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1.
Bempedoic Acid: A New Tool in the Battle Against Hyperlipidemia.
Powell, J, Piszczatoski, C
Clinical therapeutics. 2021;(2):410-420
Abstract
PURPOSE This article discusses the pharmacology of bempedoic acid, the trials that led to United States Food and Drug Administration (FDA) approval of its use, and the overall safety and efficacy of this therapy in heterozygous familial hypercholesterolemia, established atherosclerotic cardiovascular disease (ASCVD), and hyperlipidemia. METHODS A database search of PubMed and ClinicalTrials.gov was conducted for articles published between January 2012 to September 2020 and containing the key words bempedoic acid, ezetimibe, Nexletol and Nexlizet. Trials from the CLEAR series were selected, as they played a pivotal role in the establishment of FDA approval, along with additional trials published after FDA approval, which provided novel evidence on the use of bempedoic acid in the treatment of hypercholesterolemia. Publications that were not randomized, controlled trials were not included in this review. Only randomized controlled trials in which ezetimibe was used in conjunction with bempedoic acid were included in this review as they were relevant to the new FDA approval of bempedoic acid. FINDINGS The findings of the present review show that bempedoic acid is both an effective and well-tolerated option for the treatment of hypercholesterolemia when used without ezetimibe in addition to standard therapy. It also appears that the combination with ezetimibe increases the cholesterol-lowering effect more than either agent alone when added to standard therapy. IMPLICATIONS Hypercholesteremia continues to be a major contributing factor leading to ASCVD. Bempedoic acid is an additional treatment option, along with both statins and diet and exercise, for reducing cholesterol levels and ASCVD events. With the new FDA approval, bempedoic acid may offer an effective therapy for reducing low-density lipoprotein cholesterol in patients at high risk for cardiovascular events due to established ASCVD or heterozygous familial hypercholesterolemia.
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2.
Role of Bempedoic Acid in Clinical Practice.
Ballantyne, CM, Bays, H, Catapano, AL, Goldberg, A, Ray, KK, Saseen, JJ
Cardiovascular drugs and therapy. 2021;(4):853-864
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Abstract
Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.
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3.
Bempedoic Acid in the Treatment of Patients with Dyslipidemias and Statin Intolerance.
Susekov, AV, Korol, LA, Watts, GF
Cardiovascular drugs and therapy. 2021;(4):841-852
Abstract
An elevated plasma low-density lipoprotein cholesterol (LDL-C) level is a well-established atherosclerotic cardiovascular disease (ACSVD) risk factor. Randomized studies with statins (alone or in combination with other lipid-lowering drugs) have demonstrated their clinical efficacy in lowering LDL-C. Several classes of new, non-statin agents have been successfully studied and used (e.g., ezetimibe and inhibitors of proprotein convertase subtilisin/kexin type 9 [i-PSCK9]). However, many high ACSVD risk patients remain at a high residual cardiovascular risk, with at least 10% being statin intolerant. Bempedoic acid (ETC-1002) is a new inhibitor of cholesterol synthesis that targets ATP citrate lyase (ACL). Importantly, ETC-1002 is only converted into an active form in the liver and is free of muscle side effects.Area Covered: Mechanism of action of ETC-1002, clinical pharmacology, completed clinical studies with bempedoic acid, lipid-lowering efficacy/safety issues, and recent meta-analyses of trials with ETC-1002.Expert Opinion: ETC-1002 has been extensively studied in phase I-III clinical studies in over 4000 individuals from different patient populations (statin intolerance, familial hypercholesterolemia, and high ACSVD risk patients), ETC-1002 has been demonstrated to have moderate cholesterol-lowering efficacy and a good safety profile at a dose of 180 mg/day as a monotherapy and in combination with statins and ezetimibe. The ongoing study CLEAR Outcomes, with composite cardiovascular endpoints, will elucidate the role of bempedoic acid in the management of high ACSVD risk and statin-intolerant patients with hypercholesterolemia. Long-term safety data on bempedoic acid are needed to fully establish this agent in evidence-informed guidelines for managing of patients with dyslipidemias.
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4.
Prebiotic peptides, their formation, fermentation in the gut, and health implications.
Ashaolu, TJ, Ashaolu, JO
Biotechnology progress. 2021;(3):e3142
Abstract
Prebiotics can be synthesized from sources other than dietary fibers, such as proteins. The proteins, when processed into peptides have healthful or deleterious effects on the host. Outside living systems, prebiotic peptides (PP) are formed via preformation of amino acids or related monomeric building blocks, resulting in nonenzymatic polymerization/ligation to produce peptides. Whereas, inside living systems like the human gut, many metabolic pathways are involved in PP production, and mostly involve host-microbiota interactions. The interplay is responsible for PP activities and their implications on host amino acid balance and metabolism. Similar to carbohydrates fermentation, PP will yield short chain fatty acids (SCFA), but also branched chain fatty acids (BCFAs), phenols, indole, hydrogen sulfide, amines, and ammonia, capable of biologically mediating molecular signals. This holistic review considers a brief description of prebiotics, and tracks down prebiotic peptides formation processes, interactions with gut microbes, and health outcomes.
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[Effect of omega-3 supplementation during pregnancy and lactation on the fatty acid composition of breast milk in the first months of life: a narrative review].
Puca, D, Estay, P, Valenzuela, C, Muñoz, Y
Nutricion hospitalaria. 2021;(4):848-870
Abstract
Omega-3 long-chain, polyunsaturated fatty acids are essential, so they must be provided through the diet, as their biological synthesis is limited, making it essential to meet their requirements during physiological stages such as pregnancy and lactation. A narrative review was conducted on the effects of omega-3 supplementation during pregnancy and lactation on the fatty acid composition of breast milk in the first months of life. Eight randomized clinical studies were analyzed, showing a significant increase in docosahexaenoic acid (DHA) concentration in breast milk (BM) post-supplementation, compared to control groups. One study evaluated the dose needed to achieve 8 % DHA in erythrocytes and 1 % DHA in BM, reaching these levels with a supplementation close to 1 g of docosahexaenoic acid + eicosapentaenoic acid (EPA). Finally, a trial was found that used supplementation with small lipid contributions (0,59 g α-linolenic acid (ALA)), without generating significant changes in the DHA composition of LM, but in the ALA content. Therefore, it is inferred that omega-3 supplementation beneficially modifies DHA and EPA levels in the composition of BM in pregnant women and during the lactation stage, although further studies are needed to identify doses, times, beneficial effects on development, and more efficient forms of delivery of omega-3 supplementation.
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Updated clinical evidence and place in therapy of bempedoic acid for hypercholesterolemia: ANMCO position paper.
Colivicchi, F, Di Fusco, SA, Scicchitano, P, Caldarola, P, Murrone, A, Valente, S, Urbinati, S, Roncon, L, Amodeo, V, Aspromonte, N, et al
Journal of cardiovascular medicine (Hagerstown, Md.). 2021;(3):162-171
Abstract
The central role of high low-density lipoprotein cholesterol levels in atherosclerotic cardiovascular disease has led to research focused on lipid-lowering agents for cardiovascular risk reduction. Bempedoic acid is an emerging treatment for hypercholesterolemia that has recently been approved for marketing in the United States and Europe. This review focuses on its mechanism of action and summarizes the main preclinical study findings. Furthermore, we report the clinical evidence supporting and guiding its use in hypercholesterolemia management.
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7.
Biosynthesis and Functions of Very-Long-Chain Fatty Acids in the Responses of Plants to Abiotic and Biotic Stresses.
Batsale, M, Bahammou, D, Fouillen, L, Mongrand, S, Joubès, J, Domergue, F
Cells. 2021;(6)
Abstract
Very-long-chain fatty acids (i.e., fatty acids with more than 18 carbon atoms; VLCFA) are important molecules that play crucial physiological and structural roles in plants. VLCFA are specifically present in several membrane lipids and essential for membrane homeostasis. Their specific accumulation in the sphingolipids of the plasma membrane outer leaflet is of primordial importance for its correct functioning in intercellular communication. VLCFA are found in phospholipids, notably in phosphatidylserine and phosphatidylethanolamine, where they could play a role in membrane domain organization and interleaflet coupling. In epidermal cells, VLCFA are precursors of the cuticular waxes of the plant cuticle, which are of primary importance for many interactions of the plant with its surrounding environment. VLCFA are also major components of the root suberin barrier, which has been shown to be fundamental for nutrient homeostasis and plant adaptation to adverse conditions. Finally, some plants store VLCFA in the triacylglycerols of their seeds so that they later play a pivotal role in seed germination. In this review, taking advantage of the many studies conducted using Arabidopsis thaliana as a model, we present our current knowledge on the biosynthesis and regulation of VLCFA in plants, and on the various functions that VLCFA and their derivatives play in the interactions of plants with their abiotic and biotic environment.
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8.
Singlet oxygen oxidation products of carotenoids, fatty acids and phenolic prenyllipids.
Kruk, J, Szymańska, R
Journal of photochemistry and photobiology. B, Biology. 2021;:112148
Abstract
Singlet oxygen (1O2) is the major reactive oxygen species ROS causing photooxidative stress in plants which is formed predominantly in the reaction center of photosystem II during photosynthesis. To avoid deleterious effects of 1O2 oxygen on photosynthetic membrane components, plant synthesize a variety of 1O2 quenchers of lipophilic character, such as carotenoids or phenolic prenyllipids (tocopherols, plastochromanol-8, plastoquinol). In the process of chemical quenching of 1O2 by the antioxidants, both short-lived products, such as oxidized carotenoids, or relative long-lived compounds, such as oxidized phenolic prenyllipids are formed. The other target of 1O2 are unsaturated fatty acids of membrane lipids that undergo peroxidation as a result of the reaction. Some of the 1O2 oxidation products, like β-cyclocitral can be components of 1O2-signallingsignaling pathway leading to acclimatory responses of plants, while some others further fulfill antioxidant functions, like hydroxy-plastochromanol or hydroxy-plastoquinol. As most of the 1O2 oxidation products are specific compounds formed only as a results of 1O2 action, they can be very useful, specific molecular markers of 1O2-dependent oxidative stress in vivo.
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9.
Sugar or Fat? Renal Tubular Metabolism Reviewed in Health and Disease.
Gewin, LS
Nutrients. 2021;(5)
Abstract
The kidney is a highly metabolically active organ that relies on specialized epithelial cells comprising the renal tubules to reabsorb most of the filtered water and solutes. Most of this reabsorption is mediated by the proximal tubules, and high amounts of energy are needed to facilitate solute movement. Thus, proximal tubules use fatty acid oxidation, which generates more adenosine triphosphate (ATP) than glucose metabolism, as its preferred metabolic pathway. After kidney injury, metabolism is altered, leading to decreased fatty acid oxidation and increased lactic acid generation. This review discusses how metabolism differs between the proximal and more distal tubular segments of the healthy nephron. In addition, metabolic changes in acute kidney injury and chronic kidney disease are discussed, as well as how these changes in metabolism may impact tubule repair and chronic kidney disease progression.
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10.
Dietary Fatty Acids at the Crossroad between Obesity and Colorectal Cancer: Fine Regulators of Adipose Tissue Homeostasis and Immune Response.
Del Cornò, M, Varì, R, Scazzocchio, B, Varano, B, Masella, R, Conti, L
Cells. 2021;(7)
Abstract
Colorectal cancer (CRC) is among the major threatening diseases worldwide, being the third most common cancer, and a leading cause of death, with a global incidence expected to increase in the coming years. Enhanced adiposity, particularly visceral fat, is a major risk factor for the development of several tumours, including CRC, and represents an important indicator of incidence, survival, prognosis, recurrence rates, and response to therapy. The obesity-associated low-grade chronic inflammation is thought to be a key determinant in CRC development, with the adipocytes and the adipose tissue (AT) playing a significant role in the integration of diet-related endocrine, metabolic, and inflammatory signals. Furthermore, AT infiltrating immune cells contribute to local and systemic inflammation by affecting immune and cancer cell functions through the release of soluble mediators. Among the factors introduced with diet and enriched in AT, fatty acids (FA) represent major players in inflammation and are able to deeply regulate AT homeostasis and immune cell function through gene expression regulation and by modulating the activity of several transcription factors (TF). This review summarizes human studies on the effects of dietary FA on AT homeostasis and immune cell functions, highlighting the molecular pathways and TF involved. The relevance of FA balance in linking diet, AT inflammation, and CRC is also discussed. Original and review articles were searched in PubMed without temporal limitation up to March 2021, by using fatty acid as a keyword in combination with diet, obesity, colorectal cancer, inflammation, adipose tissue, immune cells, and transcription factors.