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Drugs Apr 2022The treatment of dyslipidemia continues to be a dynamic and controversial topic. Even the most appropriate therapeutic range for lipid levels-including that of... (Review)
Review
The treatment of dyslipidemia continues to be a dynamic and controversial topic. Even the most appropriate therapeutic range for lipid levels-including that of triglycerides and low-density lipoprotein cholesterol-remain actively debated. Furthermore, with ever-increasing options and available treatment modalities, the management of dyslipidemia has progressed in both depth and complexity. An understanding of appropriate lipid-lowering therapy remains an essential topic of review for practitioners across medical specialties. The goal of this review is to provide an overview of recent research developments and recommendations for patients with dyslipidemia as a means of better informing the clinical practice of lipid management. By utilizing a guideline-directed approach, we provide a reference point on optimal lipid-lowering therapies across the spectrum of dyslipidemia. Special attention is paid to long-term adherence to lipid-lowering therapies, and the benefits derived from instituting appropriate medications in a structured manner alongside monitoring. Novel therapies and their impact on lipid lowering are discussed in detail, as well as potential avenues for research going forward. The prevention of cardiovascular disease remains paramount, and this review provides a roadmap for instituting appropriate therapies in cardiovascular disease prevention.
Topics: Cardiovascular Diseases; Cholesterol, LDL; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Triglycerides
PubMed: 35303294
DOI: 10.1007/s40265-022-01691-6 -
Annals of Medicine Dec 2022Atherosclerotic heart disease is the leading cause of mortality and morbidity in the USA. Low density lipoprotein (LDL) has been the target for many hypolipidemic agents... (Review)
Review
Atherosclerotic heart disease is the leading cause of mortality and morbidity in the USA. Low density lipoprotein (LDL) has been the target for many hypolipidemic agents to modify atherosclerotic risk. Bempedoic acid is a novel hypolipidemic drug that inhibits the enzymatic activity of ATP citrate lyase in the cholesterol synthesis pathway. CLEAR Harmony, CLEAR Wisdom, CLEAR Tranquillity and CLEAR Serenity have shown safety and efficacy associated with long term administration of this drug. Studies have shown effectiveness in reducing LDL-C in both statin intolerant patients and in patients on maximally tolerated doses of statin. The fixed drug combination of bempedoic acid and ezetimibe in a recent phase III showed significant reduction in LDL compared with placebo, which might be a promising future for LDL reduction among statin intolerant patients. Bempedoic acid also reduced inflammatory markers like hs-CRP. Given these results, bempedoic acid alone and in combination with ezetimibe received the USA FDA approval for adults with heterozygous familial hypercholesterolaemia or established atherosclerotic cardiovascular disease. We present a comprehensive review exploring the underlying mechanism, pre-clinical studies, and clinical trials of bempedoic acid and discuss the potential future role of the drug in treating hyperlipidaemia.
Topics: Atherosclerosis; Cholesterol, LDL; Dicarboxylic Acids; Ezetimibe; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents
PubMed: 35533049
DOI: 10.1080/07853890.2022.2059559 -
JAMA Sep 2023Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.
OBJECTIVE
To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.
DESIGN, SETTING, AND PARTICIPANTS
This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.
INTERVENTIONS
The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.
MAIN OUTCOMES AND MEASURES
Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.
RESULTS
Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.
CONCLUSION
Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04472676.
Topics: Adult; Female; Humans; American Indian or Alaska Native; Apoprotein(a); Lipoprotein(a); Administration, Oral; Cardiovascular Agents; Hypolipidemic Agents; Double-Blind Method; Male; Adolescent; Young Adult; Middle Aged; Dose-Response Relationship, Drug; White; Black or African American; Racial Groups
PubMed: 37638695
DOI: 10.1001/jama.2023.16503 -
American Journal of Cardiovascular... Sep 2023Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular... (Review)
Review
Despite treatment with statins, patients with elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides remain at increased risk for adverse cardiovascular events. Consequently, novel pharmaceutical drugs have been developed to control and modify the composition of blood lipids to ultimately prevent fatal cardiovascular events in patients with dyslipidaemia. This article reviews established and emerging lipid-lowering drugs regarding their mechanism of action, development stage, ongoing clinical trials, side effects, effect on blood lipids and reduction in cardiovascular morbidity and mortality. We conducted a keyword search to identify studies on established and emerging lipid modifying drugs. Results were summarized in a narrative overview. Established pharmaceutical treatment options include the Niemann-Pick-C1 like-1 protein (NPC1L1) inhibitor ezetimibe, the protein convertase subtilisin-kexin type 9 (PCSK9) inhibitors alirocumab and evolocumab, fibrates as peroxisome proliferator receptor alpha (PPAR-α) activators, and the omega-3 fatty acid icosapent ethyl. Statins are recommended as the first-line therapy for primary and secondary cardiovascular prevention in patients with hypercholesterinaemia and hypertriglyceridemia. For secondary prevention in hypercholesterinaemia, second-line options such as statin add-on or statin-intolerant treatments are ezetimibe, alirocumab and evolocumab. For secondary prevention in hypertriglyceridemia, second-line options such as statin add-on or statin-intolerant treatments are icosapent ethyl and fenofibrate. Robust data for these add-on therapeutics in primary cardiovascular prevention remains scarce. Recent biotechnological advances have led to the development of innovative small molecules (bempedoic acid, lomitapide, pemafibrate, docosapentaenoic and eicosapentaenoic acid), antibodies (evinacumab), antisense oligonucleotides (mipomersen, volanesorsen, pelcarsen, olezarsen), small interfering RNA (inclisiran, olpasiran), and gene therapies for patients with dyslipidemia. These molecules specifically target new cellular pathways, such as the adenosine triphosphate-citrate lyase (bempedoic acid), PCSK9 (inclisiran), angiopoietin-like 3 (ANGPTL3: evinacumab), microsomal triglyceride transfer protein (MTP: lomitapide), apolipoprotein B-100 (ApoB-100: mipomersen), apolipoprotein C-III (ApoC-III: volanesorsen, olezarsen), and lipoprotein (a) (Lp(a): pelcarsen, olpasiran). The authors are hopeful that the development of new treatment modalities alongside new therapeutic targets will further reduce patients' risk of adverse cardiovascular events. Apart from statins, data on new drugs' use in primary cardiovascular prevention remain scarce. For their swift adoption into clinical routine, these treatments must demonstrate safety and efficacy as well as cost-effectiveness in randomized cardiovascular outcome trials.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Proprotein Convertase 9; Anticholesteremic Agents; Secondary Prevention; Hypolipidemic Agents; Ezetimibe; Cardiovascular Diseases; Hypertriglyceridemia; Pharmaceutical Preparations; Angiopoietin-Like Protein 3
PubMed: 37486464
DOI: 10.1007/s40256-023-00594-5 -
Primary Care Mar 2013Elevated levels of blood lipids are well-documented risk factors for cardiovascular disease. Current classification schemes and treatment levels for hyperlipidemia are... (Review)
Review
Elevated levels of blood lipids are well-documented risk factors for cardiovascular disease. Current classification schemes and treatment levels for hyperlipidemia are based on the National Cholesterol Education Panel's Adult Treatment Program-3 (ATP-III) guidelines. Extensive research over the past decade has raised the question whether or not ATP-III guidelines are sufficiently aggressive. New guidelines from ATP-IV are expected to be released in the near future, but in the meantime physicians are faced with uncertainty about how low to target low-density lipoprotein cholesterol, whether to pharmacologically treat high-density lipoprotein cholesterol and triglyceride levels, and how best to achieve target goals.
Topics: Cardiovascular Diseases; Complementary Therapies; Genetic Predisposition to Disease; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Hypolipidemic Agents; Lipids; Mass Screening; Risk Assessment; Risk Factors
PubMed: 23402469
DOI: 10.1016/j.pop.2012.11.003 -
Clinica E Investigacion En... May 2021Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors...
Bempedoic acid acts by inhibiting adenosine triphosphate-citrate lyase (ACL) and consequently cholesterol biosynthesis, leading to increased expression of LDL receptors and increasing low-density lipoproteins (LDL-C) plasma clearence. It is a prodrug for oral administration with intracellular activation. It is activatedin liver cells and to a lesser extent in kidney cells, being absent in adipose tissue and muscle cells. Therefore, unlike statins, its potential myotoxic effect is very limited. It has recently been approved as a lipid-lowering drug in combination with diet, with statins, or with other lipid-lowering drugs in patients with hypercholesterolaemia, mixed dyslipidaemia, statin intolerance, or when these are contraindicated. The marketing of bempedoic acid implies, in clinical practice, having a new family of lipid-lowering drugs.
Topics: Dicarboxylic Acids; Drug Therapy, Combination; Dyslipidemias; Fatty Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hypolipidemic Agents
PubMed: 33966814
DOI: 10.1016/j.arteri.2021.02.012 -
JAMA Cardiology Sep 2018In the Cholesterol Treatment Trialists Collaboration (CTTC), in patients starting with low-density lipoprotein cholesterol (LDL-C) levels of approximately 3.4 mmol/L... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
In the Cholesterol Treatment Trialists Collaboration (CTTC), in patients starting with low-density lipoprotein cholesterol (LDL-C) levels of approximately 3.4 mmol/L (131.5 mg/dL), there was a 22% reduction in major vascular events per 1-mmol/L (38.7-mg/dL) lowering of LDL-C. The magnitude of clinical benefit of further LDL-C lowering in patients already with very low LDL-C levels remains debated.
OBJECTIVE
To evaluate efficacy and safety of further lowering LDL-C levels in patient populations presenting with median LDL-C levels of 1.8 mmol/L (70 mg/dL) or less.
DATA SOURCES AND STUDY SELECTION
The CTTC was used for statin data. For nonstatin therapy, Medline database was searched (2015-April 2018). Key inclusion criteria were a randomized, double-blind, controlled cardiovascular outcome trial of LDL-C lowering with data in populations starting with LDL-C levels averaging 1.8 mmol/L (70 mg/dL) or less.
DATA EXTRACTION AND SYNTHESIS
Two authors independently extracted data into standardized data sheets, and data were analyzed using meta-analysis.
MAIN OUTCOMES AND MEASURES
The risk ratio (RR) of major vascular events (a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level.
RESULTS
In the subgroup of patients from the CTTC meta-analysis of statins with a mean LDL-C in the control arm of 1.7 mmol/L (65.7 mg/dL), 1922 major vascular events occurred and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.78 (95% CI, 0.65-0.94). For 3 trials of nonstatin LDL-C-lowering therapies added to statins, there were 50 627 patients, the median LDL-C in the control arms ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL), and 9570 major vascular events occurred. Nonstatin therapy lowered LDL-C by 0.3 to 1.2 mmol/L (11 mg/dL to 45 mg/dL), and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.79 (95% CI, 0.70-0.88). For statins and nonstatins combined, the RR was 0.79 (95% CI, 0.71-0.87; P < .001). Low-density lipoprotein cholesterol lowering was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer.
CONCLUSIONS AND RELEVANCE
There is a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL), with no observed offsetting adverse effects. These data suggest further lowering of LDL-C beyond the lowest current targets would further reduce cardiovascular risk.
Topics: Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol, LDL; Double-Blind Method; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 30073316
DOI: 10.1001/jamacardio.2018.2258 -
Molecules (Basel, Switzerland) Mar 2022Hyperlipidemia is a chronic metabolic disease caused by the abnormal metabolism of lipoproteins in the human body. Its main hazard is to accelerate systemic... (Review)
Review
Hyperlipidemia is a chronic metabolic disease caused by the abnormal metabolism of lipoproteins in the human body. Its main hazard is to accelerate systemic atherosclerosis, which causes cerebrovascular diseases such as coronary heart disease and thrombosis. At the same time, although the current hypolipidemic drugs have a certain therapeutic effect, they have side effects such as liver damage and digestive tract discomfort. Many kinds of polysaccharides from natural resources possess therapeutic effects on hyperlipidemia but still lack a comprehensive understanding. In this paper, the research progress of natural polysaccharides on reducing blood lipids in recent years is reviewed. The pharmacological mechanisms and targets of natural polysaccharides are mainly introduced. The relationship between structure and hypolipidemic activity is also discussed in detail. This review will help to understand the value of polysaccharides in lowering blood lipids and provide guidance for the development and clinical application of new hypolipidemic drugs.
Topics: Humans; Hyperlipidemias; Hypolipidemic Agents; Natural Resources; Polysaccharides
PubMed: 35335266
DOI: 10.3390/molecules27061903 -
Archives of Cardiovascular Diseases 2021
Topics: Cardiovascular Diseases; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Lipids
PubMed: 34257047
DOI: 10.1016/j.acvd.2021.05.003 -
International Journal of Molecular... Jan 2023Since lipid abnormalities tend to progress from childhood to adulthood, it is necessary to early identify and treat children and adolescents with dyslipidemia. This is... (Review)
Review
Since lipid abnormalities tend to progress from childhood to adulthood, it is necessary to early identify and treat children and adolescents with dyslipidemia. This is important in order to reduce the cardiovascular risk, delay the development of fatty streaks, slow the progression of atherosclerosis and reverse atherosclerotic plaques. Together with therapeutic lifestyle changes, statins are the most common lipid-lowering drugs. By inhibiting the endogenous cholesterol synthesis in the liver, statins increase the catabolism of LDL-C, reduce VLDL-C, IDL-C and TG and modestly increase HDL-C. Regardless of their lipid-lowering effect, statins have also pleiotropic effects. Statins have increasingly been prescribed in children and adolescents and mounting evidence suggests their beneficial role. As with adults, in children, several studies have demonstrated that statin therapy is efficient at lowering lipid levels and reducing CIMT progression and cumulative estimated atherosclerotic burden in children. Statins are generally very well-tolerated in both adults and children and adverse events are quite uncommon. When evaluating the need and the timing for statin treatment, the presence of several factors (secondary causes, familial history, additional risk factors) should also be considered. Before initiating statins, it is imperative for clinical practitioners to consult patients and families and, as with any new medication therapy, to monitor patients taking statins. Despite being safe and effective, many children with lipid disorders are not on statin therapy and are not receiving the full potential benefit of adequate lipid-lowering therapies. It is therefore important that clinicians become familiar with statins.
Topics: Adult; Adolescent; Humans; Child; Young Adult; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Hypolipidemic Agents; Dyslipidemias; Risk Factors; Atherosclerosis
PubMed: 36674877
DOI: 10.3390/ijms24021366