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Journal of Clinical Pharmacology Jan 2017Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins... (Review)
Review
Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low-density lipoprotein cholesterol, as well as reductions in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long-term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid-modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cholesterol, LDL; Disease Management; Humans; Hypercholesterolemia; PCSK9 Inhibitors; Proprotein Convertase 9
PubMed: 27195910
DOI: 10.1002/jcph.766 -
Drug Design, Development and Therapy 2017Cholesteryl ester transfer protein (CETP) facilitates movement of esterified cholesterol between high-density lipoproteins (HDLs) and apolipoprotein B-containing... (Review)
Review
Cholesteryl ester transfer protein (CETP) facilitates movement of esterified cholesterol between high-density lipoproteins (HDLs) and apolipoprotein B-containing lipoproteins. By virtue of their ability to raise HDL cholesterol and lower low-density lipoprotein cholesterol, pharmacological inhibitors of CETP have received considerable attention as potential new agents in cardiovascular prevention. While early studies of CETP inhibitors have demonstrated a lack of clinical efficacy and potential toxicity, development of the potent CETP inhibitor, anacetrapib, has moved forward, with emerging evidence suggesting a role in reducing cardiovascular events. The experience with anacetrapib and its potential for use in clinical practice are reviewed here.
Topics: Animals; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol Ester Transfer Proteins; Humans; Oxazolidinones
PubMed: 29263647
DOI: 10.2147/DDDT.S114104 -
Arquivos Brasileiros de Cardiologia Oct 2021
Topics: Anti-Inflammatory Agents; Anticholesteremic Agents; Atorvastatin; Humans; Metabolic Syndrome
PubMed: 34709301
DOI: 10.36660/abc.20210720 -
Journal of the American College of... Aug 2013
Topics: Anticholesteremic Agents; Exercise; Female; Humans; Male; Simvastatin
PubMed: 23583256
DOI: 10.1016/j.jacc.2013.03.030 -
Journal of the American College of... Dec 2016Costs and uncertainty about the benefits of nonstatin therapies limit their use. (Review)
Review
BACKGROUND
Costs and uncertainty about the benefits of nonstatin therapies limit their use.
OBJECTIVES
The authors sought to identify patients who might benefit from the addition of a nonstatin to background statin therapy.
METHODS
We performed systematic reviews of subgroup analyses from randomized trials and observational studies with statin-treated participants to determine estimated 10-year absolute risk of atherosclerotic cardiovascular disease (ASCVD) and to define high-risk and very high-risk patients. We used the relative risk reductions for the addition of a nonstatin to lower low-density lipoprotein (LDL-C) used to determine the number needed to treat (NNT) to prevent 1 ASCVD event over 5 years for each patient group and to allow comparisons with 5-year cost analyses.
RESULTS
The 10-year ASCVD risk is at least 30% (very high risk) for statin-treated participants with clinical ASCVD and comorbidities, and 20% to 29% (high risk) for those with ASCVD without comorbidities or who have heterozygous familial hypercholesterolemia. Adding ezetimibe to reduce low-density LDL-C by 20% would provide a 5-year NNT ≤50 for very high-risk patients with LDL-C ≥130 mg/dl or for high-risk patients with LDL-C ≥190 mg/dl, and an NNT ≤30 for very high-risk patients with LDL-C ≥160 mg/dl. Adding a PCSK9 monoclonal antibody to lower LDL-C by at least 50% would provide an NNT ≤50 for very high-risk and high-risk patients with LDL-C ≥70 mg/dl, and an NNT ≤30 for very high-risk and high-risk patients with an LDL-C ≥130 mg/dl.
CONCLUSIONS
Adding ezetimibe or PCSK9 monoclonal antibodies to maximally tolerated statin therapy may be cost effective in very high-risk and high-risk patients, depending on baseline LDL-C levels.
Topics: Anticholesteremic Agents; Atherosclerosis; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 27908345
DOI: 10.1016/j.jacc.2016.09.928 -
Kardiologia Polska 2022Atherosclerotic disease remains the leading cause of death worldwide. Much of atherosclerotic disease initiation and progression is driven by dyslipidemia. With the... (Review)
Review
Atherosclerotic disease remains the leading cause of death worldwide. Much of atherosclerotic disease initiation and progression is driven by dyslipidemia. With the advent of statins, ezetimibe, and more recently the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, physicians across all specialties have access to an armamentarium to address this major pathophysiological driver. Nevertheless, there is still a large unmet need in terms of optimizing pharmacotherapeutic lipid lowering strategies. This article will review the evidence pertaining to the major lipid-lowering agents that have been introduced lately, or still are under development, after the advent of statins, ezetimibe and PCSK9 inhibitors. There is cumulating evidence suggesting that there soon will be a broad specter of differential therapies across a variety of mechanistic pathways that will enter clinical medicine. Knowledge about these potential recent advances and various upcoming therapeutic options will make choice easier for physicians, and will lead to more personalized selections of available treatments.
Topics: Anticholesteremic Agents; Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; PCSK9 Inhibitors; Proprotein Convertase 9
PubMed: 35521719
DOI: 10.33963/KP.a2022.0117 -
Molecules (Basel, Switzerland) Oct 2021There are abundant natural diterpenoids in the plants of the genus from the Thymelaeaceae family, featuring a 5/7/6-tricyclic ring system and usually with an orthoester... (Review)
Review
There are abundant natural diterpenoids in the plants of the genus from the Thymelaeaceae family, featuring a 5/7/6-tricyclic ring system and usually with an orthoester group. So far, a total of 135 diterpenoids has been isolated from the species of the genus , which could be further classified into three main types according to the substitution pattern of ring A and oxygen-containing functions at ring B. A variety of studies have demonstrated that these compounds exert a wide range of bioactivities both in vitro and in vivo including anticancer, anti-inflammatory, anti-HIV, antifertility, neurotrophic, and cholesterol-lowering effects, which is reviewed herein. Meanwhile, the fascinating structure-activity relationship is also concluded in this review in the hope of providing an easy access to available information for the synthesis and optimization of efficient drugs.
Topics: Anti-HIV Agents; Anti-Inflammatory Agents; Anticholesteremic Agents; Antineoplastic Agents, Phytogenic; Daphne; Diterpenes; Humans
PubMed: 34771007
DOI: 10.3390/molecules26216598 -
International Journal of Environmental... Dec 2022In the United States, a significant amount of the population is affected by hyperlipidemia, which is associated with increased levels of serum low-density lipoprotein... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
In the United States, a significant amount of the population is affected by hyperlipidemia, which is associated with increased levels of serum low-density lipoprotein (LDL-C) and risk of cardiovascular disease. As of 2019, the guidelines set by the American College of Cardiology/American Heart Association advocate for the use of statins as the major contributor to lowering serum LDL-C. While proven to be effective, side effects, including muscle-related symptoms and new-onset diabetes mellitus, can make patients unable to tolerate statin therapy. Additionally, there is a subset of the population which does not approach a recommended LDL-C goal on statin treatment. Due to these findings, it was deemed necessary to review the literature of current statin-alternative lipid-lowering therapies.
METHODS
A systematic review of preclinical and clinical papers, and a current meta-analysis, was performed using PubMed and Google Scholar. Following the literature review, a meta-analysis was conducted using ProMeta 3.
RESULTS
Through systematic review and meta-analysis of the current literature, it is suggested that newer lipid-lowering therapies such as proprotein convertase subtilsin-kixen type 9 (PCSK9) inhibitors are a safe and effective statin alternative for the population with statin intolerance. PCSK9 inhibitors were shown to have no significant effect in causing myalgia in patients and showed no increase in adverse cardiovascular outcomes compared to a control of a current antilipemic medication regimen.
DISCUSSION
There are many statin-alternative therapies that should be investigated further as a potential replacement for patients with statin intolerance or as an addition for patients with statin resistance.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; PCSK9 Inhibitors; Cholesterol, LDL; Cardiovascular Diseases; Anticholesteremic Agents
PubMed: 36554779
DOI: 10.3390/ijerph192416899 -
Biological Chemistry Dec 2011Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes.... (Review)
Review
Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafine, naftifine, butenafine) are in clinical use, whereas mammalian enzymes' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both sufficient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.
Topics: Animals; Anticholesteremic Agents; Enzyme Inhibitors; Humans; Hypercholesterolemia; Squalene Monooxygenase; Structure-Activity Relationship
PubMed: 22050222
DOI: 10.1515/BC.2011.195 -
Drug Design, Development and Therapy 2021Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD)... (Review)
Review
Bempedoic acid is a first-in-class, oral, inhibitor of cholesterol biosynthesis that is approved for use in patients with atherosclerotic cardiovascular disease (ASCVD) and for primary prevention in individuals with heterozygous familial hypercholesterolemia (HeFH) by the United States Food and Drug Administration. Pooled data from the phase III clinical trials, CLEAR Harmony and CLEAR Wisdom, have demonstrated the safety and efficacy of bempedoic acid with regard to lowering of low-density lipoprotein cholesterol (LDL-C) in patients with HeFH as an adjunct or alternative to currently existing lipid-lowering therapies. CLEAR Outcomes is a cardiovascular outcomes trial that is currently underway that will provide additional insight as to where bempedoic acid will fit into treatment regimens among the non-statin lipid-lowering therapy options. Patients who might particularly benefit from bempedoic acid are those with HeFH and those unable to take adequate doses of statins or take any statin therapy altogether who need additional LDL-C lowering. In this review, we will discuss the profile of bempedoic acid from its design, development, and its place in therapy for the management of LDL-C for the purposes of ASCVD prevention.
Topics: Animals; Anticholesteremic Agents; Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Drug Design; Drug Development; Fatty Acids; Humans; Hyperlipoproteinemia Type II
PubMed: 34007155
DOI: 10.2147/DDDT.S251865