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1.
The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism.
Li, X, Xin, Y, Mo, Y, Marozik, P, He, T, Guo, H
Molecules (Basel, Switzerland). 2022;(2)
Abstract
Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5-2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.
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Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease.
Furtado, JD, Ruotolo, G, Nicholls, SJ, Dullea, R, Carvajal-Gonzalez, S, Sacks, FM
Arteriosclerosis, thrombosis, and vascular biology. 2022;(2):227-237
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Abstract
OBJECTIVE Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80). We measured the concentration of apoA1 in total plasma and 17 protein-based HDL subspecies at baseline and 3 months. Both CETP inhibitors increased apoA1 in HDL that contains apoC3 the most of all HDL subspecies (median placebo-adjusted percent increase: evacetrapib 99% and torcetrapib 50%). They also increased apoA1 in other HDL subspecies associated with higher coronary heart disease risk such as those involved in inflammation (α-2-macroglobulin and complement C3) or hemostasis (plasminogen), and in HDL that contains both apoE and apoC3, a complex subspecies associated with higher coronary heart disease risk. ApoA1 in HDL that contains apoC1, associated with lower risk, increased 71% and 40%, respectively. Only HDL that contains apoL1 showed no response to either drug. CONCLUSIONS CETP inhibitors evacetrapib and torcetrapib increase apoA1 in HDL subspecies that contain apoC3 and other HDL subspecies associated with higher risk of coronary heart disease. Subspecies-specific effects shift HDL subspecies concentrations toward a profile associated with higher risk, which may contribute to lack of clinical benefit from raising HDL by pharmaceutical CETP inhibition.
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Efficacy of high-dose atorvastatin or rosuvastatin loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials with GRADE qualification of available evidence.
Borovac, JA, Leth-Olsen, M, Kumric, M, D'Amario, D, Schwarz, K, Glavas, D, Bozic, J
European journal of clinical pharmacology. 2022;(1):111-126
Abstract
PURPOSE We aimed to summarize current evidence regarding the impact of a high-dose statin loading before percutaneous coronary intervention (PCI) on short-term outcomes in patients presenting with the acute coronary syndrome (ACS). METHODS This meta-analysis was based on a search of the MEDLINE, Cochrane Central Register of Controlled Trials, Ovid Journals, and SCOPUS for randomized controlled trials that compared high-dose atorvastatin or rosuvastatin with no or low-dose statin administered before planned PCI in statin-naive patients with ACS. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), myocardial infarction (MI), and all-cause mortality at 30 days. Prespecified subanalyses were performed with respect to statin and ACS type. RESULTS A total of eleven trials enrolling 6291 patients were included, of which 75.4% received PCI. High-dose statin loading was associated with an overall 43% relative risk (RR) reduction in MACCE at 30 days (RR 0.57, 95% CI 0.41-0.77) in whole ACS population. This effect was primarily driven by the 39% reduction in the occurrence of MI (RR 0.61, 95% CI 0.46-0.80). No significant effect on all-cause mortality reduction was observed (RR 0.92, 95% CI 0.67-1.26). In the setting of ST-elevation myocardial infarction (STEMI), atorvastatin loading was associated with a 33% reduction in MACCE (RR 0.67, 95% CI 0.48-0.94), while in non-ST-elevation myocardial infarction ACS (NSTE-ACS), rosuvastatin loading was associated with 52% reduction in MACCE at 30 days (RR 0.48, 95% CI 0.34-0.66). The level of evidence as qualified with GRADE was low to high, depending on the outcome. CONCLUSION A high-dose loading of statins before PCI in patients with ACS reduces MACCE and reduces the risk of MI with no impact on mortality at 30 days. Atorvastatin reduces MACCE in STEMI while rosuvastatin reduces MACCE in NSTE-ACS at 30 days.
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Antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia: A systemic review and meta-analysis of randomized studies.
Lee, S, Yang, S, Chang, MJ
PloS one. 2021;(11):e0260391
Abstract
Some studies have suggested the antihypertensive effects of statins, a class of lipid-lowering agents, particularly in patients with hypertension. However, the evidence for the role of statins in blood pressure (BP) lowering is controversial, and no meta-analysis of rosuvastatin therapy has been conducted to assess its BP-lowering effects. Therefore, the aim of this meta-analysis of randomized controlled trials (RCTs) was to investigate the effects of rosuvastatin on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with hypertension. We systematically searched the electronic databases MEDLINE, EMBASE, and Cochrane Library to identify RCTs in which patients were assigned to groups of rosuvastatin plus antihypertensive agents vs. antihypertensive agents. The three authors independently selected the studies, extracted data, and assessed methodological quality. We included five RCTs in this meta-analysis with 288 patients treated with rosuvastatin and 219 patients without rosuvastatin. The mean DBP in the rosuvastatin group was significantly lower than that in the non-rosuvastatin group by -2.12 mmHg (95% confidence interval (CI) -3.72 to -0.52; Pfixed-effects model = 0.009; I2 = 0%, Pheterogeneity = 0.97). Rosuvastatin treatment also lowered the mean SBP compared with the non-rosuvastatin treatment by -2.27 mmHg, but not significantly (95% CI - 4.75 to 0.25; Pfixed-effects model = 0.08; I2 = 0%, Pheterogeneity = 0.82). In this study, we reviewed the antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia. We demonstrated a modest significant reduction of DBP and a trend toward a lowered SBP in patients with hypertension with rosuvastatin therapy. Rosuvastatin could be beneficial to control hypertension and, consequently, contribute toward reducing the risk of cardiovascular events in patients with hypertension and dyslipidemia.
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Atorvastatin and pravastatin stimulate nitric oxide and reactive oxygen species generation, affect mitochondrial network architecture and elevate nicotinamide N-methyltransferase level in endothelial cells.
Dymkowska, D, Wrzosek, A, Zabłocki, K
Journal of applied toxicology : JAT. 2021;(7):1076-1088
Abstract
Statins belong to the most often prescribed medications, which efficiently normalise hyperlipidaemia and prevent cardiovascular complications in obese and diabetic patients. However, beside expected therapeutic results based on the inhibition of 3-hydroxyl-3-methylglutaryl-CoA reductase, these drugs exert multiple side effects of poorly understood characteristic. In this study, side effects of pravastatin and atorvastatin on EA.hy926 endothelial cell line were investigated. It was found that both statins activate proinflammatory response, elevate nitric oxide and reactive oxygen species (ROS) generation and stimulate antioxidative response in these cells. Moreover, only slight stimulation of the mitochondrial biogenesis and significant changes in the mitochondrial network organisation have been noted. Although biochemical bases behind these effects are not clear, they may partially be explained as an elevation of AMP-activated protein kinase (AMPK) activity and an increased activating phosphorylation of sirtuin 1 (Sirt1), which were observed in statins-treated cells. In addition, both statins increased nicotinamide N-methyltransferase (NNMT) protein level that may explain a reduced fraction of methylated histone H3. Interestingly, a substantial reduction of the total level of histone H3 in cells treated with pravastatin but not atorvastatin was also observed. These results indicate a potential additional biochemical target for statins related to reduced histone H3 methylation due to increased NNMT protein level. Thus, NNMT may directly modify gene activity.
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Effect of Upadacitinib on the Pharmacokinetics of Rosuvastatin or Atorvastatin in Healthy Subjects.
Mohamed, MF, Coppola, S, Feng, T, Camp, HS, Kim, E, Othman, AA
Clinical pharmacology in drug development. 2021;(11):1335-1344
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Abstract
This phase 1, 2-part, 2-period, open-label, drug-drug interaction study evaluated the potential for pharmacokinetic interactions between upadacitinib and rosuvastatin, an organic anion transporting polypeptide (OATP) 1B1 and breast cancer resistance protein substrate, or atorvastatin, a cytochrome P450 3A, OATP1B1, and OATP1B3 substrate, in 36 healthy volunteers. During period 1, a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered on day 1, followed by a washout period of 5 days. During period 2, once-daily doses of upadacitinib extended-release (30 mg) were administered on days 1 to 10, and a single dose of rosuvastatin (5 mg; part 1) or atorvastatin (10 mg; part 2) was administered 1 hour after the upadacitinib dose on day 7. Serial blood samples were collected for assays of drug concentrations. In Part 1, rosuvastatin maximum observed plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to infinity (AUCinf ) were 23% and 33% lower, respectively, when administered with upadacitinib relative to when administered alone. In part 2, atorvastatin Cmax and AUCinf was 11% and 23% lower, respectively, when administered with upadacitinib relative to when administered alone. The Cmax and AUCinf of the active metabolite ortho-hydroxyatorvastatin remained unchanged. Administration of a single 5-mg dose of rosuvastatin or a single 10-mg dose of atorvastatin had no relevant effect on upadacitinib Cmax or area under the plasma concentration-time curve. These results demonstrated that upadacitinib has no clinically relevant effect on the pharmacokinetics of rosuvastatin and atorvastatin or on substrates transported by OATP1B or breast cancer resistance protein.
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Frequency and Impact of Hyponatremia on All-Cause Mortality in Patients With Aortic Stenosis.
Ramberg, E, Greve, AM, Berg, RMG, Sajadieh, A, Haugaard, SB, Willenheimer, R, Olsen, MH, Wachtell, K, Nielsen, OW
The American journal of cardiology. 2021;:93-97
Abstract
Asymptomatic aortic stenosis (AS) is a frequent condition that may cause hyponatremia due to neurohumoral activation. We examined if hyponatremia heralds poor prognosis in patients with asymptomatic AS, and whether AS in itself is associated with increased risk of hyponatremia. The study question was investigated in 1,677 individuals that had and annual plasma sodium measurements in the SEAS (Simvastatin and Ezetimibe in AS) trial; 1,873 asymptomatic patients with mild-moderate AS (maximal transaortic velocity 2.5 to 4.0 m/s) randomized to simvastatin/ezetimibe combination versus placebo. All-cause mortality was the primary endpoint and incident hyponatremia (P-Na+ <137 mmol/L) a secondary outcome. At baseline, 4% (n = 67) had hyponatremia. After a median follow-up of 4.3 (interquartile range 4.1 to 4.6) years, 140 (9%) of those with initial normonatremia had developed hyponatremia, and 174 (10%) had died. In multiple regression Cox models, both baseline hyponatremia (hazard ratio [HR] 2.1, [95% confidence interval 1.1 to 3.8]) and incident hyponatremia (HR 1.9, [95% confidence interval 1.0 to 3.4], both p ≤ .03) was associated with higher all-cause mortality as compared with normonatremia. This association persisted after adjustment for diuretics as a time-varying covariate. Higher N-terminal pro b-type natriuretic peptide levels and lower sodium levels at baseline was associated with higher risk of incident hyponatremia. Conversely, assignment to simvastatin/ezetimibe protected against incident hyponatremia. In conclusion, both prevalent and incident hyponatremia associate with increased mortality in patients with AS. The prevalence of hyponatremia is around 4% and the incidence about 2% per year, which is comparable to that of older adults without AS.
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Serum Metabolomics Reveals Underlying Mechanisms of Cholesterol-Lowering Effects of Oat Consumption: A Randomized Controlled Trial in a Mildly Hypercholesterolemic Population.
Xu, D, Wang, S, Feng, M, Shete, V, Chu, Y, Kamil, A, Yang, C, Liu, H, Xia, H, Wang, X, et al
Molecular nutrition & food research. 2021;(9):e2001059
Abstract
INTRODUCTION The purpose of this study is to examine the effects of oat supplementation on serum lipid in a population of adults with mild hypercholesterolemia and reveal the underlying mechanisms with serum untargeted metabolomics. METHODS AND RESULTS In this placebo-controlled trial, 62 participants from Nanjing, China, with mild elevations in cholesterol are randomly assigned to receive 80 g oats (containing 3 g beta-glucan) or rice daily for 45 days. Fasting blood samples are collected at the beginning, middle, and end of the trial. Compared with the rice group, oat consumption significantly decreases serum total cholesterol (TC) (-8.41%, p = 0.005), low-density lipoprotein cholesterol (LDL-c) (-13.93%, p = 0.001), and non high-density lipoprotein cholesterol (non-HDL-c) (-10.93%, p = 0.017) levels. There are no significant between-group differences in serum triglyceride (TG), apolipoprotein B (Apo B), glycated albumin, or fasting blood glucose levels. An orthogonal partial least squares discriminant analysis (OPLS-DA) suggests a clear separation in metabolic profiles between the groups after the intervention. Twenty-one metabolites in the oat group are significantly different from those in the rice group, among which 14 metabolites show a decreased trend. In comparison, seven metabolites show an increased trend. Correlations analysis from both groups indicate that most metabolites [e.g., sphinganine and phosphatidylcholine (PC)(20:5(5Z,8Z,11Z,14Z,17Z)/20:1(11Z))] have positive correlations with serum cholesterol levels. Kyoto Encyclopedia of Gene and Genomes pathway analysis suggests that oat consumption regulated glycerophospholipid, alanine, aspartate and glutamate, sphingolipid, and retinol metabolism. CONCLUSION Oat consumption has beneficial effects on serum lipids profiles. The underlying mechanisms involve glycerophospholipid, alanine, aspartate and glutamate, sphingolipid, and retinol metabolism in adults.
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Effectiveness and Safety of Novel Nutraceutical Formulation Added to Ezetimibe in Statin-Intolerant Hypercholesterolemic Subjects with Moderate-to-High Cardiovascular Risk.
Mazza, A, Nicoletti, M, Lenti, S, Torin, G, Rigatelli, G, Pellizzato, M, Fratter, A
Journal of medicinal food. 2021;(1):59-66
Abstract
The effectiveness of statins in the primary and secondary prevention of cardiovascular (CV) diseases has been widely proven. However, the onset of adverse events associated with their use prevents to achieve the therapeutic targets recommended by the guidelines (GL) for the management of dyslipidemia. In the event of statin intolerance, the GL recommend to use bile acid sequestrants, fibrates, and ezetimibe in monotherapy, but their benefits in improving lipid pattern are quite modest. This study aims at evaluating the effectiveness and safety of a nutraceutical compound (NC) associated with ezetimibe (EZE) on the lipid profile in statin-intolerant patients with moderate-to-high CV risk. Ninety-six statin-intolerant hypertensive and hypercholesterolemic subjects treated pharmacologically with EZE 10 mg daily were randomized in open label (n = 48) to take for 3 months a NC containing Monacolin-K (MK), Berberine Hydrochloride (BC), t-Resveratrol (RES), Quercetin (QUER), and Chromium (CH) in the form of a gastro-resistant tablet that improves enteric bioaccessibility and bioavailability of these substances. The control group (n = 48) took only EZE in monotherapy at the same dosage; both groups followed a standardized lipid-lowering diet. The total serum cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine phosphokinase (CPK) levels were compared at the follow-up in both groups using Student's t-test. TC and LDL levels reduced in both groups, but were lower in the group treated with EZE + NC (-25.9% vs. -15%, P < .05 and -38.7% vs. -21.0%, P < .05, respectively). No changes were observed in either group regarding a decrease in TG (-9.4% vs. -11.7%, NS) and an increase in HDLC (+4.2% vs. +1.1%, NS). The AST, ALT, and CPK levels increased in the group treated with the EZE + NC compared to the control group, but were still within the acceptable range. There was no difference concerning the lipid-lowering treatment between gender, and no patient withdrew from the study. In the short term, the EZE + NC combination therapy is well tolerated and effective in improving TC and LDLC levels in statin-intolerant patients with moderate-to-high CV risk.
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Advances with lipid-lowering drugs for pediatric patients with familial hypercholesterolemia.
Ferrari, F, Martins, VM, Rocha, VZ, Santos, RD
Expert opinion on pharmacotherapy. 2021;(4):483-495
Abstract
INTRODUCTION Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated LDL-cholesterol (LDL-C) and early onset of atherosclerosis. AREAS COVERED The authors provide an overview of the pediatric FH scenario, with emphasis on the role of statins as the preferred pharmacological therapy, discussing their potential benefits, as well as adverse effects, and the remaining uncertainties about their use in this population. They also comment on other lipid-lowering therapies. EXPERT OPINION Statin therapy is recommended after the ages of 8-10 years old for heterozygous FH patients and can reduce LDL-C by 24-50% depending on drug type and dosage. For more severe cases, higher doses and adjuvant therapies like ezetimibe may be necessary and treatment should be started at diagnosis, as is the case of homozygous FH. Statins reduce progression of subclinical vascular disease and may reduce early cardiovascular events. The available evidence indicates safety of statins in children with no apparent harms related to growth, sexual maturation, steroid hormones, glucose levels, cognitive function, or muscle and liver problems, in comparison with placebo. Newer treatments like lomitapide, PCSK9 inhibitors, bempedoic acid and evinacumab need to be adequately evaluated in pediatric FH patients with more severe dyslipidemia.