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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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Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review.
Sniderman, AD, Thanassoulis, G, Glavinovic, T, Navar, AM, Pencina, M, Catapano, A, Ference, BA
JAMA cardiology. 2019;(12):1287-1295
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Abstract
IMPORTANCE The conventional model of atherosclerosis presumes that the mass of cholesterol within very low-density lipoprotein particles, low-density lipoprotein particles, chylomicron, and lipoprotein (a) particles in plasma is the principal determinant of the mass of cholesterol that will be deposited within the arterial wall and will drive atherogenesis. However, each of these particles contains one molecule of apolipoprotein B (apoB) and there is now substantial evidence that apoB more accurately measures the atherogenic risk owing to the apoB lipoproteins than does low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. OBSERVATIONS Cholesterol can only enter the arterial wall within apoB particles. However, the mass of cholesterol per apoB particle is variable. Therefore, the mass of cholesterol that will be deposited within the arterial wall is determined by the number of apoB particles that are trapped within the arterial wall. The number of apoB particles that enter the arterial wall is determined primarily by the number of apoB particles within the arterial lumen. However, once within the arterial wall, smaller cholesterol-depleted apoB particles have a greater tendency to be trapped than larger cholesterol-enriched apoB particles because they bind more avidly to the glycosaminoglycans within the subintimal space of the arterial wall. Thus, a cholesterol-enriched particle would deposit more cholesterol than a cholesterol-depleted apoB particle whereas more, smaller apoB particles that enter the arterial wall will be trapped than larger apoB particles. The net result is, with the exceptions of the abnormal chylomicron remnants in type III hyperlipoproteinemia and lipoprotein (a), all apoB particles are equally atherogenic. CONCLUSIONS AND RELEVANCE Apolipoprotein B unifies, amplifies, and simplifies the information from the conventional lipid markers as to the atherogenic risk attributable to the apoB lipoproteins.
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Antecedents of Soft Drusen, the Specific Deposits of Age-Related Macular Degeneration, in the Biology of Human Macula.
Curcio, CA
Investigative ophthalmology & visual science. 2018;(4):AMD182-AMD194
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Abstract
AMD pathobiology was irreversibly changed by the recent discovery of extracellular cholesterol-containing deposits in the subretinal space, between the photoreceptors and retinal pigment epithelium (RPE), called subretinal drusenoid deposits (SDDs). SDDs strikingly mirror the topography of rod photoreceptors in human macula, raising the question of whether an equivalent process results in a deposition related to foveal cones. Herein we propose that AMD's pathognomonic lesion-soft drusen and basal linear deposit (BLinD, same material, diffusely distributed)-is the leading candidate. Epidemiologic, clinical, and histologic data suggest that these deposits are most abundant in the central macula, under the fovea. Strong evidence presented in a companion article supports the idea that the dominant ultrastructural component is large apolipoprotein B,E-containing lipoproteins, constitutively secreted by RPE. Lipoprotein fatty acids are dominated by linoleate (implicating diet) rather than docosahexaenoate (implicating photoreceptors); we seek within the retina cellular relationships and dietary drivers to explain soft druse topography. The delivery of xanthophyll pigments to highly evolved and numerous Müller cells in the human fovea, through RPE, is one strong candidate, because Müller cells are the main reservoir of these pigments, which replenish from diet. We propose that the evolution of neuroglial relations and xanthophyll delivery that underlie exquisite human foveal vision came with a price, that is, soft drusen and sequela, long after our reproductive years.
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Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.
Oscarsson, J, Hurt-Camejo, E
Lipids in health and disease. 2017;(1):149
Abstract
BACKGROUND Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies. METHODS We conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included. RESULTS In humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype. CONCLUSIONS EPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.
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A systematic review and meta-analysis of randomized controlled trials of the effect of konjac glucomannan, a viscous soluble fiber, on LDL cholesterol and the new lipid targets non-HDL cholesterol and apolipoprotein B.
Ho, HVT, Jovanovski, E, Zurbau, A, Blanco Mejia, S, Sievenpiper, JL, Au-Yeung, F, Jenkins, AL, Duvnjak, L, Leiter, L, Vuksan, V
The American journal of clinical nutrition. 2017;(5):1239-1247
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Abstract
Background: Evidence from randomized controlled trials (RCTs) suggests the consumption of konjac glucomannan (KJM), a viscous soluble fiber, for improving LDL-cholesterol concentrations. It has also been suggested that the cholesterol-lowering potential of KJM may be greater than that of other fibers. However, trials have been relatively scarce and limited in sample size and duration, and the effect estimates have been inconsistent. The effect of KJM on new lipid targets of cardiovascular disease (CVD) risk is also unknown.Objective: This systematic review and meta-analysis aimed to assess the effect of KJM on LDL cholesterol, non-HDL cholesterol, and apolipoprotein B.Design: Medline, Embase, CINAHL, and the Cochrane Central databases were searched. We included RCTs with a follow-up of ≥3 wk that assessed the effect of KJM on LDL cholesterol, non-HDL cholesterol, or apolipoprotein B. Data were pooled by using the generic inverse-variance method with random-effects models and expressed as mean differences (MDs) with 95% CIs. Heterogeneity was assessed by the Cochran Q statistic and quantified by the I2 statistic.Results: Twelve studies (n = 370), 8 in adults and 4 in children, met the inclusion criteria. KJM significantly lowered LDL cholesterol (MD: -0.35 mmol/L; 95% CI: -0.46, -0.25 mmol/L) and non-HDL cholesterol (MD: -0.32 mmol/L; 95% CI: -0.46, -0.19 mmol/L). Data from 6 trials suggested no impact of KJM on apolipoprotein B.Conclusions: Our findings support the intake of ∼3 g KJM/d for reductions in LDL cholesterol and non-HDL cholesterol of 10% and 7%, respectively. The information may be of interest to health agencies in crafting future dietary recommendations related to reduction in CVD risk. This study was registered at clinicaltrials.gov as NCT02068248.
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Should apolipoprotein B replace LDL cholesterol as therapeutic targets are lowered?
Meeusen, JW, Donato, LJ, Jaffe, AS
Current opinion in lipidology. 2016;(4):359-66
Abstract
PURPOSE OF REVIEW The success of LDL cholesterol (LDL-C) as a predictor of atherosclerotic cardiovascular disease and a therapeutic target is indisputable. Apolipoprotein B (apoB) is a more contemporary and physiologically relevant measure of atherogenic lipoproteins. This report summarizes recent comparisons of apoB and LDL-C as biomarkers of cardiovascular risk. RECENT FINDINGS Multiple recent reports have found that LDL-C methods perform poorly at low concentrations (<70 mg/dl). Several meta-analyses from randomized controlled trials and large prospective observational studies have found that apoB and LDL-C provide equivalent information on risk of cardiovascular disease. More innovative analyses have asserted that apoB is a superior indicator of actual risk when apoB and LDL-C disagree. SUMMARY ApoB is more analytically robust and standardized biomarker than LDL-C. Large population studies have found that apoB is at worst clinically equivalent to LDL-C and likely superior when disagreement exists. Realistically, many obstacles prevent the wide spread adoption of apoB and for now providers and their patients must weigh the costs and benefits of apoB.
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[Familial Hypercholesterolemia and Its Related Molecules].
Ogura, M
Rinsho byori. The Japanese journal of clinical pathology. 2016;(6):657-666
Abstract
Familial hypercholesterolemia (FH) is a common genetic cause of premature coronary heart disease due to lifelong elevated plasma low-density lipoprotein (LDL) cholesterol levels. However, single gene disorders like FH have been giving some clues to develop new pharmacological interventions that reduce LDL choles- terol. Within just a few years, three classes of novel LDL-cholesterol-lowering agents are receiving regula- tory approval. Alirocumab and evolocumab are monoclonal antibodies that bind to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowering LDL by 50-70%. In Japan, evolocumab was approved for use in patients with cardiovascular disease or familial hypercholesterolemia whose LDL cholesterol levels are insuf- ficiently controlled by standard therapy, and alirocumab will be approved soon. Although definitive clinical efficacy and long-term safety data are still needed, antibody-based PCSK9 inhibitors promise to meet much of the unmet medical need in the treatment of raised LDL cholesterol. In addition, several other approaches to inhibiting PCSK9, as well as other classes of LDL-lowering therapies, are in clinical development. Further- more, lomitapide, a microsomal triglyceride transfer protein (MTP) inhibitor, and mipomersen, an antisense oligonucleotide for apolipoprotein B, inhibit the production of LDL. Since they also increase hepatic fat, only lomitapide will be approved specifically for homozygous familial hypercholesterolemia in Japan. This review summarizes the science behind the development of the newly developed LDL-lowering drugs. Finally, we discuss problems concerning FH, especially underdiagnosis. [Review].
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Hypolipidemia in a Special Operations Candidate: Case Report and Review of the Literature.
Strain, JE, Vigilante, JA, DiGeorge, NW
Journal of special operations medicine : a peer reviewed journal for SOF medical professionals. 2015;(4):1-5
Abstract
BACKGROUND A 19-year-old male military recruit who presented for a screening physical for US Naval Special Warfare Duty was found to have hypolipidemia. Medical history revealed mildly increased frequency of bowel movements, but was otherwise unremarkable. His presentation was most consistent with heterozygous familial hypobetalipoproteinemia (FHBL), and the patient was cleared for Special Operations duty. METHODS A literature search was conducted using PubMed/MEDLINE. Keywords included familial hypobetalipoproteinemia, heterozygous familial hypobetalipoproteinemia, abetalipoproteinemia, hypolipidemia, diving, special operations, and military. Results that included cases of familial hypobetalipoproteinemia were included. RESULTS Review of the literature reveals that FHBL is a genetic disorder frequently, but not always, due to a mutation in the apolipoprotein B (apoB) gene. Those with the condition should be screened for ophthalmologic, neurologic, and gastrointestinal complications. Analysis of the disease, as well as the absence of reported cases of FHBL in diving and Special Operations, suggest there is minimal increased risk in diving and Special Operations for patients who are likely heterozygous, are asymptomatic, and have a negative workup for potential complications from the disease. CONCLUSION Individuals with presumed or proven heterozygous FHBL seeking clearance for Special Operations duty should be given precautions, undergo careful questioning for history of disease-specific complications, and should have a baseline evaluation. If negative, it seems reasonable to clear the patient for Special Operations and diving.
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Association between LDL-C, Non HDL-C, and Apolipoprotein B Levels with Coronary Plaque Regression.
Masson, W, Siniawski, D, Lobo, M, Molinero, G, Giorgi, M, Huerín, M
Arquivos brasileiros de cardiologia. 2015;(1):11-9
Abstract
BACKGROUND Previous reports have inferred a linear relationship between LDL-C and changes in coronary plaque volume (CPV) measured by intravascular ultrasound. However, these publications included a small number of studies and did not explore other lipid markers. OBJECTIVE To assess the association between changes in lipid markers and regression of CPV using published data. METHODS We collected data from the control, placebo and intervention arms in studies that compared the effect of lipidlowering treatments on CPV, and from the placebo and control arms in studies that tested drugs that did not affect lipids. Baseline and final measurements of plaque volume, expressed in mm3, were extracted and the percentage changes after the interventions were calculated. Performing three linear regression analyses, we assessed the relationship between percentage and absolute changes in lipid markers and percentage variations in CPV. RESULTS Twenty-seven studies were selected. Correlations between percentage changes in LDL-C, non-HDL-C, and apolipoprotein B (ApoB) and percentage changes in CPV were moderate (r = 0.48, r = 0.47, and r = 0.44, respectively). Correlations between absolute differences in LDL-C, non‑HDL-C, and ApoB with percentage differences in CPV were stronger (r = 0.57, r = 0.52, and r = 0.79). The linear regression model showed a statistically significant association between a reduction in lipid markers and regression of plaque volume. CONCLUSION A significant association between changes in different atherogenic particles and regression of CPV was observed. The absolute reduction in ApoB showed the strongest correlation with coronary plaque regression.
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Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials.
Del Gobbo, LC, Falk, MC, Feldman, R, Lewis, K, Mozaffarian, D
The American journal of clinical nutrition. 2015;(6):1347-56
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Abstract
BACKGROUND The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. OBJECTIVES We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. DESIGN We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger's and Begg's tests. RESULTS Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (-4.7 mg/dL; 95% CI: -5.3, -4.0 mg/dL), LDL cholesterol (-4.8 mg/dL; 95% CI: -5.5, -4.2 mg/dL), ApoB (-3.7 mg/dL; 95% CI: -5.2, -2.3 mg/dL), and triglycerides (-2.2 mg/dL; 95% CI: -3.8, -0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (-11.5 mg/dL; 95% CI: -16.2, -6.8 mg/dL) than in healthy populations (-2.5 mg/dL; 95% CI: -4.7, -0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. CONCLUSIONS Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations.