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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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Abstract
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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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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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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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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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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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.
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Relations of change in plasma levels of LDL-C, non-HDL-C and apoB with risk reduction from statin therapy: a meta-analysis of randomized trials.
Thanassoulis, G, Williams, K, Ye, K, Brook, R, Couture, P, Lawler, PR, de Graaf, J, Furberg, CD, Sniderman, A
Journal of the American Heart Association. 2014;(2):e000759
Abstract
BACKGROUND Identifying the best markers to judge the adequacy of lipid-lowering treatment is increasingly important for coronary heart disease (CHD) prevention given that several novel, potent lipid-lowering therapies are in development. Reductions in LDL-C, non-HDL-C, or apoB can all be used but which most closely relates to benefit, as defined by the reduction in events on statin treatment, is not established. METHODS AND RESULTS We performed a random-effects frequentist and Bayesian meta-analysis of 7 placebo-controlled statin trials in which LDL-C, non-HDL-C, and apoB values were available at baseline and at 1-year follow-up. Summary level data for change in LDL-C, non-HDL-C, and apoB were related to the relative risk reduction from statin therapy in each trial. In frequentist meta-analyses, the mean CHD risk reduction (95% CI) per standard deviation decrease in each marker across these 7 trials were 20.1% (15.6%, 24.3%) for LDL-C; 20.0% (15.2%, 24.7%) for non-HDL-C; and 24.4% (19.2%, 29.2%) for apoB. Compared within each trial, risk reduction per change in apoB averaged 21.6% (12.0%, 31.2%) greater than changes in LDL-C (P<0.001) and 24.3% (22.4%, 26.2%) greater than changes in non-HDL-C (P<0.001). Similarly, in Bayesian meta-analyses using various prior distributions, Bayes factors (BFs) favored reduction in apoB as more closely related to risk reduction from statins compared with LDL-C or non-HDL-C (BFs ranging from 484 to 2380). CONCLUSIONS Using both a frequentist and Bayesian approach, relative risk reduction across 7 major placebo-controlled statin trials was more closely related to reductions in apoB than to reductions in either non-HDL-C or LDL-C.
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Effects of ezetimibe, simvastatin and ezetimibe/simvastatin on correlations between apolipoprotein B, LDL cholesterol and non-HDL cholesterol in patients with primary hypercholesterolemia.
Farnier, M, Guyton, JR, Jensen, E, Polis, AB, Johnson-Levonas, AO, Brudi, P
Atherosclerosis. 2013;(2):415-22
Abstract
BACKGROUND/SYNOPSIS Apolipoprotein (apo) B is highly predictive of coronary risk, especially in patients with high triglycerides (TG). This post hoc analysis evaluated the effects of lipid-lowering therapy on correlations between apoB and low-density lipoprotein cholesterol (apoB:LDL-C) and non-high-density lipoprotein cholesterol (apoB:non-HDL-C) in patients with TG< and ≥ 200 mg/dL. METHODS This analysis used data from 3 randomized clinical trials in patients with primary hypercholesterolemia receiving placebo, ezetimibe (EZE), simvastatin (SIMVA) or EZE/SIMVA for 12 weeks. Simple linear regression analyses predicted LDL-C and non-HDL-C levels corresponding to apoB values (80 mg/dL) at baseline and Week 12. RESULTS ApoB correlated with LDL-C (r ≥ 0.76) and non-HDL-C (r ≥ 0.86) at baseline. The correlations were strengthened with SIMVA and EZE/SIMVA at Week 12 (r ≥ 0.88 for LDL-C and r ≥ 0.94 for non-HDL-C). The predicted LDL-C and non-HDL-C values were lower following treatment with SIMVA or EZE/SIMVA than for placebo and EZE. For SIMVA and EZE/SIMVA, the predicted LDL-C and non-HDL-C values were closer to more aggressive LDL-C and non-HDL-C levels (i.e., 70 and 100 mg/dL, respectively). The apoB:LDL-C and apoB:non-HDL-C correlations were weaker and the predicted LDL-C values were generally lower in high TG patients than in low TG patients both at baseline and Week 12. In contrast, the predicted non-HDL-C values were generally higher in high versus low TG patients at baseline but less so at Week 12. CONCLUSION After treatment with EZE, SIMVA, or EZE/SIMVA, a given apoB value corresponds to lower LDL-C and non-HDL-C levels than those obtained from untreated patients.
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Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
Boekholdt, SM, Arsenault, BJ, Mora, S, Pedersen, TR, LaRosa, JC, Nestel, PJ, Simes, RJ, Durrington, P, Hitman, GA, Welch, KM, et al
JAMA. 2012;(12):1302-9
Abstract
CONTEXT The associations of low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), and apolipoprotein B (apoB) levels with the risk of cardiovascular events among patients treated with statin therapy have not been reliably documented. OBJECTIVE To evaluate the relative strength of the associations of LDL-C, non-HDL-C, and apoB with cardiovascular risk among patients treated with statin therapy. DESIGN Meta-analysis of individual patient data from randomized controlled statin trials in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. DATA SOURCES Relevant trials were identified by a literature search updated through December 31, 2011. Investigators were contacted and individual patient data were requested and obtained for 62,154 patients enrolled in 8 trials published between 1994 and 2008. DATA EXTRACTION Hazard ratios (HRs) and corresponding 95% CIs for risk of major cardiovascular events adjusted for established risk factors by 1-SD increase in LDL-C, non-HDL-C, and apoB. RESULTS Among 38,153 patients allocated to statin therapy, 158 fatal myocardial infarctions, 1678 nonfatal myocardial infarctions, 615 fatal events from other coronary artery disease, 2806 hospitalizations for unstable angina, and 1029 fatal or nonfatal strokes occurred during follow-up. The adjusted HRs for major cardiovascular events per 1-SD increase were 1.13 (95% CI, 1.10-1.17) for LDL-C, 1.16 (95% CI, 1.12-1.19) for non-HDL-C, and 1.14 (95% CI, 1.11-1.18) for apoB. These HRs were significantly higher for non-HDL-C than LDL-C (P = .002) and apoB (P = .02). There was no significant difference between apoB and LDL-C (P = .21). CONCLUSION Among statin-treated patients, on-treatment levels of LDL-C, non-HDL-C, and apoB were each associated with risk of future major cardiovascular events, but the strength of this association was greater for non-HDL-C than for LDL-C and apoB.
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Achievement of recommended lipid and lipoprotein levels with combined ezetimibe/statin therapy versus statin alone in patients with and without diabetes.
Guyton, JR, Betteridge, DJ, Farnier, M, Leiter, LA, Lin, J, Shah, A, Johnson-Levonas, AO, Brudi, P
Diabetes & vascular disease research. 2011;(2):160-72
Abstract
Treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as the primary target of therapy with secondary targets of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (apoB). Data were pooled from 27 randomised, double-blind, active or placebo-controlled trials in 21,794 adult hypercholesterolaemic patients (LDL-C 1.81-6.48 mmol/L) receiving ezetimibe/statin or statin for 4-24 weeks. Percentages of patients achieving various targets were calculated among diabetes (n = 6541) and non-diabetes (n = 15,253) subgroups. Significantly more patients with and without diabetes achieved specified levels of LDL-C (< 2.59, < 1.99, < 1.81 mmol/L), non-HDL-C (< 3.37, < 2.59 mmol/L) and apoB (< 0.9, < 0.8 g/L) with ezetimibe/statin versus statin. Patients with diabetes had larger mean per cent reductions in LDL-C and non-HDL-C than non-diabetes patients. A greater percentage of patients achieved both the LDL-C and apoB targets and all three LDL-C, apoB, and non-HDL-C targets with ezetimibe/statin versus statin in both subgroups. Patients with diabetes benefitted at least as much as, and sometimes more than, non-diabetes patients following treatment with ezetimibe/statin.
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A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk.
Sniderman, AD, Williams, K, Contois, JH, Monroe, HM, McQueen, MJ, de Graaf, J, Furberg, CD
Circulation. Cardiovascular quality and outcomes. 2011;(3):337-45
Abstract
BACKGROUND Whether apolipoprotein B (apoB) or non-high-density lipoprotein cholesterol (HDL-C) adds to the predictive power of low-density lipoprotein cholesterol (LDL-C) for cardiovascular risk remains controversial. METHODS AND RESULTS This meta-analysis is based on all the published epidemiological studies that contained estimates of the relative risks of non-HDL-C and apoB of fatal or nonfatal ischemic cardiovascular events. Twelve independent reports, including 233 455 subjects and 22 950 events, were analyzed. All published risk estimates were converted to standardized relative risk ratios (RRRs) and analyzed by quantitative meta-analysis using a random-effects model. Whether analyzed individually or in head-to-head comparisons, apoB was the most potent marker of cardiovascular risk (RRR, 1.43; 95% CI, 1.35 to 1.51), LDL-C was the least (RRR, 1.25; 95% CI, 1.18 to 1.33), and non-HDL-C was intermediate (RRR, 1.34; 95% CI, 1.24 to 1.44). The overall comparisons of the within-study differences showed that apoB RRR was 5.7%>non-HDL-C (P<0.001) and 12.0%>LDL-C (P<0.0001) and that non-HDL-C RRR was 5.0%>LDL-C (P=0.017). Only HDL-C accounted for any substantial portion of the variance of the results among the studies. We calculated the number of clinical events prevented by a high-risk treatment regimen of all those >70th percentile of the US adult population using each of the 3 markers. Over a 10-year period, a non-HDL-C strategy would prevent 300 000 more events than an LDL-C strategy, whereas an apoB strategy would prevent 500 000 more events than a non-HDL-C strategy. CONCLUSIONS These results further validate the value of apoB in clinical care.
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When is equal not equal?
Sniderman, AD, Williams, K, McQueen, MJ, Furberg, CD
Journal of clinical lipidology. 2010;(2):83-8
Abstract
The meta-analysis of the Emerging Risk Factor Collaboration demonstrated that the hazard ratios (HR) of the major cholesterol markers and the major apolipoproteins for vascular disease did not differ significantly in the studies they examined. Their conclusion was that they were functionally interchangeable. We believe there are important limitations in the execution of this study. Nevertheless, even if their findings are correct for groups, their conclusions do not follow for individuals. Conventionally, the HR expresses the increase in risk per standard deviation change for that parameter in a group. However, the predicted risk of vascular disease from an atherogenic parameter depends on its concentration within the individual. Depending on the composition of the apoB lipoproteins, individuals may have either concordant or discordant levels of cholesterol and apoB. For those who are concordant, the two markers predict equal risk. For those who are discordant, the predicted risks for the individual are different. We demonstrate that substantial discordance in the individual HR of non-high-density lipoprotein cholesterol and apoB is common. The result is that even with identical overall HR, apoB points to higher risk in a substantial number of individuals whereas the converse is the case for non- high-density lipoprotein cholesterol. Because we are concerned with risks in individuals, not groups, this discordance is important to appreciate and analyze. Our objective should be to learn how to combine the information from parameters rather than eliminate them and we need to focus on evaluation of risk in individuals and not just groups.