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1.
Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges.
Packard, C, Chapman, MJ, Sibartie, M, Laufs, U, Masana, L
Heart (British Cardiac Society). 2021;(17):1369-1375
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Abstract
Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk of coronary heart disease and stroke. Guidelines for the management of dyslipidaemia from the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) were updated in late 2019 in light of recent intervention trials involving the use of innovative lipid-lowering agents in combination with statins. The new guidelines advocate achieving very low LDL-C levels in individuals at highest risk, within the paradigm of 'lower is better'. With the advent of combination therapy using ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitors in addition to statins, the routine attainment of extremely low LDL-C levels in the clinic has become a reality. Moreover, clinical trials in this setting have shown that, over the 5-7 years of treatment experience to date, profound LDL-C lowering leads to further reduction in cardiovascular events compared with more moderate lipid lowering, with no associated safety concerns. These reassuring findings are bolstered by genetic studies showing lifelong very low LDL-C levels (<1.4 mmol/L; <55 mg/dL) are associated with lower cardiovascular risk than in the general population, with no known detrimental health effects. Nevertheless, long-term safety studies are required to consolidate the present evidence base. This review summarises key data supporting the ESC/EAS recommendation to reduce markedly LDL-C levels, with aggressive goals for LDL-C in patients at highest risk, and provides expert opinion on its significance for clinical practice.
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2.
Efficacy and Safety of Evinacumab for the Treatment of Hypercholesterolemia: A Meta-Analysis.
Jin, M, Meng, F, Yang, W, Liang, L, Wang, H, Fu, Z
Journal of cardiovascular pharmacology. 2021;(3):394-402
Abstract
Angiopoietin-like protein 3 is essential in lipid metabolism regulation. However, the efficacy and safety of evinacumab (angiopoietin-like protein 3 inhibition drug) for hypercholesterolemia treatment is unknown. In this study, a meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of evinacumab. RCTs published between January 1, 2000, and November 1, 2020, were obtained from PubMed, Embase, and Cochrane Library. All RCTs evaluating the efficacy and safety of evinacumab were included without language restrictions. Our primary end points included the percent change of low-density lipoprotein cholesterol (LDL-C) from baseline and the incidence of at least one treatment emergent adverse events including nasopharyngitis, influenza-like illness, headache, dizziness, injection-site reaction, increased aspartate aminotransferase, increased alanine aminotransferase, and any other discomfort during treatments. Percentage changes of triglycerides and high-density lipoprotein cholesterol (HDL-C) from baseline indicated secondary end points. A random-effects model was used to assess pooled data if there was moderate to high heterogeneity between studies. Four studies with 5 RCTs (568 participants) were identified. Evinacumab significantly reduced LDL-C [mean difference (MD) -33.123%, 95% confidence interval (CI), -48.639% to -17.606%, P < 0.0001], triglycerides (MD -50.959%, 95% CI, -56.555% to -45.362%, P < 0.0001), and HDL-C (MD -12.773%, 95% CI, -16.359% to -9.186%, P < 0.0001) compared with placebo. The incidence of at least 1 treatment emergent adverse events was not significantly different between evinacumab and placebo groups (relative risk 1.080, 95% CI, 0.901-1.296, P = 0.405). Evinacumab decreased triglycerides, LDL-C, and HDL-C without significant adverse effects, indicating that it can be a therapeutic strategy for hypercholesterolemia.
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PCSK9 and atherosclerosis: Looking beyond LDL regulation.
Ragusa, R, Basta, G, Neglia, D, De Caterina, R, Del Turco, S, Caselli, C
European journal of clinical investigation. 2021;(4):e13459
Abstract
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is involved in cholesterol homeostasis. After binding to the complex low-density lipoprotein (LDL)-receptor, PCSK9 induces its intracellular degradation, thus reducing serum LDL clearance. In addition to the well-known activity on the hepatic LDL receptor-mediated pathway, PCSK9 has been, however, associated with vascular inflammation in atherogenesis. Indeed, PCSK9 is expressed by various cell types that are involved in atherosclerosis (e.g. endothelial cells, smooth muscle cells and macrophages) and is detected inside human atherosclerotic plaques. We here analyse the biology of PCSK9 and its possible involvement in molecular processes involved in atherosclerosis, beyond the regulation of circulating LDL cholesterol levels.
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4.
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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New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4.
Nurmohamed, NS, Navar, AM, Kastelein, JJP
Journal of the American College of Cardiology. 2021;(12):1564-1575
Abstract
Adding to the foundation of statins, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), novel, emerging low-density lipoprotein cholesterol (LDL-C)-lowering therapies are under development for the prevention of cardiovascular disease. Inclisiran, a small interfering RNA molecule that inhibits PCSK9, only needs to be dosed twice a year and has the potential to help overcome current barriers to persistence and adherence to lipid-lowering therapies. Bempedoic acid, which lowers LDL-C upstream from statins, provides a novel alternative for patients with statin intolerance. Angiopoetin-like 3 protein (ANGPTL3) inhibitors have been shown to provide potent LDL-C lowering in patients with homozygous familial hypercholesterolemia without major adverse effects as seen with lomitapide and mipomersen, and may reduce the need for apheresis. Finally, CETP inhibitors may yet be effective with the development of obicetrapib. These novel agents provide the clinician the tools to effectively lower LDL-C across the entire range of LDL-C-induced elevation of cardiovascular risk, from primary prevention and secondary prevention to null-null homozygous familial hypercholesterolemia patients.
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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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7.
Bempedoic Acid: A New Drug for an Old Problem.
Nguyen, D, Du, N, Sulaica, EM, Wanat, MA
The Annals of pharmacotherapy. 2021;(2):246-251
Abstract
OBJECTIVE To review the pharmacology, pharmacokinetics, safety, and efficacy of bempedoic acid for low-density lipoprotein cholesterol (LDL-C) reduction. DATA SOURCES A PubMed search was conducted from January 2000 to June 15, 2020, using the keyword bempedoic acid for phase III clinical trials published in the English language. STUDY SELECTION AND DATA EXTRACTION Articles related to the Food and Drug Administration (FDA) approval of bempedoic acid and other trials relating to the safety and efficacy of this drug were included. DATA SYNTHESIS The findings from this review show that bempedoic acid is a safe and effective option for lowering LDL-C levels in patients requiring LDL-C lowering for primary or secondary prevention of cardiovascular events. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE Statin therapy remains the mainstay of treatment for both primary and secondary prevention. However, many patients cannot tolerate statin therapy because of statin-associated muscle symptoms. Bempedoic acid may be a reasonable adjunct for LDL-C reduction, though further evaluation of cardiovascular outcomes with bempedoic acid in this population is needed. CONCLUSIONS The recent FDA approval of bempedoic acid offers an additional option for lowering LDL-C levels in patients with atherosclerotic cardiovascular disease or heterozygous familial hyperlipidemia. Additional data regarding effect on long-term cardiovascular outcomes with bempedoic acid are currently being studied.
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How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors.
Cybulska, B, Kłosiewicz-Latoszek, L, Penson, PE, Nabavi, SM, Lavie, CJ, Banach, M, ,
Progress in cardiovascular diseases. 2021;:65-74
Abstract
There is a strong evidence that more marked lowering of low-density lipoprotein cholesterol (LDL-C) leads to progressively lower risk of cardiovascular disease (CVD) events. The evidence on validity of this hypothesis comes from epidemiological, genetic and clinical studies. The hypothesis "the lower the better" has been recently strongly supported by the results of secondary prevention trials with PCSK9 inhibitors. The combination of PCSK9 inhibitors and statins has resulted in achieving extremely low LDL-C levels with additional reduction of CVD events in secondary prevention. However, despite large clinical benefits, the safety of aggressive LDL-C lowering should be always taken into consideration, and there is still an ongoing discussion on whether very low LDL-C might result in some non-CVD adverse events. However, based on the available knowledge, so far the serious adverse events associated with achieving of very low LDL-C levels or intensive drug therapy have not been noted. These positive clinical effects were reflected in current ESC/EAS Guidelines (2019) for dyslipidaemia management. The experts strongly recommended the LDL-C lowering to levels that have been achieved in trials of PCSK9 inhibitors. In this state of the art review, we aimed to finally justify the critical need for LDL-C reduction to very low levels in secondary prevention patients in order to be as low as possible, as early as possible, and preferably lifelong.
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Why patients with familial hypercholesterolemia are at high cardiovascular risk? Beyond LDL-C levels.
Bianconi, V, Banach, M, Pirro, M, ,
Trends in cardiovascular medicine. 2021;(4):205-215
Abstract
Familial hypercholesterolemia (FH) is a common genetic cause of elevated low-density lipoprotein cholesterol (LDL-C) due to defective clearance of circulating LDL particles. All FH patients are at high risk for premature cardiovascular disease (CVD) events due to their genetically determined lifelong exposure to high LDL-C levels. However, different rates of CVD events have been reported in FH patients, even among those with the same genetic mutations and comparable LDL-C levels. Hence, additional CVD risk modifiers, beyond LDL-C, may contribute to increase CVD risk in the FH population. In this review, we discuss the overall CVD risk burden of the FH population. Additionally, we revise the prognostic impact of several traditional and emerging predictors of CVD risk and we provide an overview of the role of specific tools to stratify CVD risk in FH patients in order to ensure them a more personalized treatment approach.
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Optimum lipid testing for diabetic patients to enhance clinical care.
Devaraj, S, Jialal, I
Diabetes & metabolic syndrome. 2021;(1):461-464
Abstract
BACKGROUND AND AIMS Dyslipidemia is a common problem in diabetic patients that predisposes to premature ASCVD. Dyslipidemia in Type 2 diabetes (T2DM) is very common and is characterized by hypertriglyceridemia (HTG) with decreased levels of high-density lipoprotein (HDL)-cholesterol. METHODS Recommendations for lipid testing in diabetics from the Canadian, European and American guidelines will be discussed in this mini-review. RESULTS It is crucial to obtain appropriate lipid testing in patients with TG > 2.3 mmol/L and or LDL-C< 1.8 mmol/L. We also discuss the utility of the different measures of calculated LDL-C and their pitfalls. CONCLUSION In conclusion, we propose obtaining a non-HDL-C (preferred) or direct -LDL-C or apo B level to manage diabetic patients with dyslipidemia and optimize care. Also in some patients with a strong FH of premature ASCVD and have few or no risk factors, Lp (a) can be assayed to optimize statin therapy.