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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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2.
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.
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3.
Aortic valvular stenosis: Novel therapeutic strategies.
Natorska, J, Kopytek, M, Undas, A
European journal of clinical investigation. 2021;(7):e13527
Abstract
BACKGROUND Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non-surgical AS treatment, at least in patients with mild-to-moderate AS. MATERIALS AND METHODS The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021. RESULTS Growing evidence indicates that therapies using proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, simvastatin/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro-inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs. CONCLUSION Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin/ezetimibe combination, lipoprotein(a)-lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.
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4.
Emerging agents for the treatment and prevention of stroke: progress in clinical trials.
Safouris, A, Magoufis, G, Tsivgoulis, G
Expert opinion on investigational drugs. 2021;(10):1025-1035
Abstract
INTRODUCTION Recent years have witnessed unprecedented progress in stroke care, but unmet needs persist regarding the efficacy of acute treatment and secondary prevention. Novel approaches are being tested to enhance the efficacy of thrombolysis or provide neuroprotection in non-thrombolized patients. AREAS COVERED The current review highlights pharmaceutical agents under evaluation in clinical trials concerning the acute, subacute, and chronic phase post-stroke. We examine the evidence in favor of tenecteplase as an alternative thrombolytic drug to alteplase, nerinetide as a promising neuroprotective agent, and glibenclamide for reducing edema in malignant hemispheric infarction. We discuss the use of ticagrelor and the promising novel category of factor XI inhibitors in the subacute phase after stroke. We offer our insights on combined rivaroxaban and antiplatelet therapy, PCSK-9 inhibitors, and other non-statin hypolipidemic agents, as well as novel antidiabetic agents that have been shown to reduce cardiovascular events in the long-term. EXPERT OPINION Current approaches in stroke treatment and stroke prevention have already transformed stroke care from a linear one-for-all treatment paradigm to a more individualized approach that targets specific patient subgroups with novel pharmaceutical agents. This tendency enriches the therapeutic armamentarium with novel agents developed for specific stroke subgroups. ABBREVIATIONS IVT: intravenous thrombolysis; RCTs: randomized-controlled clinical trials; TNK: Tenecteplase; COVID-19: Coronavirus 2019 Disease; EXTEND-IA TNK The Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke trial; AIS: acute ischemic stroke; NNT: number needed to treat; MT: mechanical thrombectomy; sICH: symptomatic intracranial hemorrhage; mRS: modified Rankin Scale; AHA/ASA: American Heart Association/American Stroke Association; ESO: European Stroke Organization; NA-1: Nerinetide; ENACT Evaluating Neuroprotection in Aneurysm Coiling Therapy; CTA: CT angiography; TIA: transient ischemic attack; CHANCE Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events; LOF: loss-of-function; PRINCE Platelet Reactivity in Acute Nondisabling Cerebrovascular Events; THALES Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke and Death; CHANCE-2: Clopidogrel With Aspirin in High-risk Patients With Acute Non-disabling Cerebrovascular Events II; FXI: Factor XI; PACIFIC-STROKE Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-NonCardioembolic Stroke study; COMPASS Cardiovascular Outcomes for People Using Anticoagulation Strategies; CANTOS-ICAD: Combination Antithrombotic Treatment for Prevention of Recurrent Ischemic Stroke in Intracranial Atherosclerotic Disease; SAMMPRIS Stenting and Aggressive Medical Therapy for Preventing Recurrent Stroke in Intracranial Stenosis; WASID Warfarin-Aspirin Symptomatic Intracranial Disease; SPARCL Stroke Prevention by Aggressive Reduction in Cholesterol Levels; LDL-C: low-density lipoprotein cholesterol; TST: Treat Stroke to Target; IMPROVE-IT: Improved Reduction of Outcomes: Vytorin Efficacy International Trial; PCSK9: proprotein convertase subtilisin-kexin type 9; FOURIER Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; CLEAR Cholesterol Lowering via Bempedoic acid, an ACL-inhibiting Regimen; REDUCE-IT: Reduction of Cardiovascular Events With EPA Intervention Trial; STRENGTH Outcomes Study to Assess STatin Residual Risk Reduction With EpaNova in HiGh CV Risk PatienTs With Hypertriglyceridemia; ACCORD Action to Control Cardiovascular Risk in Diabetes; ADVANCE Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; VADT Veterans Affairs Diabetes Trial; GLP-1R: Glucagon-like peptide-1 receptor; SGLT2: sodium-glucose cotransporter 2; CONVINCE COlchicine for preventioN of Vascular Inflammation in Non-CardioEmbolic stroke; PROBE Prospective Randomized Open-label Blinded Endpoint assessment.
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Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition.
Black, DM, Miller, M, Heinonen, TM, Zhang, G
Journal of cardiovascular pharmacology. 2021;(4):496-500
Abstract
Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.
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6.
Dyslipidemia Management in Adults With Diabetes.
Lazarte, J, Hegele, RA
Canadian journal of diabetes. 2020;(1):53-60
Abstract
Lipid abnormalities beyond elevated low-density lipoprotein (LDL) cholesterol contribute to increased risk of atherosclerotic cardiovascular disease (ASCVD) in type 2 diabetes. We searched for English language randomized controlled trials of lipid-lowering therapies primarily since 2012 that included patients with diabetes. Diet and lifestyle advice are always a starting point for ASCVD prevention in diabetes. After almost 30 years of widespread clinical use in diabetes, statin treatment to reduce LDL cholesterol remains the cornerstone of drug therapy to prevent ASCVD. Ezetimibe appears to be particularly beneficial for high-risk statin-treated patients with diabetes. Similarly, currently available proprotein convertase subtilisin kexin type 9 inhibitors-alirocumab and evolocumab-both reduce ASCVD risk in statin-treated patients with diabetes. High-dose icosapent ethyl is another worthwhile add-on treatment, especially in statin-treated patients with diabetes in whom triglyceride levels remain elevated. Fibrates might reduce ASCVD risk in patients with diabetes with high triglyceride and low high-density lipoprotein cholesterol; however, fibrates are more strongly recommended for prophylaxis of pancreatitis in patients with severe hypertriglyceridemia and may also slow progression of diabetic retinopathy. Several existing and newer drug treatments reduce ASCVD risk through LDL cholesterol and/or triglyceride reduction in patients with diabetes. Novel approaches using antisense oligonucleotides and monoclonal antibodies may provide potential future therapies for diabetic dyslipidemia.
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7.
New agents to reduce cholesterol levels: implications for nephrologists.
Del Vecchio, L, Baragetti, I, Locatelli, F
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(2):213-218
Abstract
Statins and ezetimibe effectively reduce the burden of cardiovascular (CV) disease in patients with chronic kidney disease (CKD). Unfortunately, many subjects still die or have CV events despite cholesterol-lowering therapy. This is particularly true in patients with more advanced CKD. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that induces the degradation of the low-density lipoprotein receptor by targeting it for lysosomal destruction. Its inhibition causes a dramatic fall in cholesterol levels on top of maximized statin therapy. This goal is obtained with different therapeutic approaches, spanning from monoclonal antibodies to non sense oligonucleotides and silencing RNA (siRNA). Two human, monoclonal antibodies are approved for clinical use; they are still very expensive. Both agents significantly lower cholesterol levels. Evolocumab and alirocumab reduce significantly the risk for CV disease without relevant safety issues. Inclisiran is an siRNA molecule that produces PCSK9-specific RNA silencing. Data from a Phase II study showed significant cholesterol-lowering efficacy. The experience accumulated so far is limited in the CKD population. PCSK9 inhibition also has the potential to reduce the burden of CV in this subset by obtaining a much greater decrease in serum cholesterol compared with statin therapy or ezetimibe. Doubts exist that this approach will improve the outcome of dialysis patients, in whom vascular calcifications predominate.
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8.
Familial hypercholesterolemia: Detect, treat, and ask about family.
Shah, NP, Ahmed, HM, Wilson Tang, WH
Cleveland Clinic journal of medicine. 2020;(2):109-120
Abstract
Familial hypercholesterolemia is an autosomal dominant disorder that affects the metabolism of low-density lipo-protein cholesterol (LDL-C) through mutations in the gene for LDL receptor (LDLR), and less commonly in those for apolipoprotein B (APOB), proprotein convertase subtili-sin-kexin type 9 (PCSK9), and others. Patients with these mutations have elevated plasma levels of LDL-C and, as a result, an increased risk of atherosclerotic cardiovascular disease beginning in childhood, leading to significant risk of illness and death.
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9.
Cholesterol Lowering and Stroke: No Longer Room for Pleiotropic Effects of Statins - Confirmation from PCSK9 Inhibitor Studies.
Salvatore, T, Morganti, R, Marchioli, R, De Caterina, R
The American journal of medicine. 2020;(1):95-99.e6
Abstract
BACKGROUND The relationship between cholesterol levels and stroke has been much less clear than the relationship between cholesterol levels and coronary heart disease. This is likely mostly due to the inadequate power of older studies and the low intensity of cholesterol-lowering interventions available at the time. Because a reduction in stroke has been, conversely, clearly observed in trials with statins, for long "pleiotropic" effects of such drugs, unrelated to cholesterol lowering, have been invoked. In a previous analysis of all randomized trials of cholesterol-lowering treatments reporting on stroke we had, however, reached the conclusion that any cholesterol lowering is related to a significant reduction of stroke, in a relationship that appeared to exist for both statin and nonstatin cholesterol-lowering interventions. Outcome results of the FOURIER trial with evolocumab, SPIRE-1 and -2 with bococizumab, and ODYSSEY OUTCOMES trial with alirocumab now offer the opportunity of clearly confirming or confuting this concept. METHODS We here report on an updated meta-regression of the relationship of total cholesterol changes that occur with various drugs or treatments and changes in the risk of stroke compared with control. RESULTS Relative risk (RR) figure found in FOURIER, SPIRE-1/2, and ODYSSEY OUTCOMES (0.79, 0.60, and 0.79) are extremely close to the RRs of 0.79, 0.79, and 0.84, respectively, predicted by our new meta-regression. CONCLUSIONS These findings offer definitive proof that the pure total (and low-density lipoprotein) cholesterol lowering, with any available lipid-lowering intervention, reduces stroke risk proportional to the extent of cholesterol reduction, without the need of invoking "pleiotropic" effects of any such treatment.
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10.
Management of LDL-cholesterol after an acute coronary syndrome: Key comparisons of the American and European clinical guidelines to the attention of the healthcare providers.
Gencer, B, Giugliano, RP
Clinical cardiology. 2020;(7):684-690
Abstract
Guidelines for the management of blood cholesterol were updated in the past year in the United States and Europe, reflecting a more intensive approach to lowering low-density lipoprotein cholesterol (LDL-C). The American College of Cardiology/American Heart Association task force on practice guideline released the 2018 guideline on the management of blood cholesterol on behalf of several American societies. Approximately 9 months later, the European Society of Cardiology/European Atherosclerosis Society published their 2019 guideline for the management of dyslipidemias. Both guidelines have similarities for the management of patients with acute coronary syndromes. Both emphasize risk assessment of patients as a main approach to guide therapy; those at higher risk of cardiovascular disease have a greater clinical benefit of LDL-C reduction by at least 50%. Both guidelines reinforce the indication to lower LDL-C as an important modifiable risk factor and consider the addition of nonstatin agents, such as ezetimibe and proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, in addition to lifestyle counseling and high-intensity statin for further reduction of LDL-C levels. However, the guidelines have differences in the concepts of treatment thresholds (≥70 mg/dL in the United States) vs treatment goals (< 55 mg/dL in Europe), in the definition of very high-risk category and in the classes for recommendation for the use of PCSK9 inhibitors.