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Apolipoprotein B discordance with low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).
Cao, J, Nomura, SO, Steffen, BT, Guan, W, Remaley, AT, Karger, AB, Ouyang, P, Michos, ED, Tsai, MY
Journal of clinical lipidology. 2020;(1):109-121.e5
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BACKGROUND Discordant levels of apolipoprotein B (apo B) relative to low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) may be associated with subclinical atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE The present study investigated whether discordance between apo B and LDL-C or non-HDL-C levels was associated with subclinical ASCVD measured by coronary artery calcium (CAC). METHODS This study was conducted in a subpopulation of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, aged 45 to 84 years, free of ASCVD, and not taking lipid-lowering medications at the baseline (2000-2002) (prevalence analytic N = 4623; incidence analytic N = 2216; progression analytic N = 3947). Apo B discordance relative to LDL-C and non-HDL-C was defined using residuals and percentile rankings (>5/10/15 percentile). Associations with prevalent and incident CAC (CAC > 0 vs CAC = 0) were assessed using prevalence ratio/relative risk regression and CAC progression (absolute increase/year) using multinomial logistic regression. RESULTS Higher apo B levels were associated with CAC prevalence, incidence, and progression. Apo B discordance relative to LDL-C or non-HDL-C was inconsistently associated with CAC prevalence and progression. Discordantly high apo B relative to LDL-C and non-HDL-C was associated with CAC progression. Associations for apo B discordance with non-HDL-C remained after further adjustment for metabolic syndrome components. CONCLUSION Apo B was associated with CAC among adults aged ≥45 years not taking statins, but provided only modest additional predictive value of apo B for CAC prevalence, incidence, or progression beyond LDL-C or non-HDL-C. Apo B discordance may still be important for ASCVD risk assessment and further research is needed to confirm findings.
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Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials.
Khan, SU, Khan, MU, Valavoor, S, Khan, MS, Okunrintemi, V, Mamas, MA, Leucker, TM, Blaha, MJ, Michos, ED
European journal of preventive cardiology. 2020;(12):1255-1268
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AIMS: The effect of therapeutic lowering of apolipoprotein B (apoB) on mortality and major adverse cardiovascular events is uncertain. It is also unclear whether these potential effects vary by different lipid-lowering strategies. METHODS A total of 29 randomized controlled trials were selected using PubMed, Cochrane Library and EMBASE through 2018. We selected trials of therapies which ultimately clear apolipoprotein B particles by upregulating low-density lipoprotein receptor (LDL-R) expression (statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants) or therapies which reduce apolipoprotein B independent of LDL-R (cholesteryl ester transfer protein inhibitor, fibrates, niacin, omega-3 fatty acids) with sample size of ≥1000 patients and follow-up of ≥1 year. The meta-regression and meta-analyses were constructed using a random effects model. RESULTS In 332,912 patients, meta-regression analyses showed relative risks of 0.95 for all-cause mortality (95% confidence interval 0.92-0.99) and 0.93 (0.88-0.98) for cardiovascular mortality for every 10 mg/dL decrease in apolipoprotein B by all interventions combined. Reduction in all-cause mortality was limited to statins (0.92 (0.86-0.98)). For MACE, the relative risk per 10 mg/dL reduction in apolipoprotein B was 0.93 (0.90-0.97) for all therapies combined, with both statin (0.88 (0.83-0.93)) and non-statin therapies (0.96 (0.94-0.99)). which clear apolipoprotein B by upregulating LDL-R showing significant reductions; whereas interventions which lower apolipoprotein B independent of LDL-R did not demonstrate this effect (1.02 (0.81-1.30)). CONCLUSION While both statin and established non-statin therapies (PCSK9 inhibitor and ezetimibe) reduced cardiovascular risk per decrease in apolipoprotein B, interventions which reduce apolipoprotein B independently of LDL-R were not associated with cardiovascular benefit.
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Pharmacokinetic and pharmacodynamic assessment of alirocumab in patients with familial hypercholesterolemia associated with proprotein convertase subtilisin/kexin type 9 gain-of-function or apolipoprotein B loss-of-function mutations.
Hopkins, PN, Krempf, M, Bruckert, E, Donahue, S, Yang, F, Zhang, Y, DiCioccio, AT
Journal of clinical lipidology. 2019;(6):970-978
Abstract
BACKGROUND Familial hypercholesterolemia is characterized by high levels of low-density lipoprotein cholesterol (LDL-C), and causes of familial hypercholesterolemia include apolipoprotein B (APOB) loss-of-function mutations (LOFm) and proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations (GOFm). OBJECTIVE The aim of this study was to compare the pharmacokinetics and pharmacodynamics of alirocumab between patients with APOB LOFm vs PCSK9 GOFm. METHODS Patients (6 APOB LOFm and 17 PCSK9 GOFm carriers) with LDL-C ≥70 mg/dL on maximally tolerated lipid-lowering therapies received alirocumab 150 mg at Weeks 0, 2, 4, and 6, placebo at Week 8, alirocumab at Week 10, placebo at Weeks 12 and 14, then completed a follow-up period at Week 22. RESULTS At Week 8, mean ± standard error (SE) alirocumab concentration was lower in APOB LOFm carriers compared with PCSK9 GOFm carriers (12.12 ± 1.81 vs 16.74 ± 2.53 mg/L). APOB LOFm carriers had higher mean ± SE total PCSK9 (6.56 ± 0.73 mg/L) and lower mean ± SE free PCSK9 (0.025 ± 0.016 mg/L) at Week 8 compared with PCSK9 GOFm carriers (4.21 ± 0.35 and 0.11 ± 0.035 mg/L for total and free PCSK9, respectively). Despite this observed greater PCSK9 suppression, mean ± SE percent LDL-C reduction was lower in APOB LOFm (55.3 ± 1.0%) compared with PCSK9 GOFm carriers (73.1 ± 0.9%). Treatment-emergent adverse events occurred in 16 patients (94.1%) in the PCSK9 GOFm group and 5 patients (83.3%) in the APOB LOFm group. CONCLUSIONS Overall, PCSK9 inhibition with alirocumab results in clinically meaningful reductions in LDL-C in both APOB LOFm and PCSK9 GOFm carriers, although reductions were greater in the PCSK9 GOFm carriers. The results indicate a possible underlying contributor to hypercholesterolemia other than PCSK9 in patients with APOB LOFm. CLINICAL TRIAL REGISTRATION NCT01604824; clinicaltrials.gov.
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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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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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N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels.
Alexander, VJ, Xia, S, Hurh, E, Hughes, SG, O'Dea, L, Geary, RS, Witztum, JL, Tsimikas, S
European heart journal. 2019;(33):2785-2796
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AIMS: Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis. METHODS AND RESULTS The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18-65) with triglyceride levels ≥90 or ≥200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, -42%, -73%, -81%, and -92% in apoC-III, and -12%, -7%, -42%, -73%, and -77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of -66%, -84%, and -89% in apoC-III, and -59%, -73%, and -66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals. CONCLUSION Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile. ClinicalTrials.gov Identifier: NCT02900027.
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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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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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Association between angiopoietin-like protein 2 and lectin-like oxidized low-density lipoprotein receptor 1 ligand containing apolipoprotein B in patients with type 2 diabetes.
Suzuki, T, Takebayashi, K, Hara, K, Tsuchiya, T, Inukai, T
The Journal of international medical research. 2018;(10):4167-4180
Abstract
Objective This study was performed to evaluate the association of the serum level of angiopoietin-like protein 2 (ANGPTL2) with circulating inflammatory markers and oxidized and modified low-density lipoprotein (LDL) cholesterol as evaluated by lectin-like oxidized LDL receptor 1 ligand containing apolipoprotein B (LAB) in patients with type 2 diabetes. Methods The study included 70 patients with type 2 diabetes hospitalized for glycemic control and 9 control subjects. Results The serum level of ANGPTL2 was significantly higher in the patients with type 2 diabetes than in the healthy controls. There was a significant positive correlation between ANGPTL2 and the high-sensitivity C-reactive protein, fibrinogen, and LAB levels and a significant negative correlation between ANGPTL2 and the estimated glomerular filtration rate (eGFR). Conclusions These results suggest that the serum ANGPTL2 level has a close positive association with inflammatory markers, especially fibrinogen and oxidized and modified LDL as evaluated by LAB. The data also suggest that the serum ANGPTL2 level is influenced by renal function as reflected by the eGFR.
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Bariatric surgery improves lipoprotein profile in morbidly obese patients by reducing LDL cholesterol, apoB, and SAA/PON1 ratio, increasing HDL cholesterol, but has no effect on cholesterol efflux capacity.
Kjellmo, CA, Karlsson, H, Nestvold, TK, Ljunggren, S, Cederbrant, K, Marcusson-Ståhl, M, Mathisen, M, Lappegård, KT, Hovland, A
Journal of clinical lipidology. 2018;(1):193-202
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BACKGROUND Bariatric surgery has been shown to reduce cardiovascular events and cause-specific mortality for coronary artery disease in obese patients. Lipoprotein biomarkers relating to low-density lipoprotein (LDL), high-density lipoprotein (HDL), their subfractions, and macrophage cholesterol efflux have all been hypothesized to be of value in cardiovascular risk assessment. OBJECTIVES The objective of this study was to examine the effect of a lifestyle intervention followed by bariatric surgery on the lipid profile of morbidly obese patients. METHODS Thirty-four morbidly obese patients were evaluated before and after lifestyle changes and then 1 year after bariatric surgery. They were compared with 17 lean subjects. Several lipoprotein metrics, serum amyloid A (SAA), serum paraoxonase-1 (PON1), and macrophage cholesterol efflux capacity (CEC) were assessed. RESULTS Average weight loss after the lifestyle intervention was 10.5% and 1 year after bariatric surgery was 33.9%. The lifestyle intervention significantly decreased triglycerides (TGs; -28.7 mg/dL, P < .05), LDL cholesterol (LDL-C; -32.3 mg/dL, P < .0001), and apolipoprotein B (apoB; -62.9 μg/mL, P < .001). Bariatric surgery further reduced TGs (-36.7 mg/dL, P < .05), increased HDL cholesterol (+12 mg/dL, P < .0001), and reductions in LDL-C and apoB were sustained. Bariatric surgery reduced large, buoyant LDL (P < .0001), but had no effect on the small, dense LDL. The large HDL subfractions increased (P < .0001), but there was no effect on the smaller HDL subfractions. The ratio for SAA/PON1 was reduced after the lifestyle intervention (P < .01) and further reduced after bariatric surgery (P < .0001). Neither the lifestyle intervention nor bariatric surgery had any effect on CEC. CONCLUSIONS Lifestyle intervention followed by bariatric surgery in 34 morbidly obese patients showed favorable effects on TGs, LDL-C, and apoB. HDL cholesterol and apoA1 was increased, apoB/apoA1 ratio as well as SAA/PON1 ratio reduced, but bariatric surgery did not influence CEC.
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Effect of psyllium (Plantago ovata) fiber on LDL cholesterol and alternative lipid targets, non-HDL cholesterol and apolipoprotein B: a systematic review and meta-analysis of randomized controlled trials.
Jovanovski, E, Yashpal, S, Komishon, A, Zurbau, A, Blanco Mejia, S, Ho, HVT, Li, D, Sievenpiper, J, Duvnjak, L, Vuksan, V
The American journal of clinical nutrition. 2018;(5):922-932
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BACKGROUND Studies have identified viscous dietary fiber as potentially attenuating cholesterol, including psyllium, which reduces LDL cholesterol and thus may complement cardiovascular disease (CVD) treatment. OBJECTIVES The aims of this study were to update evidence on the effect of psyllium on LDL cholesterol and to provide an assessment of its impact on alternate markers: non-HDL cholesterol and apolipoprotein B (apoB). DESIGN Medline, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched through 3 October 2017. Independent reviewers extracted relevant data and assessed risk of bias. We included randomized controlled trials with a duration of ≥3 wk that assessed the effect of psyllium on blood lipids in individuals with or without hypercholesterolemia. 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 Cochran's Q statistic and quantified by the I2 statistic. Overall quality of the evidence was assessed by using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. RESULTS We included 28 trials in our analysis (n = 1924). Supplementation of a median dose of ∼10.2 g psyllium significantly reduced LDL cholesterol (MD = -0.33 mmol/L; 95% CI: -0.38, -0.27 mmol/L; P < 0.00001), non-HDL cholesterol (MD = -0.39 mmol/L; 95% CI: -0.50, -0.27 mmol/L; P < 0.00001), and apoB (MD = -0.05 g/L; 95% CI: -0.08, -0.03 g/L; P < 0.0001). Effect estimates for LDL cholesterol and non-HDL cholesterol were graded as moderate quality on the basis of downgrades for inconsistency and graded as high quality for apoB. CONCLUSION Psyllium fiber effectively improves conventional and alternative lipids markers, potentially delaying the process of atherosclerosis-associated CVD risk in those with or without hypercholesterolemia. This trial is registered at www.clinicaltrials.gov as NCT03346733.
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Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials.
Henry, RR, Müller-Wieland, D, Taub, PR, Bujas-Bobanovic, M, Louie, MJ, Letierce, A, Ginsberg, HN
Diabetes, obesity & metabolism. 2018;(7):1632-1641
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AIMS: This analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials. MATERIALS AND METHODS Data from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo-controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe-controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL-C. RESULTS LDL-C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non-MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non-MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) and HDL-C. Overall, the percentage change at Week 24 in LDL-C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection-site reactions occurred more frequently in alirocumab vs control groups. CONCLUSIONS Across study pools, alirocumab-associated reductions in LDL-C, apolipoprotein B, and non-HDL-C were significant vs control, and did not vary by MetS status.