molecular mechanism responsible for anthracycline-induced cardiotoxicity remains poorly understood, although experimental and clinical studies have shown that oxidative stress plays the main role. Hence, antioxidant agents, especially dexrazoxane, and also other drug classes (statins, β-blockers) proved to have a beneficial effect in protecting against anthracycline-induced cardiotoxicity. According to previous clinical trials, the major highrisk factors for anthracycline-induced cardiotoxicity are age, body weight, female gender, radiotherapy, and other diseases such as Down syndrome, familial dilated cardiomyopathy, diabetes and hypertension. Consequently, further studies are needed to elucidate the molecular pathogenesis of anthracycline-induced cardiotoxicity and also to discover new cardioprotective agents against anthracycline-induced cardiotoxicity.

The 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 the current knowledge, nutraceuticals might exert significant lipid-lowering, and their use has several advantages – they have natural origins and are mainly extracted from natural products, they are mostly safe and very well tolerated and their use is supported by the findings from randomizded controlled trials and meta-analyses, finally the lipid-lowering effect of most nutraceuticals is multimechanistic, what makes them potential candidates for improving the effects of current lipid-lowering drugs when used in combination. However, still a number of important questions need to be addressed, including whether longer durations of therapy would result in a better response, and what is the the safety profile of nutraceuticals, especially at doses higher than those consumed in an average diet. In addition, data regarding the impact of nutraceuticals supplementation on the incidence of cardiovascular outcomes are lacking, and it is not clear if additional lipid lowering by nutraceuticals can modify the residual cardiovascular risk that remains following statin therapy.

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.

Objective Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes mellitus. There are also reports of an effect of these drugs in reducing inflammation through inhibition of tumor necrosis factor-α (TNF-α) that is an important mediator for several inflammatory processes. The present systematic review and meta-analysis was performed to evaluate the effect of DPP-4 inhibitors on circulating TNF-α levels in T2DM patients. Methods A systematic review and meta-analysis was undertaken on all controlled trials of DPP-4 inhibitors that included measurement of TNF-α. The search included PubMed-Medline, Scopus, ISI Web of Knowledge and Google Scholar databases. Quantitative data synthesis was performed using a random-effects model, with standardized mean difference (SMD) and 95% confidence interval (CI) as summary statistics. Meta-regression and leave-one-out sensitivity analysis were performed to assess the modifiers of treatment response. Results Eight eligible articles (6 with sitagliptin and 2 with vildagliptin) comprising 9 treatment arms were selected for this meta-analysis. Meta-analysis suggested a significant reduction of circulating TNF-α concentrations following treatment with DPP-4 inhibitors (SMD: -1.84, 95% CI: -2.88, −0.80, p = 0.001). The effect size was robust in the sensitivity analysis and not mainly driven by a single study. A subgroup analysis did not suggest any significant difference between the TNF-α-lowering activity of sitagliptin (SMD: -1.49, 95% CI: -2.89, −0.10) and vildagliptin (SMD: -2.80, 95% CI: -4.98, −0.61) (p = 0.326). Conclusion This meta-analysis of the 8 available controlled trials showed that DPP-4 inhibition in patients with type 2 diabetes mellitus was associated with significant reductions in plasma TNF-α levels with no apparent difference between sitagliptin and vildagliptin.

Smoking is an important risk factor for cardiovascular disease (CVD) morbidity and mortality. The impact of statin therapy on CVD risk by smoking status has not been fully investigated. Therefore we assessed the impact of statin therapy on CVD outcomes by smoking status through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). The literature search included EMBASE, ProQuest, CINAHL and PUBMED databases to 30 January 2016 to identify RCTs that investigated the effect of statin therapy on cumulative incidence of major CVD endpoints (e.g. non-fatal myocardial infarction, revascularization, unstable angina, and stroke). Relative risks (RR) ratios were calculated from the number of events in different treatment groups for both smokers and non-smokers. Finally 11 trials with 89,604 individuals were included. The number of smokers and non-smokers in the statin groups of the analyzed studies was 8826 and 36,090, respectively. The RR for major CV events was 0.73 (95% confidence interval [CI]: 0.67-0.81; p<0.001) in nonsmokers and 0.72 (95%CI: 0.64-0.81; p<0.001) in smokers. Moderate to high heterogeneity was observed both in non-smokers (I2=77.1%, p<0.001) and in smokers (I2=51.6%, p=0.024) groups. Smokers seemed to benefit slightly more from statins than non-smokers according to the number needed to treat (NNT) analysis (23.5 vs 26.8) based on RRs applied to the control event rates. The number of avoided events per 1000 individuals was 42.5 (95%CI: 28.9-54.6) in smokers and 37.3 (95%CI: 27.2-46.4) in non-smokers. In conclusion, this meta-analysis suggests that the effect of statins on CVD is similar for smokers and non-smokers, but in terms of NNTs and number of avoided events, smokers seem to benefit more although non-significantly.

BACKGROUND: Vitamin D supplementation has been suggested to play a role in modulating plasma adipokine concentrations but the evidence is inconclusive. PURPOSE: To elucidate the role of vitamin D supplementation on adipokines we performed a systematic review and a meta-analysis of randomized placebo-controlled trials (RCTs). METHODS: The search included PUBMED, Scopus, Web of Science and Google Scholar (through July 1, 2015) to detect RCTs investigating the impact of vitamin D supplementation on plasma adipokine concentrations. RESULTS: We identified 9 RCTs and 484 participants. Meta-analysis of data from 7 studies did not find a significant change in plasma adiponectin concentrations following vitamin D supplementation (mean difference [MD]: 4.45%, 95%CI: -3.04, 11.93, p=0.244; Q=2.18, I2=0%) (Figure 1). In meta-regression, changes in plasma adiponectin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: 0.25; 95%CI: -0.69, 1.19; p=0.603) and changes in serum 25-hydroxy vitamin D [25(OH)D] levels (slope: -0.02; 95%CI: -0.15, 0.12; p=0.780). Meta-analysis of data from 6 studies did not find a significant change in plasma leptin concentrations following vitamin D supplementation (MD: -4.51%, 95%CI: -25.13, 16.11, p=0.668; Q=6.41, I2=21.97%) (Figure 2). Sensitivity analysis showed that this effect size is sensitive to one of the studies; removing it resulted in a significant reduction in plasma leptin levels (MD: -12.81%, 95%CI: -24.33, -1.30, p=0.029). In meta-regression, changes in plasma leptin concentrations following vitamin D supplementation were found to be independent of treatment duration (slope: -1.93; 95%CI: -4.08, 0.23; p=0.080). However, changes in serum 25(OH)D were found to be significantly associated with changes in plasma leptin levels following vitamin D supplementation (slope: 1.05; 95%CI: 0.08, 2.02; p=0.033). CONCLUSION: Current data did not indicate a significant effect of vitamin D supplementation on adiponectin and leptin levels.

INTRODUCTION: Statin therapy may lower plasma lipids concentrations, but the evidence in HIV-infected patients is still unclear. PURPOSE: We assessed the impact of statin therapy on plasma lipids concentrations through a systematic review of the literature and meta-analysis of available randomized controlled trials (RCTs). METHODS: The literature search included PUBMED, SCOPUS, Web of Science and Google Scholar up to October 30, 2015 to identify RCTs investigating the impact of statin therapy on plasma lipid parameters in HIV patients. The meta-analysis was performed using either a fixed-effects or random-effect model according to I2 statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). RESULTS: 12 RCTs with 697 participants were finally included. Overall, the impact of statins on plasma concentrations of total cholesterol, LDL-C, HDL-C, triglycerides and non-HDL-C was assessed in 10, 9, 8, 8 and 2 studies, respectively. Meta-analysis suggested significant reductions in plasma concentrations of LDL-C (WMD: -0.72 mmol/L [-27.8 mg/dL], 95%CI: -1.04, -0.39, p<0.001) (figure), total cholesterol (WMD: -1.03 mmol/L [-39.8 mg/dL], 95%CI: -1.42, -0.64, p<0.001) (figure) and non-HDL-C (WMD: -0.81 mmol/L [-31,3 mg/dl], 95%CI: -1.32, -0.30, p=0.002) (figure), and elevations in HDL-C (WMD: 0.072 mmol/L [2.8 mg/dL], 95%CI: 0.053, 0.092, p<0.001) following treatment with statins. No significant alteration in plasma TG concentrations was found (WMD: -0.16 mmol/L [-14.2 mg/dL], 95%CI: -0.61, 0.29, p=0.475). All these effects were robust in sensitivity analysis, suggesting that the computed effect is not driven by any single study. In subgroup analysis, no significant difference was found among different statins in terms of changing plasma concentrations of LDL-C, HDL-C and TG. However, atorvastatin was found to be more efficacious in reducing plasma total cholesterol concentrations (p < 0.001). CONCLUSIONS: This meta-analysis suggested significant reductions in plasma concentrations of LDL-C, total cholesterol and non-HDL-C, and elevations in HDL-C, but no significant alteration in plasma TG following treatment with statins in HIV patients.

BACKGROUND: Evidence about the optimal time of day at which to administer statins is lacking. OBJECTIVE: To synthesize evidence about effects of morning versus evening statin administration on lipid profile. METHODS: We searched PubMed, SCOPUS, Web of Science and Embase databases (from inception up to July 24th, 2016) to identify the relevant studies. Mean differences (MDs) between the change scores in lipid parameters were pooled using a fixed-effect model. RESULTS: Eleven articles with 1034 participants were eligible for the analysis. The pooled analysis comparing effects of morning versus evening administration of statins on plasma total cholesterol (TC) (p=0.10), high density lipoprotein cholesterol (HDL-C) (p=0.90) and triglycerides (TG) (p=0.45) was not statistically significant. Low density lipoprotein cholesterol (LDL-C) lowering was statistically greater in the evening-dose group (MD: 3.24 mg/dl, 95%CI: 1.23, 5.25, p=0.002). Subgroup analysis according to statin half-lives showed that evening-dose of statins was significantly superior to morning-dose for lowering LDL-C in case of both short and long half-life statins (MD: 9.68 mg/dl, 95%CI: 3.32, 16.03, p=0.003, and 2.53 mg/dl, 95%CI: 0.41, 4.64, p=0.02, respectively), and also for TC reduction in case of short half-life statins only (p=0.0005). CONCLUSIONS: LDL-C and TC lowering were significantly greater in the evening-dose than in the morning-dose