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The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia.
Penson, PE, Banach, M
Current atherosclerosis reports. 2020;(11):67
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Abstract
PURPOSE OF REVIEW We aimed to summarize recent guidelines, position papers, and high-quality clinical research relating the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease. RECENT FINDINGS It is essential that individuals at high risk of cardiovascular disease receive guideline-directed evidence-based therapies to reduce their risk of morbidity and mortality from cardiovascular events. Compared with conventional therapeutics, nutraceuticals have undergone relatively little investigation in randomized controlled trials. Thus, recommendations for nutraceuticals in international guidelines are rare, and nutraceuticals should not be used preferentially in place of statins. Nevertheless, recent position papers from the International Lipid Expert Panel and clinical evidence from studies of triglyceride reduction by polyunsaturated fatty acid administration demonstrate that nutraceuticals do have an important role in optimizing therapy in individuals at high risk of cardiovascular disease. Roles for nutraceuticals include as follows: (1) managing residual risk associated with lipids other than low-density lipoprotein cholesterol (LDL-C); (2) managing non-lipid-mediated residual risk; (3) optimizing LDL-C treatment in statin intolerance; (4) optimizing LCL-C treatment when add-on therapies for statins are not available; (5) as adjuncts to lifestyle for individuals at high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The strength of evidence for each of these applications is variable. In addition to guideline-directed therapeutics, nutraceuticals may have roles in optimizing preventative therapy and targeting residual risk in individuals at high risk of ASCVD. Application of Good Manufacturing Practice and randomized controlled trials when producing and evaluating nutraceuticals will expand the armoury of evidence-based agents for the prevention of ASCVD.
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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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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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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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Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature.
Sreedharan, AV, Pek, SLT, Tan, TH, Tavintharan, S, Yap, F
Journal of clinical lipidology. 2020;(5):639-645
Abstract
Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1_941-1) (1845 + 1_1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose.
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Potential COVID-19 therapeutics from a rare disease: weaponizing lipid dysregulation to combat viral infectivity.
Sturley, SL, Rajakumar, T, Hammond, N, Higaki, K, Márka, Z, Márka, S, Munkacsi, AB
Journal of lipid research. 2020;(7):972-982
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 has resulted in the death of more than 328,000 persons worldwide in the first 5 months of 2020. Herculean efforts to rapidly design and produce vaccines and other antiviral interventions are ongoing. However, newly evolving viral mutations, the prospect of only temporary immunity, and a long path to regulatory approval pose significant challenges and call for a common, readily available, and inexpensive treatment. Strategic drug repurposing combined with rapid testing of established molecular targets could provide a pause in disease progression. SARS-CoV-2 shares extensive structural and functional conservation with SARS-CoV-1, including engagement of the same host cell receptor (angiotensin-converting enzyme 2) localized in cholesterol-rich microdomains. These lipid-enveloped viruses encounter the endosomal/lysosomal host compartment in a critical step of infection and maturation. Niemann-Pick type C (NP-C) disease is a rare monogenic neurodegenerative disease caused by deficient efflux of lipids from the late endosome/lysosome (LE/L). The NP-C disease-causing gene (NPC1) has been strongly associated with viral infection, both as a filovirus receptor (e.g., Ebola) and through LE/L lipid trafficking. This suggests that NPC1 inhibitors or NP-C disease mimetics could serve as anti-SARS-CoV-2 agents. Fortunately, there are such clinically approved molecules that elicit antiviral activity in preclinical studies, without causing NP-C disease. Inhibition of NPC1 may impair viral SARS-CoV-2 infectivity via several lipid-dependent mechanisms, which disturb the microenvironment optimum for viral infectivity. We suggest that known mechanistic information on NPC1 could be utilized to identify existing and future drugs to treat COVID-19.
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7.
Rosuvastatin/Ezetimibe: A Review in Hypercholesterolemia.
Lamb, YN
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(4):381-392
Abstract
Rosuvastatin/ezetimibe combines two lipid-lowering agents: rosuvastatin, an HMG-CoA reductase inhibitor (i.e. statin) with particularly strong inhibitory effects on hepatic cholesterol synthesis, and ezetimibe, which inhibits the intestinal absorption of cholesterol. A fixed-dose combination (FDC) of rosuvastatin/ezetimibe is indicated as an adjunctive therapy to diet for the management of primary hypercholesterolemia in adults in numerous countries worldwide. In well-designed clinical trials evaluating the therapeutic efficacy of rosuvastatin/ezetimibe administered as either separate agents or as an FDC, rosuvastatin/ezetimibe was significantly more effective than rosuvastatin monotherapy (including at double the dose of rosuvastatin) or simvastatin/ezetimibe in reducing low-density lipoprotein cholesterol (LDL-C) and total cholesterol in adults with hypercholesterolemia. Furthermore, rosuvastatin/ezetimibe enabled significantly higher proportions of patients to achieve recommended LDL-C levels than rosuvastatin monotherapy or simvastatin/ezetimibe. Rosuvastatin/ezetimibe did not significantly differ from rosuvastatin monotherapy with respect to incidences of treatment-related or serious adverse events in these short-term trials and displayed a similar safety profile to simvastatin/ezetimibe. While additional cardiovascular outcomes data and head-to-head comparisons with atorvastatin/ezetimibe would be of interest, rosuvastatin/ezetimibe is a potent and generally well-tolerated drug combination that extends the range of options available for the pharmacological management of primary hypercholesterolemia in adults.
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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.
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Medical Management for Secondary Stroke Prevention.
Kim, AS
Continuum (Minneapolis, Minn.). 2020;(2):435-456
Abstract
PURPOSE OF REVIEW This article reviews the evidence base and recommendations for medical management for secondary stroke prevention. RECENT FINDINGS Recent developments for secondary stroke prevention include evidence to support the use of short-term dual antiplatelet therapy after minor stroke and transient ischemic attack, direct oral anticoagulants for nonvalvular atrial fibrillation, reversal agents for direct oral anticoagulant-associated hemorrhage, and aspirin rather than presumptive anticoagulation with a direct oral anticoagulant for embolic stroke of undetermined source. SUMMARY Most strokes are preventable. The mainstays of medical management for secondary stroke prevention include antihypertensive therapy; antithrombotic therapy, with antiplatelet agents for most stroke subtypes or anticoagulants such as warfarin or a direct oral anticoagulant for cardioembolic stroke specifically; cholesterol-lowering therapy, principally with statins, but with potential roles for ezetimibe or proprotein convertase subtilisin/kexin type 9 inhibitors in selected patients; and glycemic control to prevent microvascular complications from diabetes mellitus or pioglitazone in selected patients with insulin resistance but not diabetes mellitus.
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10.
Are current dietary guidelines relevant to subjects on cholesterol-lowering drugs?
Salter, AM
The Proceedings of the Nutrition Society. 2020;(1):88-94
Abstract
The present paper reviews the evidence as to whether patients on lipid-lowering drugs should restrict dietary SFA intake. Premature mortality from atherosclerotic CVD has fallen dramatically in many high-income countries. This appears to be due to a combination of improved treatment following a cardiovascular event and reduced risk factors, including LDL-cholesterol. Whether this reduction is due to changes in dietary habits, or the increasing availability of highly potent cholesterol-reducing drugs remains to be firmly established. While reducing dietary SFA intake has been the cornerstone of public health nutrition policy for several decades, the efficacy of such dietary changes has been challenged in recent years. While there remains a lack of consensus in the literature, there is an emerging view that dietary advice should be specifically modified to emphasise replacing SFA with PUFA in the diet rather than carbohydrate. The advice to moderate dietary SFA intake given to the general population is usually also given to those individuals at high risk of CVD who are prescribed lipid-lowering drugs. There is limited evidence to suggest that any potential benefit of such a diet on LDL-cholesterol may be offset by a concurrent decrease in HDL-cholesterol. However, as diets rich in SFA are frequently energy-dense, and rich in red and processed meat (potential risk factors for CVD in themselves), it would seem prudent to continue to advise patients on lipid-lowering drugs to maintain a low-fat diet.