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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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Abstract
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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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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Abstract
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.
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Impact of Novel Low-Density Lipoprotein-Cholesterol Assessment on the Utility of Secondary Non-High-Density Lipoprotein-C and Apolipoprotein B Targets in Selected Worldwide Dyslipidemia Guidelines.
Sathiyakumar, V, Park, J, Quispe, R, Elshazly, MB, Michos, ED, Banach, M, Toth, PP, Whelton, SP, Blumenthal, RS, Jones, SR, et al
Circulation. 2018;(3):244-254
Abstract
BACKGROUND Selected dyslipidemia guidelines recommend non-high-density lipoprotein-cholesterol (non-HDL-C) and apolipoprotein B (apoB) as secondary targets to the primary target of low-density lipoprotein-cholesterol (LDL-C). After considering 2 LDL-C estimates that differ in accuracy, we examined: (1) how frequently non-HDL-C guideline targets could change management; and (2) the utility of apoB targets after meeting LDL-C and non-HDL-C targets. METHODS We analyzed 2518 adults representative of the US population from the 2011 to 2012 National Health and Nutrition Examination Survey and 126 092 patients from the Very Large Database of Lipids study with apoB. We identified all individuals as well as those with high-risk clinical features, including coronary artery disease, diabetes mellitus, and metabolic syndrome who met very high- and high-risk guideline targets of LDL-C <70 and <100 mg/dL using Friedewald estimation (LDL-CF) and a novel, more accurate method (LDL-CN). Next, we examined those not meeting non-HDL-C (<100, <130 mg/dL) and apoB (<80, <100 mg/dL) guideline targets. In those meeting dual LDL-C and non-HDL-C targets (<70 and <100 mg/dL, respectively, or <100 and <130 mg/dL, respectively), we determined the proportion of individuals who did not meet guideline apoB targets (<80 or <100 mg/dL). RESULTS A total of 7% to 9% and 31% to 36% of individuals had LDL-C <70 and <100 mg/dL, respectively. Among those with LDL-CF<70 mg/dL, 14% to 15% had non-HDL-C ≥100 mg/dL, and 7% to 8% had apoB ≥80 mg/dL. Among those with LDL-CF<100 mg/dL, 8% to 10% had non-HDL-C ≥130 mg/dL and 2% to 3% had apoB ≥100 mg/dL. In comparison, among those with LDL-CN<70 or 100 mg/dL, only ≈2% and ≈1% of individuals, respectively, had non-HDL-C and apoB values above guideline targets. Similar trends were upheld among those with high-risk clinical features: ≈0% to 3% of individuals with LDL-CN<70 mg/dL had non-HDL-C ≥100 mg/dL or apoB ≥80 mg/dL compared with 13% to 38% and 9% to 25%, respectively, in those with LDL-CF<70 mg/dL. With LDL-CF or LDL-CN<70 mg/dL and non-HDL-C <100 mg/dL, 0% to 1% had apoB ≥80 mg/dL. Among all dual LDL-CF or LDL-CN<100 mg/dL and non-HDL-C <130 mg/dL individuals, 0% to 0.4% had apoB ≥100 mg/dL. These findings were robust to sex, fasting status, and lipid-lowering therapy status. CONCLUSIONS After more accurately estimating LDL-C, guideline-suggested non-HDL-C targets could alter management in only a small fraction of individuals, including those with coronary artery disease and other high-risk clinical features. Furthermore, current guideline-suggested apoB targets provide modest utility after meeting cholesterol targets. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489.
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Do apolipoproteins improve coronary risk prediction in subjects with metabolic syndrome? Insights from the North Italian Brianza cohort study.
Gianfagna, F, Veronesi, G, Guasti, L, Chambless, LE, Brambilla, P, Corrao, G, Mancia, G, Cesana, G, Ferrario, MM
Atherosclerosis. 2014;(1):175-81
Abstract
OBJECTIVE We assessed predictive abilities and clinical utility of CVD risk algorithms including ApoB and ApoAI among non-diabetic subjects with metabolic syndrome (MetS). METHODS Three independent population-based cohorts (3677 35-74 years old) were enrolled in Northern Italy, adopting standardized MONICA procedures. Through Cox models, we assessed the associations between lipid measures and first coronary events, as well as the changes in discrimination and reclassification (NRI) when standard lipids or apolipoproteins were added to the CVD risk algorithm including non-lipids risk factors. Finally, the best models including lipids or apolipoproteins were compared. RESULTS During the 14.5 years median follow-up time, 164 coronary events were validated. All measures showed statistically significant associations with the endpoint, while in the MetS subgroup HDL-C and ApoAI (men, HR = 1.59; 95%CI: 0.96-2.65) were not associated. Models including HDL-C plus TC and ApoB plus ApoAI for lipids and apolipoproteins, respectively, showed the best predictive values. When ApoB plus ApoAI replaced TC plus HDL-C, NRI values improved in subjects with MetS (13.8; CI95%: -5.1,53.1), significantly in those previously classified at intermediate risk (44.5; CI95% 13.8,129.6). In this subgroup, 5.5% of subjects was moved in the high (40.0% of expected events) and 17.0% in the low risk class (none had an event at 10 years). CONCLUSIONS ApoB and ApoAI could improve coronary risk prediction when used as second level biomarkers in non-diabetic subjects with MetS classified at intermediate risk. The absence of cases moved downward suggests the gain in avoiding treatments in non-cases and favor the use of apolipoproteins for risk assessment.
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Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes).
Albers, JJ, Slee, A, O'Brien, KD, Robinson, JG, Kashyap, ML, Kwiterovich, PO, Xu, P, Marcovina, SM
Journal of the American College of Cardiology. 2013;(17):1575-9
Abstract
OBJECTIVES This study sought to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial. BACKGROUND Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1. METHODS Individuals with CV disease and low baseline levels of high-density lipoprotein cholesterol were randomized to simvastatin plus placebo or simvastatin, plus extended-release niacin ([ERN], 1,500 to 2,000 mg/day), with ezetimibe added as needed, in both groups, to maintain an on-treatment low-density lipoprotein cholesterol in the range of 40 to 80 mg/dl. Hazard ratios (HRs) were used to evaluate the relationship between levels of apoA-1, apoB, and Lp(a), and CV events in each treatment group. RESULTS Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR: 1.17 [p = 0.018] and HR: 1.19 [p = 0.016]). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin plus placebo (baseline HR: 1.24 [p = 0.002] and on-study HR: 1.21 [p = 0.017]) and the simvastatin plus ERN group (baseline HR: 1.25 [p = 0.001] and on-study HR: 1.18 [p = 0.028]). The ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events. CONCLUSIONS Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk, despite favorable lipoprotein changes.
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Achievement of specified low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol apolipoprotein B, and high-sensitivity C-reactive protein levels with ezetimibe/simvastatin or atorvastatin in metabolic syndrome patients with and without atherosclerotic vascular disease (from the VYMET study).
Robinson, JG, Ballantyne, CM, Hsueh, W, Rosen, J, Lin, J, Shah, A, Lowe, RS, Hanson, ME, Tershakovec, AM
Journal of clinical lipidology. 2011;(6):474-82
Abstract
BACKGROUND Metabolic syndrome (MetS) and atherosclerotic vascular disease (AVD) are associated with increased coronary heart disease risk. OBJECTIVE To assess percent change from baseline in lipids and high-sensitivity C-reactive protein (hs-CRP) levels and the proportion of subjects reaching specified low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B (Apo B) single, dual, and triple targets and hs-CRP <2 mg/L among subjects with and without AVD treated with ezetimibe/simvastatin or atorvastatin for 6 weeks. METHODS Adults (N = 1143) with MetS and hypercholesterolemia were randomized to starting and next higher doses of ezetimibe/simvastatin (10/20 or 10/40 mg) or atorvastatin (10, 20, or 40 mg). RESULTS Ezetimibe/simvastatin produced significantly greater reductions in evaluated lipids than atorvastatin for most prespecified dose comparisons. More subjects without AVD achieved LDL-C levels <100 mg/dL, non-HDL-C levels <130 mg/dL, and dual LDL-C/non-HDL targets (83%-92% vs 62%-76%) and Apo B <90 mg/dL or triple targets (65%-75% vs 41%-49%) with 40 mg of atorvastatin or 10/20-40 mg of ezetimibe/simvastatin compared with 10 or 20 mg of atorvastatin, respectively. More subjects with AVD achieved LDL-C<70 mg/dL and non-HDL-C<100 mg/dL single and dual targets (65%-80%) and Apo B <80 mg/dL (53%-63%) with 10/20-40 mg of ezetimibe/simvastatin than with 40 mg of atorvastatin (40%-49%). More subjects achieved triple lipid targets with 10/20-40 mg of ezetimibe/simvastatin versus 10-40 mg of atorvastatin (50%-63% vs 24%-40%). Achievement of hs-CRP <2 mg/L was similar across all doses regardless of AVD status. CONCLUSIONS More intensive therapy was required for >80% of subjects to achieve LDL-C <100 mg/dL and non-HDL-C <130 mg/dL and for the majority of subjects to achieve lower levels of LDL-C <70 mg/dL, non-HDL-C <100 mg/dL, and/or Apo B <90 mg/dL. The effect of ezetimibe on cardiovascular risk reduction has yet to be established. (Clintrials.gov no: NCT00409773).
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Apolipoprotein B and non-high-density lipoprotein cholesterol are better risk markers for coronary artery disease than low-density lipoprotein cholesterol in hypertriglyceridemic metabolic syndrome patients.
Boumaiza, I, Omezzine, A, Rejeb, J, Rebhi, L, Kalboussi, N, Ben Rejeb, N, Nabli, N, Ben Abdelaziz, A, Boughazala, E, Bouslama, A
Metabolic syndrome and related disorders. 2010;(6):515-22
Abstract
BACKGROUND Metabolic syndrome is highly prevalent in the general population. Small dense low-density lipoprotein (sd-LDL) particles have been considered as a risk marker in metabolic syndrome diagnosis. Apolipoprotein B (ApoB) concentration reflects the number of LDL particles and is closely associated with atherosclerosis. The aim of this study was to compare the associations of ApoB, non-high-density lipoprotein cholesterol (NHDL-C), and low-density lipoprotein cholesterol (LDL-C) with metabolic syndrome and its relationship with significant coronary stenosis (SCS) in a Tunisian population. METHODS We enrolled 192 patients, who underwent coronary angiography. The body mass index, blood lipids, fasting glucose, insulin concentration, and blood pressure of every patient were measured. Metabolic syndrome was diagnosed according to the International Diabetes Federation criteria. RESULTS The frequency of metabolic syndrome was 58.3%. The comparison of the lipidic parameters between subject with and without metabolic syndrome showed a significant increase in ApoB and NHDL-C but not in LDL-C. By considering triglyceride (TG) limits (TG ≤ 0.9 mmol/L and TG > 1.70 mmol/L), we noted no differences in ApoB, NHDL-C, and LDL-C between subjects with and without metabolic syndrome in triglyceridemia ≤0.9 mmol/L. In triglyceridemia >1.70 mmol/L, a significant increase in ApoB and NHDL-C, but not in LDL-C, was noted. These results seem to consolidate the probability of increased sd-LDL in hypertriglyceridemic metabolic syndrome subjects. Indeed, in our study the odds ratio (OR) of SCS associated with metabolic syndrome is 3.81 (P = 0.007) in the studied population. This risk increases to 8.70 (P = 0.026) in hypertriglyceridemic subjects and seems to be associated with ApoB and NHDL-C (OR = 1.87, P = 0.038; OR = 1.26, P = 0.048). CONCLUSIONS This study suggests that ApoB and NHDL-C seem to be more correlated to SCS in metabolic syndrome with hypertriglyceridemia than LDL-C.
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Apolipoprotein measurements: is more widespread use clinically indicated?
Davidson, MH
Clinical cardiology. 2009;(9):482-6
Abstract
Apolipoprotein (apo) B may be a more sensitive measure of atherogenicity than low-density lipoprotein cholesterol (LDL-C) and a better index for assessing cardiovascular risk. The refined risk assessment provided by apo B may be important in patients at high cardiometabolic risk such as those with diabetes mellitus or metabolic syndrome, as these conditions are often associated with normal LDL-C values but increased numbers of small, dense low-density lipoprotein (LDL) particles (indicating increased levels of apo B). Although apo B is not currently a treatment target in the United States cholesterol-lowering guidelines, a consensus conference endorsed by the American Diabetes Association and the American College of Cardiology recently recommended that apo B be added as a therapeutic target in patients at high cardiometabolic risk and in patients with clinical cardiovascular disease or diabetes. Suggested target goals are < 90 for high risk and < 80 mg/dL for highest risk patients. Current clinical data indicate that intensive statin therapy can lower apo B to meet this aggressive goal. While the proatherogenic/antiatherogenic ratio of apo B/apo A-I is a better risk discriminator than the single proatherogenic measurement (apo B), clinical trial data are lacking regarding the impact of increasing apo A-I and high-density lipoprotein on outcomes.
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Apolipoprotein B, apolipoprotein A-I, insulin resistance and the metabolic syndrome.
Sniderman, AD, Faraj, M
Current opinion in lipidology. 2007;(6):633-7
Abstract
PURPOSE OF REVIEW The goal of identifying subjects with metabolic syndrome is to detect those at higher risk of developing cardiovascular disease. Evidence continues to accumulate as to the superiority of apolipoprotein B and apolipoprotein A-I over the conventional lipoprotein lipids as markers of vascular risk. It would seem reasonable, therefore, to redefine the dyslipidemia of the metabolic syndrome incorporating apolipoproteins. Therefore, our objective is to elucidate how apolipoprotein B and apolipoprotein A-I amplify evidence of the interactions amongst metabolic syndrome, insulin resistance, abdominal obesity, and vascular risk. RECENT FINDINGS In several large epidemiological studies, including the NHANES III database, apolipoprotein B/apolipoprotein A-I ratio was tightly linked to the metabolic syndrome and each of its components, the descending order being: low HDL cholesterol, high triglyceride, high waist circumference, high glucose, and high blood pressure. Moreover, apolipoprotein B associates more closely with inflammatory markers and insulin resistance than triglyceride and all cholesterol markers. Yet despite close association of the apolipoprotein B/apolipoprotein A-I ratio to metabolic syndrome, both are independent predictors of future myocardial infarction. SUMMARY We believe that the dyslipidemia of the metabolic syndrome should be redefined to include apolipoprotein B and apolipoprotein A-I.
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Effect of a statin on hepatic apolipoprotein B-100 secretion and plasma campesterol levels in the metabolic syndrome.
Watts, GF, Chan, DC, Barrett, PH, O'Neill, FH, Thompson, GR
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2003;(7):862-5
Abstract
OBJECTIVE We aimed to study the effect of atorvastatin, a statin, on cholesterol synthesis and absorption and VLDL-apoB metabolism in obese men with the metabolic syndrome. METHODS A total of 25 dyslipidaemic obese men were randomized to atorvastatin (n=13) (40 mg/day) or matching placebo (n=12) for 6 weeks. Hepatic secretion and fractional catabolic rate (FCR) of VLDL-apoB was measured using an intravenous bolus of d(3)-leucine before and after treatment. ApoB isotopic enrichment was measured using GCMS and multicompartmental modelling. Plasma lathosterol: cholesterol and campesterol:cholesterol ratios were determined to assess cholesterol synthesis and cholesterol absorption, respectively. RESULTS Compared with placebo, atorvastatin significantly decreased (P<0.05) total cholesterol, triglyceride, LDL-cholesterol and VLDL-apoB. Plasma lathosterol:cholesterol ratio decreased from 26.4+/-2.4 to 8.8+/-0.8, while the campesterol:cholesterol ratio increased from 26.5+/-4.4 to 38.6+/-5.8 (P<0.01). Atorvastatin also increased VLDL-apoB FCR from 3.82+/-0.33 to 6.30+/-0.75 pools/day (P<0.01), but did not significantly alter VLDL-apoB secretion (12.8+/-1.7 to 13.8+/-2.0 mg/kg/day). CONCLUSIONS In obesity, atorvastatin inhibits cholesterogenesis but increases intestinal cholesterol absorption. The increased cholesterol absorption may counteract the inhibitory effect on hepatic VLDL-apoB secretion, but it does not apparently influence enhanced catabolism of VLDL-apoB.