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Efficacy of Evolocumab vs low-density lipoprotein cholesterol apheresis in patients with familial hypercholesterolemia and high cardiovascular risk (EVOLAFER01).
Torres, E, Goicoechea, M, Hernández, A, Rodríguez Ferrero, ML, García, A, Macías, N, Anaya, F
Journal of clinical apheresis. 2020;(1):9-17
Abstract
UNLABELLED Low-density lipoprotein (LDL) apheresis has been considered the last option to treat refractory hyperlipidemia in patients with familiar hypercholesterolemia (FH). Evolocumab is a monoclonal antibody which has shown significant reduction of low-density lipoprotein cholesterol (LDL-C) serum levels and cardiovascular events. The aim of the study was to examine the comparative impact of LDL-apheresis vs Evolocumab vs the combination of both LDL-apheresis and Evolocumab on lipid and lipoprotein parameters, and other metabolic/inflammatory measures. DESIGN OF THE STUDY Non-randomized open case series study of 10 adult patients diagnosed with FH already on long-term LDL-apheresis therapy. The study was developed in three consecutive phases to compare LDL-apheresis, Evolocumab treatment and the combination of both. Laboratory parameters were collected pre and post LDL-apheresis and before Evolocumab administration. The primary endpoint was the reduction of LDL-C during the three phases. RESULTS Reduction of LDL-C levels with Evolocumab were 31.4% vs LDL-apheresis from 153 ± 35 mg/dL to 105 ± 56 mg/dL (P < .001). Reduction of Lp(a) was also significantly higher with Evolocumab (45.5%) than LDL-apheresis from 36 (6-119) to 20 (3-41) mg/dL, P = .027. In addition, HDL-C and apo-A increased after Evolocumab treatment, from 41 ± 6 to 46 ± 8 mg/dL (P = .003) and from 124 ± 13 to 144 ± 25 mg/dL (P = .001), respectively. No changes in immunological or inflammatory parameters were observed and no serious adverse events were recorded. CONCLUSION Evolocumab reduces LDL-C and Lp(a) more effectively than LDL-apheresis and combination of Evolocumab plus LDL-apheresis could be a therapeutic alternative to get lower LDL-C and Lp(a) levels in patients with very high cardiovascular risk.
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Small Dense Low-Density Lipoprotein Cholesterol and Carotid Intimal Medial Thickness Progression.
Ikezaki, H, Furusyo, N, Yokota, Y, Ai, M, Asztalos, BF, Murata, M, Hayashi, J, Schaefer, EJ
Journal of atherosclerosis and thrombosis. 2020;(10):1108-1122
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AIM: The association between small dense low-density lipoprotein cholesterol (sdLDL-C) levels and carotid intimal medial thickness (cIMT) progression has not been evaluated fully. We assessed specialized lipoproteins, including sdLDL-C, with regard to cIMT progression in a prospective observational study in Japan. METHODS Plasma total cholesterol, direct LDL-C, sdLDL-C, LDL-triglycerides (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL2-C, HDL3-C, triglycerides, Lp(a), and adiponectin were measured in 2,030 men and women (median age 59 years, free of cardiovascular disease (CVD) and off cholesterol lowering medication). At both baseline and after a five-year follow-up, cIMT was assessed. Univariate, multivariate regression, and least square analyses were performed to examine the relationships between direct LDL-C, sdLDL-C, and other lipoproteins with cIMT progression. RESULTS The median cIMT at baseline was 0.63 mm and five-year progression was 0.18 mm. After adjustment for standard CVD risk factors, including age, gender, systolic blood pressure, total cholesterol, HDL-C, smoking, diabetes, and hypertension treatment, only direct LDL-C, sdLDL-C, and the sdLDL-C/LDL-C ratio were associated with cIMT progression. Even in subjects with direct LDL-C <100 mg/dL, who were considered at low CVD risk, elevated sdLDL-C were associated with cIMT progression (P for trend=0.009) in a model with established CVD risk factors, although the sdLDL-C/LDL-C ratio did not. Those correlations did not change by including triglycerides as a controlling factor or excluding premenopausal women from the analyzed population. CONCLUSIONS Small dense LDL-C has a stronger relationship with cIMT progression than LDL-C does; therefore, measuring sdLDL-C may allow for the formulation of optimal therapy for CVD prevention.
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Functional training added to intradialytic cycling lowers low-density lipoprotein cholesterol and improves dialysis adequacy: a randomized controlled trial.
Bogataj, Š, Pajek, J, Buturović Ponikvar, J, Pajek, M
BMC nephrology. 2020;(1):352
Abstract
BACKGROUND Exercise has various positive effects on hemodialysis patients. However, there is no clear evidence which type of exercise yields better results. This study aimed to determine the effects of guided functional training added to the intradialytic cycling on dialysis adequacy and biochemical parameters in hemodialysis patients. Additionally, we aimed to investigate if patients could transfer functional exercise to an unsupervised home environment and retain gained improvements. METHODS Randomization was done to a functional training intervention group (INT) (n = 20) or intradialytic cycling control group (CON) (n = 20). The INT attended a pre-dialysis functional training in the first 8 weeks. In the second 8 weeks, they performed functional exercises at unsupervised home environment on non-dialysis days. During the whole study, both groups participated in the intradialytic cycling program. RESULTS Both groups demonstrated a significant increase in dialysis adequacy (Kt/V) in the eight (0.15, 95% CI 0.06 to 0.24; p = 0.003 for INT and 0.21, 95% CI 0.11 to 0.3; p < 0.001 for CON) and the 16th study week (0.13, 95% CI 0.03 to 0.24; p = 0.017 for INT and 0.13, 95% CI 0.03 to 0.22; p = 0.013 for CON) compared to their baseline values with no significant between-group differences. At week eight, the total cholesterol was significantly lowered in the INT (- 0.34 mmol/L, 95% CI - 0.6 to - 0.07; p = 0.016) and remained lower at week 16 (- 0.32 mmol/L, 95% CI - 0.64 to - 0.01; p = 0.049) with no significant changes in the CON. Low-density lipoprotein levels in the INT were significantly reduced after 8 weeks (- 0.35 mmol/L, 95% CI - 0.64 to - 0.06; p = 0.022) and remained reduced after 16 weeks (- 0.28 mmol/L, 95% CI - 0.52 to - 0.03; p = 0.030). There were no significant differences found for albumin, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, and hemoglobin in both groups. CONCLUSIONS We demonstrated that functional training added to intradialytic cycling improved lipid profile and dialysis adequacy. Additionally, the effects of the unsupervised, home-based program were preserved during the second study phase. This study supports the assumption that combined training is more effective compared to solely intradialytic exercise. TRIAL REGISTRATION ClinicalTrials.Gov, NCT03334123 . Registered 07 November 2017.
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Effect of pharmacist interventions on reducing low-density lipoprotein cholesterol (LDL-C) levels: A systematic review and meta-analysis.
Dixon, DL, Khaddage, S, Bhagat, S, Koenig, RA, Salgado, TM, Baker, WL
Journal of clinical lipidology. 2020;(3):282-292.e4
Abstract
BACKGROUND Clinical practice guidelines recommend team-based care as one strategy to improve dyslipidemia outcomes. Randomized controlled trials (RCTs) have demonstrated that pharmacist interventions reduce low-density lipoprotein cholesterol (LDL-C) levels. OBJECTIVE The objective of the study was to conduct a meta-analysis to determine the effectiveness of pharmacist interventions on reducing LDL-C levels. METHODS A literature search of RCTs published after January 1, 2000 was performed using MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Included RCTs evaluated a pharmacist intervention compared with usual care, reported baseline and follow-up LDL-C levels, and enrolled at least 100 patients. Mean differences in LDL-C and other lipid parameters were calculated using a random effects model. RESULTS Twenty-six RCTs (n = 22,095 patients) were included in the meta-analysis. Compared with usual care, pharmacist interventions significantly reduced LDL-C levels by -7.9 mg/dL (95% confidence interval (CI) -11.43 to -4.35; I2 = 94%). A subgroup analysis revealed a greater reduction in LDL-C (-13.73 mg/dL; 95% CI -24.07 to -3.40; I2 = 96%) when LDL-C was the sole primary outcome. Significant improvements in total cholesterol (-12.73 mg/dL, 95% CI -19.18 to -6.27), triglycerides (-13.25 mg/dL, 95% CI -26.10 to -0.41), and high-density lipoprotein cholesterol (1.75 mg/dL, 95% CI 0.03 to 3.46) were also found. CONCLUSION Pharmacist interventions significantly reduced LDL-C levels compared with usual care. Further research is warranted to determine the optimal pharmacist intervention for reducing LDL-C levels and to evaluate the comprehensive role of pharmacists in lipid management.
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Rise in Low-Density Lipoprotein Cholesterol during Hospitalization is Related with Poor Outcome at Discharge in Patients with Acute Ischemic Stroke.
Yuan, HW, Yang, YN, Chen, HF, Ji, RJ, Lin, YJ, Guo, RY, Peng, GP, Liang, H, Luo, B
Cerebrovascular diseases (Basel, Switzerland). 2020;(1):88-96
Abstract
BACKGROUND The statistical association between a short-term rise in low-density lipoprotein cholesterol (LDL-C) levels and the short-term outcome of acute ischemic stroke remains unknown. We aimed to evaluate the association in acute ischemic stroke patients during hospitalization. METHODS Patients with acute ischemic stroke who received statin at discharge were enrolled in this multicenter registry study. LDL-C values were measured on the first day after admission and on the day before discharge to determine the rise in LDL-C levels. Poor outcome was defined as a modified Ranking Scale score ≥2 at discharge. The National Institutes of Health Stroke Scale increase from admission to discharge by 2 points was defined as clinical deterioration. Logistic regression analyses were used to analyze the relationship between LDL-C rise during hospitalization and poor outcome at discharge. Variables that were significantly different between the LDL-C rise and LDL-C fall groups were considered in adjustment for confounding variables in model 1. Age, sex, and those variables in model 1 were considered in adjustment for confounding variables in model 2. RESULTS Among the 676 patients, 110 (16.3%) showed a rise in LDL-C levels during hospitalization. Multivariate analyses showed that LDL-C at admission <1.6 mmol/L was significantly correlated with LDL-C rise during hospitalization (p < 0.001). There were significantly more patients with a poor outcome in the "LDL-C rise" group than in the "LDL-fall" group (p = 0.002). Multiple models consistently showed that LDL-C rise increased the risk of a poor outcome at discharge in model 1 (OR [95% CI] 1.351 [1.059-1.723], p = 0.016) and model 2 (OR [95% CI] 1.370 [1.071-1.751], p = 0.012). LDL-C rise also increased the risk of clinical deterioration, although its p value only was 0.043 in model 1 and 0.048 in model 2. CONCLUSIONS Rise in LDL-C during hospitalization from acute ischemic stroke is an independent predictor of poor outcome at discharge. In particular, patients with lower LDL-C values at admission are a higher at risk, and LDL-C in these patients should thus be monitored while in hospital.
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Effect of Evolocumab on Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a): A Pooled Analysis of Phase 2 and Phase 3 Studies.
Toth, PP, Jones, SR, Monsalvo, ML, Elliott-Davey, M, López, JAG, Banach, M
Journal of the American Heart Association. 2020;(5):e014129
Abstract
Background Dyslipidemia guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) as additional targets of therapy and consider lipoprotein(a) a significant cardiovascular risk marker. The current analysis evaluates the effects of evolocumab on these parameters in various patient populations over time. Methods and Results Data from 7690 patients, 4943 of whom received at least 1 dose of evolocumab, in 15 phase 2 and phase 3 studies with a duration ranging from 12 weeks to 5 years were pooled based on study length, patient population, and ezetimibe or placebo comparator groups. Patients could receive intensive statin therapy but not in the statin intolerance and monotherapy studies. The effects of evolocumab on percent change from baseline for non-HDL-C, ApoB, and lipoprotein(a) and achievement of treatment goals for non-HDL-C and ApoB were examined. Compared with placebo, evolocumab at both approved dosing regimens substantially reduced mean non-HDL-C (Q2W dose: -49% to -56%, monthly dose: -48% to -52%), mean ApoB (Q2W dose: -46% to -52%, monthly dose: -40% to -48%), and median lipoprotein(a) (Q2W dose: -22% to -38%, monthly dose: -20% to -33%) at 12 weeks. Effects on all 3 parameters persisted over 5 years. Lipid-lowering effects were consistent among the patient populations examined (hypercholesterolemia/mixed dyslipidemia, statin intolerance, heterozygous familial hypercholesterolemia, and type 2 diabetes mellitus). Conclusions In this pooled analysis, evolocumab substantially reduced non-HDL-C, ApoB, and lipoprotein(a) compared with placebo. The effect was consistent and maintained in various patient populations over 5 years.
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Snacking on whole almonds for 6 weeks improves endothelial function and lowers LDL cholesterol but does not affect liver fat and other cardiometabolic risk factors in healthy adults: the ATTIS study, a randomized controlled trial.
Dikariyanto, V, Smith, L, Francis, L, Robertson, M, Kusaslan, E, O'Callaghan-Latham, M, Palanche, C, D'Annibale, M, Christodoulou, D, Basty, N, et al
The American journal of clinical nutrition. 2020;(6):1178-1189
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BACKGROUND There is convincing evidence that daily whole almond consumption lowers blood LDL cholesterol concentrations, but effects on other cardiometabolic risk factors such as endothelial function and liver fat are still to be determined. OBJECTIVES We aimed to investigate whether isoenergetic substitution of whole almonds for control snacks with the macronutrient profile of average snack intakes, had any impact on markers of cardiometabolic health in adults aged 30-70 y at above-average risk of cardiovascular disease (CVD). METHODS The study was a 6-wk randomized controlled, parallel-arm trial. Following a 2-wk run-in period consuming control snacks (mini-muffins), participants consumed either whole roasted almonds (n = 51) or control snacks (n = 56), providing 20% of daily estimated energy requirements. Endothelial function (flow-mediated dilation), liver fat (MRI/magnetic resonance spectroscopy), and secondary outcomes as markers of cardiometabolic disease risk were assessed at baseline and end point. RESULTS Almonds, compared with control, increased endothelium-dependent vasodilation (mean difference 4.1%-units of measurement; 95% CI: 2.2, 5.9), but there were no differences in liver fat between groups. Plasma LDL cholesterol concentrations decreased in the almond group relative to control (mean difference -0.25 mmol/L; 95% CI: -0.45, -0.04), but there were no group differences in triglycerides, HDL cholesterol, glucose, insulin, insulin resistance, leptin, adiponectin, resistin, liver function enzymes, fetuin-A, body composition, pancreatic fat, intramyocellular lipids, fecal SCFAs, blood pressure, or 24-h heart rate variability. However, the long-phase heart rate variability parameter, very-low-frequency power, was increased during nighttime following the almond treatment compared with control (mean difference 337 ms2; 95% CI: 12, 661), indicating greater parasympathetic regulation. CONCLUSIONS Whole almonds consumed as snacks markedly improve endothelial function, in addition to lowering LDL cholesterol, in adults with above-average risk of CVD.This trial was registered at clinicaltrials.gov as NCT02907684.
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Evidence That Baseline Levels of Low-Density Lipoproteins Cholesterol Affect the Clinical Response of Graves' Ophthalmopathy to Parenteral Corticosteroids.
Naselli, A, Moretti, D, Regalbuto, C, Arpi, ML, Lo Giudice, F, Frasca, F, Belfiore, A, Le Moli, R
Frontiers in endocrinology. 2020;:609895
Abstract
BACKGROUND High dose intravenous glucocorticoid (ivGC) therapy is the first line treatment in moderate to severe Graves' ophthalmopathy (GO) and is associated with a clinical response rate ranging from 50% to 80%. Recently, a positive correlation between total cholesterol and low-density lipoproteins cholesterol (LDLc) with GO presentation and activity has been described. OBJECTIVE We aimed at evaluating whether, in patients with moderate to severe active GO treated with ivGC therapy, cholesterol, and LDLc could represent valuable predictive factors of medium-term GO outcome. METHODS This single center retrospective study was conducted in a consecutive series of 87 patients undergone ivGC therapy because affected by moderate to severe active GO. Clinical outcome of GO was evaluated at week 6 (W6) and 12 (W12) in respect to baseline conditions (week 0) by the seven points CAS according to EUGOGO recommendations. Univariate analysis and binary logistic regression were performed for the outcome variable W12CAS. RESULTS In patients with active GO, an early positive clinical response to ivGC therapy (as evaluated by CAS at 6W) was a strong determinant (OR=13) of the clinical outcome at week 12. Moreover, high levels of LDLc at baseline were positively associated with a reduction in the likelihood of being classified as improved at 12W. Patients with LDLc >193.6 mg/dl were very likely to respond negatively to ivGC therapy independently from the response at 6W. Based on these results, we propose a predictive decision-making model to be tested in future prospective studies. DISCUSSION We found that, in patients with active GO, both an early clinical response to ivGC therapy and baseline LDLc levels are significant determinants of GO outcome (W12CAS). These data support the need of a cholesterol-lowering treatment before addressing these patients to ivGC therapy.
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Role of Lipid-Lowering Therapy in Low-Density Lipoprotein Cholesterol Goal Attainment: Focus on Patients With Acute Coronary Syndrome.
Wang, Q, Liang, C
Journal of cardiovascular pharmacology. 2020;(6):658-670
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Dyslipidemia is a major risk factor for cardiovascular (CV) disease, which is the leading cause of death globally. Acute coronary syndrome (ACS) is a common cause of death, accounting for nearly half of the global burden of CV mortality. Epidemiologic studies have identified low-density lipoprotein cholesterol (LDL-C) as an independent CV risk factor, and this is now the primary target for initiating and adjusting lipid-lowering therapies in most current guidelines. Evidence from pivotal studies supports the use of high-intensity statin therapy and a lower level for optimal LDL-C in secondary prevention of atherosclerotic CV disease, especially in patients with ACS undergoing percutaneous coronary intervention. However, current research has identified a gap between the target LDL-C goal attainment and target LDL-C levels recommended by the guidelines. Statins have proven benefits in the management of CV disease and are the cornerstone of lipid-lowering management in patients with ACS. Recent randomized controlled trials have also demonstrated the benefits of cholesterol absorption inhibitors and proprotein convertase subtilisin/kexin type 9 inhibitors. This review summarizes the current evidence for LDL-lowering therapy in patients with ACS, with an emphasis on the importance of LDL-C goal attainment, rapid LDL-C lowering, and duration of LDL-C-lowering therapy.
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Serum folate modified the association between low-density lipoprotein cholesterol and carotid intima-media thickness in Chinese hypertensive adults.
Ding, C, Bi, C, Lin, T, Hu, L, Huang, X, Liu, L, Liu, C, Song, Y, Tang, G, Wang, B, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(12):2303-2311
Abstract
BACKGROUND AND AIMS While folate is known for its importance in cardiovascular health, it is unknown whether folate status can modify the association between low-density lipoprotein cholesterol (LDL-C) and carotid intima-media thickness (CIMT). We aimed to investigate this question in a Chinese hypertensive population, who are at high-risk of low folate and atherosclerosis. METHODS AND RESULTS This report included 14,970 hypertensive adults (mean age 64.5 years; 40.3% male) from the China Stroke Primary Prevention Trial (CSPPT) and analyzed the fasting serum LDL-C and folate, and CIMT data obtained at the last follow-up visit. LDL-C was calculated using the Friedewald equation. Serum folate levels were measured by chemiluminescent immunoassay. CIMT was measured by ultrasound. Non-parametric smoothing plots, multivariate linear regression analysis, subgroup analyses and interaction testing were performed to examine the LDL-C-CIMI relationship and effect modification by folate. Consistent with graphic plots, multivariate linear regression showed that LDL-C levels were independently and positively associated with CIMT (β = 7.69, 95%CI: 5.76-9.62). More importantly, the relationship between LDL-C and CIMT was significantly attenuated with increasing serum folate levels (1st tertile: β = 10.06, 95%CI: 6.67-13.46; 2nd tertile: β = 6.81, 95%CI: 3.55-10.07; 3rd tertile: β = 5.96, 95%CI: 2.55-9.36; P-interaction = 0.045). Subgroup analyses showed the association between LDL-C and CIMT across serum folate tertiles was robust among various strata (all P-interaction >0.05). CONCLUSIONS Among Chinese hypertensive adults, the serum folate levels could modify the association between LDL-C and CIMT. Our findings, if further confirmed, have important clinical implications.