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Journal of Clinical Lipidology 2022In contrast to strong evidence-based clinical recommendations for lipid-lowering treatment, there is no analogous definitive diagnostic definition of... (Review)
Review
In contrast to strong evidence-based clinical recommendations for lipid-lowering treatment, there is no analogous definitive diagnostic definition of hypercholesterolemia and its various subtypes. For many clinicians, guideline indications for hypolipidemic treatment can become broadly conflated with hypercholesterolemia in a non-specific sense. In this statement, we propose a unified definition and mechanism-based classification of hypercholesterolemia, which in turn should help to stratify patients and guide efficient diagnosis without interfering with the current strategies of ASCVD risk reduction.
Topics: Humans; Hypercholesterolemia
PubMed: 36229375
DOI: 10.1016/j.jacl.2022.09.006 -
Methodist DeBakey Cardiovascular Journal 2019The extract of red yeast rice (RYR) is the most effective cholesterol-lowering nutraceutical on the market. In particular, its effectiveness is directly related to the... (Review)
Review
The extract of red yeast rice (RYR) is the most effective cholesterol-lowering nutraceutical on the market. In particular, its effectiveness is directly related to the amount of monacolin K within the extract (up to 10 mg/day). Consuming monacolin K on a daily basis reduces low-density lipoprotein (LDL) cholesterol plasma levels between 15% and 25% within 6 to 8 weeks. Certainly, the decrease in LDL-cholesterol is accompanied by a similar reduction in total cholesterol, non-high-density lipoprotein cholesterol, plasma apolipoprotein B, matrix metalloproteinases 2 and 9, and high-sensitivity C-reactive protein. Furthermore, the RYR lipid-lowering effect is associated with significant improvements in pulse wave velocity and endothelial function, which are validated and reliable biomarker tools able to detect vascular aging. Although it has a mechanism of action similar to statins, a daily consumption of between 3 and 10 mg monacolin K has only minimal associated risks, and mild myalgias are seen only in the frailest patients (those who also cannot tolerate minimal dosages of statin). The monacolin K found in RYR is a safe and effective supplement for managing mild to moderate hypercholesterolemia in people with no additional cardiovascular risk factors.
Topics: Animals; Biological Products; Biomarkers; Cholesterol; Dietary Supplements; Down-Regulation; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lovastatin; Treatment Outcome
PubMed: 31687098
DOI: 10.14797/mdcj-15-3-192 -
Nutrition, Metabolism, and... May 2021To systematically evaluate the evidence regarding the effects of foods on LDL cholesterol levels and to compare the findings with current guidelines. (Meta-Analysis)
Meta-Analysis
AIMS
To systematically evaluate the evidence regarding the effects of foods on LDL cholesterol levels and to compare the findings with current guidelines.
DATA SYNTHESIS
From inception through June 2019, we searched PubMed, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials for guidelines, systematic reviews, and RCTs (for coffee intake only) of at least 13 days duration. Additionally, we searched Trip database for guidelines from 2009 through Oct 2019. Language was restricted to English. The strength of evidence was evaluated using The Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A total of 37 guidelines, 108 systematic reviews, and 20 RCTs were included. With high evidence, foods high in unsaturated and low in saturated and trans fatty acids (e.g. rapeseed/canola oil), with added plant sterols/stanols, and high in soluble fiber (e.g. oats, barley, and psyllium) caused at least moderate (i.e. 0.20-0.40 mmol/L) reductions in LDL cholesterol. Unfiltered coffee caused a moderate to large increase. Soy protein, tomatoes, flaxseeds, and almonds caused small reductions. With moderate evidence, avocados and turmeric caused moderate to large reductions. Pulses, hazelnuts, walnuts, high-fiber/wholegrain foods, and green tea caused small to moderate reductions, whereas sugar caused a small increase. Other identified foods were either neutral or had low or very low evidence regarding their effects.
CONCLUSIONS
Several foods distinctly modify LDL cholesterol levels. The results may aid future guidelines and dietary advice for hypercholesterolemia.
Topics: Adult; Biomarkers; Cholesterol, LDL; Diet; Diet, Healthy; Down-Regulation; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Nutritive Value; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Risk Reduction Behavior; Treatment Outcome; Young Adult
PubMed: 33762150
DOI: 10.1016/j.numecd.2020.12.032 -
American Journal of Respiratory and... Feb 2022The biological functions of cholesterol are diverse, ranging from cell membrane integrity, cell membrane signaling, and immunity to the synthesis of steroid and sex... (Review)
Review
The biological functions of cholesterol are diverse, ranging from cell membrane integrity, cell membrane signaling, and immunity to the synthesis of steroid and sex hormones, vitamin D, bile acids, and oxysterols. Multiple studies have demonstrated hypocholesterolemia in sepsis, the degree of which is an excellent prognosticator of poor outcomes. However, the clinical significance of hypocholesterolemia has been largely unrecognized. We undertook a detailed review of the biological roles of cholesterol, the impact of sepsis, its reliability as a prognosticator in sepsis, and the potential utility of cholesterol as a treatment. Sepsis affects cholesterol synthesis, transport, and metabolism. This likely impacts its biological functions, including immunity, hormone and vitamin production, and cell membrane receptor sensitivity. Early preclinical studies show promise for cholesterol as a pleiotropic therapeutic agent. Hypocholesterolemia is a frequent condition in sepsis and an important early prognosticator. Low plasma concentrations are associated with wider changes in cholesterol metabolism and its functional roles, and these appear to play a significant role in sepsis pathophysiology. The therapeutic impact of cholesterol elevation warrants further investigation.
Topics: Cholesterol; Humans; Hypercholesterolemia; Prognosis; Sepsis
PubMed: 34715007
DOI: 10.1164/rccm.202105-1197TR -
Biochemical Pharmacology Jul 2021More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken... (Review)
Review
More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.
Topics: Animals; Clinical Trials as Topic; Drug Development; Gene Transfer Techniques; Genetic Therapy; Humans; Hypercholesterolemia; Nervous System Diseases; RNA, Small Interfering
PubMed: 33513339
DOI: 10.1016/j.bcp.2021.114432 -
Thyroid : Official Journal of the... Sep 2019Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating... (Review)
Review
Thyroid hormones (THs) exert a strong influence on mammalian lipid metabolism at the systemic and hepatic levels by virtue of their roles in regulating circulating lipoprotein, triglyceride (TAG), and cholesterol levels, as well as hepatic TAG storage and metabolism. These effects are mediated by intricate sensing and feedback systems that function at the physiological, metabolic, molecular, and transcriptional levels in the liver. Dysfunction in the pathways involved in lipid metabolism disrupts hepatic lipid homeostasis and contributes to the pathogenesis of metabolic diseases, such as nonalcoholic fatty liver disease (NAFLD) and hypercholesterolemia. There has been strong interest in understanding and employing THs, TH metabolites, and TH mimetics as lipid-modifying drugs. THs regulate many processes involved in hepatic TAG and cholesterol metabolism to decrease serum cholesterol and intrahepatic lipid content. TH receptor β analogs designed to have less side effects than the natural hormone are currently being tested in phase II clinical studies for NAFLD and hypercholesterolemia. The TH metabolites, 3,5-diiodo-l-thyronine (T2) and T1AM (3-iodothyronamine), have different beneficial effects on lipid metabolism compared with triiodothyronine (T3), although their clinical application is still under investigation. Also, prodrugs and glucagon/T3 conjugates have been developed that direct TH to the liver. TH-based therapies show clinical promise for the treatment of NAFLD and hypercholesterolemia. Strategies for limiting side effects of TH are being developed and may enable TH metabolites and analogs to have specific effects in the liver for treatments of these conditions. These liver-specific effects and potential suppression of the hypothalamic/pituitary/thyroid axis raise the issue of monitoring liver-specific markers of TH action to assess clinical efficacy and dosing of these compounds.
Topics: Animals; Humans; Hypercholesterolemia; Lipid Metabolism; Liver; Mice; Non-alcoholic Fatty Liver Disease; Receptors, Thyroid Hormone; Thyroid Hormones
PubMed: 31389309
DOI: 10.1089/thy.2018.0664 -
Drugs Feb 2021Inclisiran (Leqvio; Novartis) is a first-in-class, cholesterol-lowering small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine carbohydrates... (Review)
Review
Inclisiran (Leqvio; Novartis) is a first-in-class, cholesterol-lowering small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine carbohydrates (GalNAc). Inclisiran received its first approval in December 2020 in the EU for use in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet. It is intended for use in combination with a statin or a statin with other lipid-lowering therapies in patients unable to reach low-density lipoprotein cholesterol goals with the maximum tolerated statin dose. In patients who are statin-intolerant or for whom a statin is contraindicated, inclisiran can be used alone or in combination with other lipid-lowering therapies. Inclisiran is administered as a twice-yearly subcutaneous injection. This article summarizes the milestones in the development of inclisiran leading to this first approval for primary hypercholesterolaemia or mixed dyslipidaemia.
Topics: Anticholesteremic Agents; Dyslipidemias; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Injections, Subcutaneous; RNA, Small Interfering
PubMed: 33620677
DOI: 10.1007/s40265-021-01473-6 -
Biomedicine & Pharmacotherapy =... Sep 2020The ease of breeding, low cost of maintenance, and relatively short period for developing atherosclerosis make rodents ideal for atherosclerosis research. However, none... (Review)
Review
The ease of breeding, low cost of maintenance, and relatively short period for developing atherosclerosis make rodents ideal for atherosclerosis research. However, none of the current models accurately model human lipoprotein profile or atherosclerosis progression since each has its advantages and disadvantages. The advent of transgenic technologies much supports animal models' establishment. Notably, two classic transgenic mouse models, apoE-/- and Ldlr-/-, constitute the primary platforms for studying underlying mechanisms and development of pharmaceutical approaches. However, there exist crucial differences between mice and humans, such as the unhumanized lipoprotein profile, and the different plaque progression and characteristics. Among rodents, hamsters and guinea pigs might be the more realistic models in atherosclerosis research based on the similarities in lipoprotein metabolism to humans. Studies involving rat models, a rodent with natural resistance to atherosclerosis, have revealed evidence of atherosclerotic plaques under dietary induction and genetic manipulation by novel technologies, notably CRISPR-Cas9. Ldlr-/- hamster models were established in recent years with severe hyperlipidemia and atherosclerotic lesion formation, which could offer an alternative to classic transgenic mouse models. In this review, we provide an overview of classic and innovative small rodent models in atherosclerosis researches, including mice, rats, hamsters, and guinea pigs, focusing on their lipoprotein metabolism and histopathological changes.
Topics: Animals; Atherosclerosis; Cricetinae; Diet, High-Fat; Disease Models, Animal; Disease Progression; Genetic Predisposition to Disease; Guinea Pigs; Hypercholesterolemia; Lipoproteins; Mice, Knockout, ApoE; Phenotype; Plaque, Atherosclerotic; Rats, Transgenic; Receptors, LDL; Species Specificity
PubMed: 32574973
DOI: 10.1016/j.biopha.2020.110426 -
Clinica E Investigacion En... May 2021The lipid theory of atherosclerosis dates back more than a century. Despite this, some authors have questioned the relevance of hypercholesterolaemia in its development....
The lipid theory of atherosclerosis dates back more than a century. Despite this, some authors have questioned the relevance of hypercholesterolaemia in its development. Multiple experimental, epidemiological, and clinical evidence underpins this association. Atherosclerotic cardiovascular disease remains as the major cause of mortality in the world. Recent genetic studies of Mendelian randomisation and randomised clinical trials aimed at LDL cholesterol reduction, are summarised in this article. They, unequivocally ratify the aetiological role of LDL cholesterol in the development of atherosclerosis. Thus, LDL cholesterol lowering is the cornerstone of lipid lowering therapy for the reduction of cardiovascular complications of atherosclerosis.
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Humans; Hypercholesterolemia; Randomized Controlled Trials as Topic
PubMed: 33966809
DOI: 10.1016/j.arteri.2020.12.004 -
Medicina (Kaunas, Lithuania) May 2021Cardiovascular disease (CVD) is the leading cause of death globally and hypercholesterolemia is one of the major risk factors associated with CVD. Due to a growing body... (Meta-Analysis)
Meta-Analysis Review
Cardiovascular disease (CVD) is the leading cause of death globally and hypercholesterolemia is one of the major risk factors associated with CVD. Due to a growing body of research on side effects and long-term impacts of conventional CVD treatments, focus is shifting towards exploring alternative treatment approaches such as Ayurveda. However, because of a lack of strong scientific evidence, the safety and efficacy profiles of such interventions have not been well established. The current study aims to conduct a systematic review and meta-analyses to explore the strength of evidence on efficacy and safety of Ayurvedic herbs for hypercholesterolemia. : Literature searches were conducted using databases including Medline, Cochrane Database, AMED, Embase, AYUSH research portal, and many others. All randomized controlled trials on individuals with hypercholesterolemia using Ayurvedic herbs (alone or in combination) with an exposure period of ≥ 3 weeks were included, with primary outcomes being total cholesterol levels, adverse events, and other cardiovascular events. The search strategy was determined with the help of the Cochrane Metabolic and Endocrine Disorders Group. Two researchers assessed the risk of each study individually and discrepancies were resolved by consensus or consultation with a third researcher. Meta-analysis was conducted using the inverse variance method and results are presented as forest plots and data summary tables using Revman v5.3. A systematic review of 32 studies with 1386 participants found randomized controlled trials of three Ayurvedic herbs, (garlic), (guggulu), and (black cumin) on hypercholesterolemia that met inclusion criteria. The average duration of intervention was 12 weeks. Meta-analysis of the trials showed that guggulu reduced total cholesterol and low-density lipoprotein levels by 16.78 mg/dL (95% C.I. 13.96 to 2.61; -value = 0.02) and 18.78 mg/dL (95% C.I. 34.07 to 3.48; = 0.02), respectively. Garlic reduced LDL-C by 10.37 mg/dL (95% C.I. -17.58 to -3.16; -value = 0.005). Black cumin lowered total cholesterol by 9.28 mg/dL (95% C.I. -17.36, to -1.19, -value = 0.02). Reported adverse side effects were minimal. There is moderate to high level of evidence from randomized controlled trials that the Ayurvedic herbs guggulu, garlic, and black cumin are moderately effective for reducing hypercholesterolemia. In addition, minimal evidence was found for any side effects associated with these herbs, positioning them as safe adjuvants to conventional treatments.
Topics: Cardiovascular Diseases; Garlic; Humans; Hypercholesterolemia; Hyperlipidemias; Medicine, Ayurvedic
PubMed: 34071454
DOI: 10.3390/medicina57060546