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Impact of Lipid-Lowering Therapy on Mortality According to the Baseline Non-HDL Cholesterol Level: A Meta-Analysis.
Masson, W, Lobo, M, Siniawski, D, Molinero, G, Huerín, M, Nogueira, JP
High blood pressure & cardiovascular prevention : the official journal of the Italian Society of Hypertension. 2019;(4):263-272
Abstract
INTRODUCTION Previous report showed that more intensive lipid-lowering therapy was associated with less mortality when baseline LDL-C levels were > 100 mg/dL. Non-HDL-C is a better predictor of cardiovascular risk than simpler LDL-C. AIM: The objective of this meta-analysis was to define the impact of lipid-lowering therapy on the reduction of total and cardiovascular mortality by different baseline levels of non-HDL-C. METHODS We performed a meta-analysis including randomized, controlled clinical trials of lipid-lowering therapy, reporting mortality with a minimum of 6 months of follow-up, searching in PubMed/Medline, EMBASE and Cochrane Clinical Trials databases. The random-effects model and meta-regression were performed. RESULTS Twenty nine trials of lipid-lowering drugs, including 233,027 patients, were considered eligible for the analyses. According to the baseline non-HDL-C level, the results on cardiovascular mortality were: (1) ≥ 190 mg/dL: OR 0.63 (95% CI 0.53-0.76); (2) 160-189 mg/dL: OR 0.82 (95% CI 0.75-0.89); (3) 130-159 mg/dL: OR 0.71 (95% CI 0.52-0.98); (4) < 130 mg/dL: OR 0.95 (95% CI 0.87-1.05). When evaluating mortality from any cause, the results were the following: (1) ≥ 190 mg/dL: OR 0.70 (95% CI 0.61-0.82); (2) 160-189 mg/dL: OR 0.91 (95% CI 0.83-0.98); (3) 130-159 mg/dL; OR 0.88 (95% CI 0.77-1.00); (4) < 130 mg/dL: OR 0.98 (95% CI 0.91-1.06). The meta-regression analysis showed a significant association between baseline non-HDL-C and mortality. CONCLUSIONS In these meta-analyses, lipid-lowering therapy was associated with reduction in the risk of all-cause and cardiovascular mortality when baseline non-HDL-C levels were above than 130 mg/dL.
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Hypoglycemic and Hypolipemic Effects of a New Lecithin Formulation of Bergamot Polyphenolic Fraction: A Double Blind, Randomized, Placebo- Controlled Study.
Mollace, V, Scicchitano, M, Paone, S, Casale, F, Calandruccio, C, Gliozzi, M, Musolino, V, Carresi, C, Maiuolo, J, Nucera, S, et al
Endocrine, metabolic & immune disorders drug targets. 2019;(2):136-143
Abstract
OBJECTIVE Hyperlipemia represents an independent risk factor in the development of atherosclerosis in patients undergoing type 2 diabetes mellitus (DM). Moreover, the pharmacological treatment of dyslipemia in patients undergoing type 2 DM (e.g. by means of statins), is accompanied by relevant side effects and oral supplementation with natural antioxidants, such as Citrus polyphenols, has recently been suggested to improve cardioprotection in such patients. However, due to the poor gastrointestinal absorption of polyphenols, novel formulations have recently been developed for getting a better bioavailability of polyphenolic rich fractions of citrus species extract rich in polyphenols. METHODS Here, we investigated the effect of standard bergamot polyphenolic fraction (BPF®) as well as of its phytosomal formulation (BPF Phyto), in patients with type 2 DM and hyperlipemia. A randomized, double blind, placebo-controlled study was carried out in 60 patients suffering from type 2 DM and mixed hyperlipemia. Patients were divided into three groups: one receiving placebo, the second receiving standard BPF and the third BPF Phyto. RESULTS In the groups receiving BPF and BPF Phyto, a significant reduction of fasting plasma glucose, serum LDL cholesterol and triglycerides accompanied by increased HDL cholesterol was observed. This effect was associated with significant reduction of small dense atherogenic LDL particles, as detected by means of proton NMR Spectroscopy, thus confirming the hypolipemic and hypoglycemic effect of bergamot extract both when using standard formulation as well as BPF Phyto. No differences were seen in the therapeutic response among groups receiving BPF and BPF Phyto, thus suggesting a substantial bioequivalence in their hypoglycemic and hypolipemic profile. However, when comparing the pharmacokinetic profile of naringin (the major component of BPF) and its metabolites, in patients treated with BPF Phyto, an at least 2,5 fold increase in its absorption was found, confirming in human studies the better profile of BPF Phyto compared to standard BPF. CONCLUSION These data suggest that better absorption and tissue distribution of BPF Phyto formulation represents an innovative approach in supplementation treatments of cardiometabolic disorders.
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Proanthocyanidins of Natural Origin: Molecular Mechanisms and Implications for Lipid Disorder and Aging-Associated Diseases.
Nie, Y, Stürzenbaum, SR
Advances in nutrition (Bethesda, Md.). 2019;(3):464-478
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Abstract
Proanthocyanidins are phytonutrients formed by oligomerization or polymerization of subunits catechin, epicatechin, and their gallic acid esters. Proanthocyanidins are a component of many plants and thus form an integral part of the human diet. Oligomeric proanthocyanidins are currently marketed as medicinal products that target vascular disorders and chronic pathological conditions, many of which are age-associated. Proanthocyanidins are also characterized by their effects on energy homeostasis. Not dissimilar to their chemically synthesized counterparts, naturally extracted proanthocyanidins act via inhibition of lipases, stimulation of energy expenditure, or suppression of appetite. Here we review the current knowledge-base and highlight challenges and future impacts regarding involvement of proanthocyanidins in global lipid metabolism, with a focus on the molecular mechanisms and pathological conditions that progress with aging.
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Lipid-Lowering Agents in Older Individuals: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
Ponce, OJ, Larrea-Mantilla, L, Hemmingsen, B, Serrano, V, Rodriguez-Gutierrez, R, Spencer-Bonilla, G, Alvarez-Villalobos, N, Benkhadra, K, Haddad, A, Gionfriddo, MR, et al
The Journal of clinical endocrinology and metabolism. 2019;(5):1585-1594
Abstract
BACKGROUND The efficacy of lipid-lowering agents on patient-important outcomes in older individuals is unclear. METHODS We included randomized trials that enrolled individuals aged 65 years or older and that included at least 1 year of follow-up.Pairs of reviewers selected and appraised the trials. RESULTS We included 23 trials that enrolled 60,194 elderly patients. For primary prevention, statins reduced the risk of coronary artery disease [CAD; relative risk (RR): 0.79, 95% CI: 0.68 to 0.91] and myocardial infarction (MI; RR: 0.45, 95% CI: 0.31 to 0.66) but not all-cause or cardiovascular mortality or stroke. These effects were imprecise in patients with diabetes, but there was no significant interaction between diabetes status and the intervention effect. For secondary prevention, statins reduced all-cause mortality (RR: 0.80, 95% CI: 0.73 to 0.89), cardiovascular mortality (RR: 0.68, 95% CI: 0.58 to 0.79), CAD (RR: 0.68, 95% CI: 0.61 to 0.77), MI (RR: 0.68, 95% CI: 0.59 to 0.79), and revascularization (RR: 0.68, 95% CI: 0.61 to 0.77). Intensive (vs less-intensive) statin therapy reduced the risk of CAD and heart failure. Niacin did not reduce the risk of revascularization, and fibrates did not reduce the risk of stroke, cardiovascular mortality, or CAD. CONCLUSION High-certainty evidence supports statin use for secondary prevention in older individuals. Evidence for primary prevention is less certain. Data in older individuals with diabetes are limited; however, no empirical evidence has shown a significant difference based on diabetes status.
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Impact of ursodeoxycholic acid on circulating lipid concentrations: a systematic review and meta-analysis of randomized placebo-controlled trials.
Simental-Mendía, LE, Simental-Mendía, M, Sánchez-García, A, Banach, M, Serban, MC, Cicero, AFG, Sahebkar, A
Lipids in health and disease. 2019;(1):88
Abstract
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.
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Management and diagnosis of mitochondrial fatty acid oxidation disorders: focus on very-long-chain acyl-CoA dehydrogenase deficiency.
Yamada, K, Taketani, T
Journal of human genetics. 2019;(2):73-85
Abstract
Mitochondrial fatty acid oxidation disorders (FAODs) are caused by defects in β-oxidation enzymes, including very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein (TFP), carnitine palmitoyltransferase-2 (CPT2), carnitine-acylcarnitine translocase (CACT) and others. During prolonged fasting, infection, or exercise, patients with FAODs present with hypoglycemia, rhabdomyolysis, cardiomyopathy, liver dysfunction, and occasionally sudden death. This article describes the diagnosis, newborn screening, and treatment of long-chain FAODs with a focus on VLCAD deficiency. VLCAD deficiency is generally classified into three phenotypes based on onset time, but the classification should be comprehensively determined based on genotype, residual enzyme activity, and clinical course, due to a lack of apparent genotype-phenotype correlation. With the expansion of newborn screening for FAODs, several issues have arisen, such as missed detection, overdiagnosis (including detection of benign/asymptomatic type), and poor prognosis of the neonatal-onset form. Meanwhile, dietary management and restriction of exercise have been unnecessary for patients with the benign/asymptomatic type of VLCAD deficiency with a high fatty acid oxidation flux score. Although L-carnitine therapy for VLCAD/TFP deficiency has been controversial, supplementation with L-carnitine may be accepted for CPT2/CACT and multiple acyl-CoA dehydrogenase deficiencies. Recently, a double-blind, randomized controlled trial of triheptanoin (seven-carbon fatty acid triglyceride) versus trioctanoin (regular medium-chain triglyceride) was conducted and demonstrated improvement of cardiac functions on triheptanoin. Additionally, although the clinical efficacy of bezafibrate remains controversial, a recent open-label clinical trial showed efficacy of this drug in improving quality of life. These drugs may be promising for the treatment of FAODs, though further studies are required.
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Relation between baseline LDL-cholesterol and cardiovascular outcomes in high cardiovascular risk hypertensive patients: A post-hoc SPRINT data analysis.
Nguyen, LS, Procopi, N, Salem, JE, Squara, P, Funck-Brentano, C
International journal of cardiology. 2019;:159-161
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Abstract
BACKGROUND Patients at increased cardiovascular (CV) risk, noticeably hypertensive patients, have multiple CV risk factors which may be treatment targets. LDL-cholesterol is one of such targets. Using the SPRINT cohort, studying the cardiovascular outcomes of hypertensive patients at increased CV risk, this post-hoc study aimed to assess the association of LDL-C with CV outcomes. METHODS Clinical outcomes were those defined in SPRINT a composite of various CV outcomes, all-cause mortality, and CV mortality. Association between LDL-C and the primary outcome was analyzed using survival regression adjusted on confounding factors (age, sex, body-mass index, active smoking status, eGFR-estimated kidney function, history of CV disease, Framingham risk score, SPRINT treatment arm (intensive or control), baseline high-density-lipoprotein-bound cholesterol, and co-treatments by aspirin and statins). RESULTS LDL-C was not associated with the primary outcome in the overall cohort (n = 9631). Among patients in secondary prevention (i.e. with a previous history of CV disease) (n = 1562), LDL-C was marginally associated with the incidence of the primary outcome (adjusted hazard-ratio 1.005 (95% CI = 1.002-1.009), p = 0.005 (per 1 mg/dl increase)) however, discrimination was poor with a ROC AUC of 0.54, p = 0.087. There was no association between LDL-C and the primary outcome in other subgroup analyses (those under statin or not, and those in primary prevention). CONCLUSION This post-hoc analysis of SPRINT indicates that LDL-C levels do not influence cardiovascular events over a period of 3 years in a large cohort of hypertensive patients at increased risk of cardiovascular events but without previous history of clinical cardiovascular disease other than stroke.
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Effects of antihypertensives, lipid-modifying drugs, glycaemic control drugs and sodium bicarbonate on the progression of stages 3 and 4 chronic kidney disease in adults: a systematic review and meta-analysis.
Taylor, KS, Mclellan, J, Verbakel, JY, Aronson, JK, Lasserson, DS, Pidduck, N, Roberts, N, Fleming, S, O'Callaghan, CA, Bankhead, CR, et al
BMJ open. 2019;(9):e030596
Abstract
OBJECTIVE To evaluate the effects of drug interventions that may modify the progression of chronic kidney disease (CKD) in adults with CKD stages 3 and 4. DESIGN Systematic review and meta-analysis. METHODS Searching MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, International Clinical Trials Registry Platform, Health Technology Assessment, Science Citation Index, Social Sciences Citation Index, Conference Proceedings Citation Index and Clinical Trials Register, from March 1999 to July 2018, we identified randomised controlled trials (RCTs) of drugs for hypertension, lipid modification, glycaemic control and sodium bicarbonate, compared with placebo, no drug or a drug from another class, in ≥40 adults with CKD stages 3 and/or 4, with at least 2 years of follow-up and reporting renal function (primary outcome), proteinuria, adverse events, maintenance dialysis, transplantation, cardiovascular events, cardiovascular mortality or all-cause mortality. Two reviewers independently screened citations and extracted data. For continuous outcomes, we used the ratio of means (ROM) at the end of the trial in random-effects meta-analyses. We assessed methodological quality with the Cochrane Risk of Bias Tool and confidence in the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS We included 35 RCTs and over 51 000 patients. Data were limited, and heterogeneity varied. Final renal function (estimated glomerular filtration rate) was 6% higher in those taking glycaemic control drugs (ROM 1.06, 95% CI 1.02 to 1.10, I2=0%, low GRADE confidence) and 4% higher in those taking lipid-modifying drugs (ROM 1.04, 95% CI 1.00 to 1.08, I2=88%, very low GRADE confidence). For RCTs of antihypertensive drugs, there were no significant differences in renal function. Treatment with lipid-modifying drugs led to a 36% reduction in cardiovascular disease and 26% reduction in all-cause mortality. CONCLUSIONS Glycaemic control and lipid-modifying drugs may slow the progression of CKD, but we found no pooled evidence of benefit nor harm from antihypertensive drugs. However, given the data limitations, further research is needed to confirm these findings. PROSPERO REGISTRATION NUMBER CRD42015017501.
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Comparing the serum TAG response to high-dose supplementation of either DHA or EPA among individuals with increased cardiovascular risk: the ComparED study.
Allaire, J, Vors, C, Harris, WS, Jackson, KH, Tchernof, A, Couture, P, Lamarche, B
The British journal of nutrition. 2019;(11):1223-1234
Abstract
Studies have shown that the reduction in serum TAG concentrations with long-chain n-3 fatty acid supplementation is highly variable among individuals. The objectives of the present study were to compare the proportions of individuals whose TAG concentrations lowered after high-dose DHA and EPA, and to identify the predictors of response to both modalities. In a double-blind, controlled, crossover study, 154 men and women were randomised to three supplemented phases of 10 weeks each: (1) 2·7 g/d of DHA, (2) 2·7 g/d of EPA and (3) 3 g/d of maize oil, separated by 9-week washouts. As secondary analyses, the mean intra-individual variation in TAG was calculated using the standard deviation from the mean of four off-treatment samples. The response remained within the intra-individual variation (±0·25 mmol/l) in 47 and 57 % of participants after DHA and EPA, respectively. Although there was a greater proportion of participants with a reduction >0·25 mmol/l after DHA than after EPA (45 υ. 32 %; P 0·25 mmol/l after both DHA and EPA had higher non-HDL-cholesterol, TAG and insulin concentrations compared with other responders at baseline (all P < 0·05). In conclusion, supplementation with 2·7 g/d DHA or EPA had no meaningful effect on TAG concentrations in a large proportion of individuals with normal mean TAG concentrations at baseline. Although DHA lowered TAG in a greater proportion of individuals compared with EPA, the magnitude of TAG lowering among them was similar.
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Effect of lipid-lowering treatment in cardiovascular disease prevalence in familial hypercholesterolemia.
Perez-Calahorra, S, Laclaustra, M, Marco-Benedí, V, Lamiquiz-Moneo, I, Pedro-Botet, J, Plana, N, Sanchez-Hernandez, RM, Amor, AJ, Almagro, F, Fuentes, F, et al
Atherosclerosis. 2019;:245-252
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Abstract
BACKGROUND AND AIMS The impact on heterozygous familial hypercholesterolemia (HeFH) health led by high-intensity lipid-lowering therapy (HILLT) is unknown, and the question remains if there is still an unacceptably high residual risk to justify treatment with new lipid-lowering drugs. METHODS This observational, retrospective, multicenter, national study in Spain, whose information was obtained from a national dyslipemia registry, was designed to establish the current prevalence of cardiovascular disease (CVD) in HeFH and to define the impact of HILLT on CVD in this population. Odds were estimated using several logistic regression models with progressive adjustment. RESULTS 1958 HeFH, mean age 49.3 ± 14.3 years, were included in the analysis. At inclusion in the registry, 295 patients (15.1%) had suffered CVD and 164 (55.6%) had suffered the first event before the onset lipid-lowering treatment. Exposition to treatment associated more than ten times lower odds for CVD than in subjects naïve to treatment (OR 0.085, 95% CI 0.063-0.114, p < 0.001). A first CVD event after a mean treatment period of 9.1 ± 7.2 years occurred in 131 out of 1615 (8.1%) HeFH subjects, and 115 (87.8%) of them were on HILLT. CONCLUSIONS Current prevalence of CVD among HeFH is one third of that reported before the statins era. Early initiation and prolonged lipid-lowering treatment was associated with a reduction in CVD. New cases of CVD, in spite of HILLT, appeared mostly among patients accumulating risk factors and probably they may be considered for further lipid-lowering drugs.