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Effect of Rosuvastatin on Cholesterol Efflux Capacity and Endothelial Function in Type 2 Diabetes Mellitus and Dyslipidemia.
Jung, KY, Kim, KM, Han, SK, Yun, HM, Oh, TJ, Choi, SH, Park, KS, Jang, HC, Lim, S
Circulation journal : official journal of the Japanese Circulation Society. 2018;(5):1387-1395
Abstract
BACKGROUND Quality and quantity of high-density lipoprotein cholesterol (HDL-C) may be associated with cardiovascular risk. We investigated the effect of rosuvastatin on cholesterol efflux (CE) for HDL function and vascular health.Methods and Results:We enrolled 30 dyslipidemic patients with type 2 diabetes mellitus and 20 healthy subjects as controls. Vascular health was assessed on flow-medicated dilation (FMD), nitroglycerin-induced dilatation of the brachial artery and carotid artery intima-media thickness (cIMT). These parameters were compared between patients and controls, and between baseline and at 12 weeks of treatment with rosuvastatin 20 mg. Age and body mass index were 49.8±11.3 years and 25.8±3.7 kg/m2in the patients, and 28.8±3.2 years and 22.4±2.4 kg/m2in the controls, respectively. The biomarkers related to lipid and glucose metabolism and lipoprotein (a), high-sensitivity C-reactive protein, and cIMT were significantly higher, and CE and FMD were significantly lower in the patients than in the controls. In the patients, rosuvastatin 20 mg decreased low-density lipoprotein cholesterol by 54.1% and increased HDL-C by 4.8%. The CE increased significantly after rosuvastatin treatment (12.26±2.72% vs. 14.05±4.14%). FMD also increased, and lipoprotein (a) and cIMT decreased significantly and were associated with changes of CE. CONCLUSIONS Rosuvastatin-induced changes in HDL function are significantly associated with cardiovascular benefit.
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Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia.
Yamashita, S, Arai, H, Yokote, K, Araki, E, Suganami, H, Ishibashi, S, ,
Journal of clinical lipidology. 2018;(5):1267-1279.e4
Abstract
BACKGROUND Cardiovascular risk is negatively correlated with cholesterol efflux capacity (CEC) from macrophages to high-density lipoproteins (HDLs) and positively correlated with fasting and nonfasting triglyceride-rich lipoproteins (TRLs). Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, robustly decreases the fasting TRL level, increases the HDL cholesterol (HDL-C) level, and improves the atherogenic lipoprotein subclass profile, with an adverse event rate comparable to that of placebo treatment in previous clinical studies. OBJECTIVE This study aimed to investigate the effects of pemafibrate on CEC and postprandial hyperlipidemia. METHODS Using a single-center, double-blind, randomized, two-by-two crossover design, 33 patients were assigned to receive either 0.4 mg/d pemafibrate (twice daily) or placebo first. The assigned study drug was administered for 4 weeks. Subsequently, the alternate study drug was administered for another 4 weeks. CEC was measured using HDLs obtained from fasting blood samples. A meal tolerance test was performed to examine the postprandial lipid levels at weeks 0, 4, and 8. RESULTS CEC, HDL-C, and apolipoprotein A-I levels increased after pemafibrate treatment compared with placebo administration. Moreover, the percent change in CEC was correlated with that of HDL-C and apolipoprotein A-I levels. TRL levels markedly decreased after pemafibrate treatment in both fasting and nonfasting states. CONCLUSIONS These findings suggest that pemafibrate enhances reverse cholesterol transport and may retard the progression and even promote the regression of atherosclerosis by comprehensively ameliorating the atherogenic lipid profile.
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Cardiovascular outcomes during extended follow-up of the AIM-HIGH trial cohort.
Probstfield, JL, Boden, WE, Anderson, T, Branch, K, Kashyap, M, Fleg, JL, Desvigne-Nickens, P, McBride, R, McGovern, M, ,
Journal of clinical lipidology. 2018;(6):1413-1419
Abstract
BACKGROUND Epidemiologic studies have shown that low levels of high-density lipoprotein-cholesterol (HDL-C) and elevated triglycerides are independent predictors of cardiovascular (CV) events, though randomized trials of HDL-C-raising therapies to reduce clinical events have been largely disappointing. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial failed to show that extended release niacin (ERN) reduced CV events in patients with atherogenic dyslipidemia who were on statin-based therapy. OBJECTIVE We sought to determine whether extended follow-up of AIM-HIGH participants changed these null results. METHODS AIM-HIGH was a placebo-controlled trial of 3414 patients with established CV disease, low baseline HDL-C, and elevated triglycerides levels randomized to ERN 1500-2000 mg/d vs placebo. Participants also received simvastatin with or without ezetimibe to attain on-treatment low-density lipoprotein cholesterol levels of 40-80 mg/dL. The trial was halted after a mean 3-year follow-up because of futility. RESULTS Among 3236 participants alive at the end of blinded study, 2613 (81%; ERN = 1,312, placebo = 1301) were followed a mean 1.1 additional years. Ninety-five percent of subjects remained on statin, but only 4% on ERN. At a mean total follow-up of 4.1 years, there were 343 primary CV endpoints in the ERN arm and 305 CV endpoints in placebo participants (HR 1.11, 95% CI 0.96, 1.30). Ischemic stroke was also not significantly different after extended follow-up in the two groups (2.2% vs 1.5%, P = .13). CONCLUSIONS In patients with CV disease and atherogenic dyslipidemia on statin-based therapy, 3 years of ERN treatment did not lower CV event rates. An additional year of follow-up off assigned treatment did not alter these findings.
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Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: Rationale and design of the STRENGTH trial.
Nicholls, SJ, Lincoff, AM, Bash, D, Ballantyne, CM, Barter, PJ, Davidson, MH, Kastelein, JJP, Koenig, W, McGuire, DK, Mozaffarian, D, et al
Clinical cardiology. 2018;(10):1281-1288
Abstract
It is uncertain whether omega-3 fatty acids are beneficial in statin-treated patients. Epanova is a mix of omega-3 free fatty acids, not requiring co-ingestion with food, which can lower triglycerides by up to 31%. STRENGTH will examine whether Epanova 4 g daily reduces the rate of cardiovascular events in statin-treated patients with hypertriglyceridemia and low levels of HDL-C at high risk for developing cardiovascular events. STRENGTH is a randomized, double-blind, placebo-controlled trial. Patients had a triglyceride level ≥ 180 to <500 mg/dL and HDL-C < 42 mg/dL (men) or < 47 mg/dL (women) in the presence of either (1) established atherosclerotic cardiovascular disease, (2) diabetes with one additional risk factor, or (3) were other high-risk primary prevention patients, based on age and risk factor assessment. Patients should be treated with a statin, for >4 weeks, and have LDL-C < 100 mg/dL, but were also eligible if LDL-C was ≥100 mg/dL while on maximum tolerated statin therapy. The study will extend from October 30, 2014 to October 30, 2019. 13 086 patients were randomized to Epanova 4 g or placebo daily in addition to standard medical therapy. The primary efficacy outcome is time to first event of cardiovascular death, myocardial infarction, stroke, coronary revascularization or hospitalization for unstable angina. The trial will continue until 1600 patients reach the primary endpoint, with a median duration of therapy of 3 years. STRENGTH will determine whether Epanova 4 g daily will reduce cardiovascular events in statin-treated high-risk patients with hypertriglyceridemia and low HDL-C levels.
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Changes in HDL-c concentrations after 16 weeks of combined training in postmenopausal women: characteristics of positive and negative responders.
Diniz, TA, Rossi, FE, Fortaleza, ACS, Neves, LM, Christofaro, DGD, Buonani, C, Lira, FS, Campos, EZ, Prado, WLD, Freitas, IF
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2018;(1):38-44
Abstract
This study aimed to investigate the individual characteristics of body composition and metabolic profile that could explain interindividual variation in high-density lipoprotein cholesterol (HDL-c) concentrations in response to 16 weeks of combined strength plus aerobic (combined) training in postmenopausal women. The participants were divided into tertiles based on percentage of changes in HDL-c concentrations after combined training. Only women in the upper tertile (positive responders: Δ > 10.4%; n = 19) and lower tertile (negative responders: Δ < -1.4%; n = 19) were considered for analyses. The total body fat (BF), trunk fat (TF), android fat (AF), gynoid fat, and lean body mass were estimated by dual-energy X-ray absorptiometry. The metabolic profile - glucose, triacylglycerol, total cholesterol, HDL-c, low-density lipoprotein cholesterol, and very-low-density lipoprotein (VLDL) - were assessed. After 16 weeks, both positive and negative responders presented similar improvement in body composition, such as a decrease in percentage and kilograms of BF, TF, and AF, and increase in lean body mass (p value for time < 0.05). As expected, there was an effect of time and also a significant interaction (time vs. group) (p value < 0.001) in the improvement of HDL-c, with higher values for positive responders. Regarding metabolic profile, there were significant interactions (time vs. group) for triacylglycerol (p value = 0.032) and VLDL (p value = 0.027) concentrations, with lower values for positive responders. Our results suggests there is heterogeneity in combined training-induced HDL-c changes in postmenopausal women, and the positive responders were those who presented more pronounced decreases in triacylglycerol and VLDL concentrations.
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The impact of argan oil on plasma lipids in humans: Systematic review and meta-analysis of randomized controlled trials.
Ursoniu, S, Sahebkar, A, Serban, MC, Banach, M, ,
Phytotherapy research : PTR. 2018;(3):377-383
Abstract
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.
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Dietary linoleic acid interacts with FADS1 genetic variability to modulate HDL-cholesterol and obesity-related traits.
Dumont, J, Goumidi, L, Grenier-Boley, B, Cottel, D, Marécaux, N, Montaye, M, Wagner, A, Arveiler, D, Simon, C, Ferrières, J, et al
Clinical nutrition (Edinburgh, Scotland). 2018;(5):1683-1689
Abstract
BACKGROUND & AIMS Blood levels of polyunsaturated fatty acids (PUFAs) are under control of endogenous synthesis via Δ5- and Δ6-desaturases, encoded by the FADS1 and FADS2 genes, respectively and of diet. Genome-wide associations studies (GWAS) reported associations between polymorphisms in FADS1-FADS2 and variations in plasma concentrations of PUFAs, HDL- and LDL-cholesterol and triglycerides. However, it is not established whether dietary PUFAs intake modulates these associations. We assessed whether dietary linoleic acid (LA) or α-linolenic acid (ALA) modulate the association between the FADS1 rs174547 polymorphism (a GWAS hit) and lipid and anthropometric phenotypes. METHODS Dietary intakes of LA and ALA, FADS1 rs174547 genotypes, lipid and anthropometric variables were determined in three French population-based samples (n = 3069). These samples were stratified according to the median dietary LA (<9.5 and ≥9.5 g/d) and ALA (<0.80 and ≥0.80 g/d) intakes. The meta-analysis was performed using a random-effect. RESULTS Our meta-analysis confirmed the association between rs174547 and plasma lipid levels and revealed an association with waist circumference and body mass index. These associations were not modified by dietary ALA intake (all p-interaction > 0.05). In contrast, the associations with HDL-cholesterol levels, waist circumference and BMI were modulated by the dietary intake of LA (p interaction < 0.05). In high LA consumers only, the rs174547 minor allele was significantly associated with lower HDL-cholesterol levels (β = -0.05 mmol/L, p = 0.0002). Furthermore, each copy of the rs174547 minor allele was associated with a 1.58 cm lower waist circumference (p = 0.0005) and a 0.46 kg m-2 lower BMI (p = 0.01) in the low LA intake group, but not in the high LA intake group. CONCLUSIONS The present study suggests that dietary LA intake may modulate the association between the FADS gene variants and HDL-cholesterol concentration, waist circumference and BMI. These gene-nutrient interactions, if confirmed, suggest that subjects carrying the rs174547 minor allele might benefit from low dietary LA intakes.
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HDLs and the pathogenesis of atherosclerosis.
Schwertani, A, Choi, HY, Genest, J
Current opinion in cardiology. 2018;(3):311-316
Abstract
PURPOSE OF REVIEW Plasma levels of HDL cholesterol are a biomarker of cardiovascular health but not a therapeutic target, as demonstrated by the failure of pharmacological modulation of HDL cholesterol to prevent or treat atherosclerotic cardiovascular disease. In health, HDL particles exert pleiotropic effects against atherosclerosis, including cholesterol removal from foam cells, vasodilatory effects through vascular endothelial cell nitric oxide production, decreased vascular inflammation and oxidative damage, endothelial cell proliferation and antiapoptotic effects. RECENT FINDINGS These functional effects of HDL are independent of the cholesterol mass and are related to the proteome and lipidome. In disease states and with the ageing process, HDL components are extensively modified and may no longer play a beneficial role but are retained in the atheroma and contribute to atherosclerosis. We have recently shown that desmocollin 1 (DSC1) acts as an apolipoprotein (apo) A-I binding protein that is highly expressed in atherosclerotic plaques and inhibits atheroprotective HDL functions by retaining apoA-I. The apoA-I retention hypothesis proposes that macrophages express DSC1 in a maladaptive process that renders apoA-I inactive and contributes to atherosclerosis. SUMMARY HDL loses their beneficial properties in ageing and disease states. Novel pathways may present new therapeutic avenues to restore their biological functions.
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Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis.
Kaseda, R, Tsuchida, Y, Gamboa, JL, Zhong, J, Zhang, L, Yang, H, Dikalova, A, Bian, A, Davies, S, Fogo, AF, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2018;(6):582-591
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Abstract
BACKGROUND AND AIMS Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD. METHODS AND RESULTS HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA. CONCLUSION Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.
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Lipid profile and effect of statin treatment in pooled phase II and phase III baricitinib studies.
Taylor, PC, Kremer, JM, Emery, P, Zuckerman, SH, Ruotolo, G, Zhong, J, Chen, L, Witt, S, Saifan, C, Kurzawa, M, et al
Annals of the rheumatic diseases. 2018;(7):988-995
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Abstract
OBJECTIVES Lipid profiles are altered by active disease in patients with rheumatoid arthritis (RA) and may be further modified by treatment with Janus kinase inhibitors and other disease-modifying antirheumatic drugs. METHODS Lipid data were analysed from phase II and III studies of 4 mg (n=997) and 2 mg (n=479) oral baricitinib administered once daily in patients with moderate-to-severe active RA. Lipoprotein particle size and number and GlycA were evaluated with nuclear magnetic resonance in one phase III study. The effect of statin therapy on lipid levels was evaluated in patients on statins at baseline and in patients who initiated statins during the study. RESULTS Treatment with baricitinib was associated with increased levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides, but no significant change in LDL-C:HDL-C ratio. Lipid levels plateaued after 12 weeks of treatment. Baricitinib treatment increased large LDL and decreased small, dense LDL particle numbers and GlycA. Lipid changes from baseline were not significantly different between baseline statin users and non-users. In patients who initiated statin therapy during the study, LDL-C, triglycerides (baricitinib 4 mg only) and apolipoprotein B decreased to pre-baricitinib levels; HDL-C and apolipoprotein A-I levels remained elevated. CONCLUSIONS Baricitinib was associated with increased LDL-C, HDL-C and triglyceride levels, but did not alter the LDL-C:HDL-C ratio. Evaluation of cardiovascular event rates during long-term treatment is warranted to further characterise these findings and their possible clinical implications. TRIAL REGISTRATION NUMBER NCT00902486, NCT01469013, NCT01185353, NCT01721044, NCT01721057, NCT01711359, NCT01710358, NCT01885078.