Atherosclerotic cardiovascular disease (ASCVD) is a significant health challenge, and apolipoprotein B (ApoB)-containing lipoproteins are increasingly recognized as central to its progression. Initially labelled as the \"low-density lipoprotein hypothesis,\" our understanding of the etiology of ASCVD has evolved into the \"ApoB principle,\" which highlights the causal and consistent role of all ApoB lipoproteins in ASCVD development. We review the large body of data from genetic studies, to epidemiologic studies, to clinical trials that support this foundational principle. We also provide an overview of the recommendations from guideline committees across the globe on dyslipidemia management and compare these with recent Canadian guidelines. With a few key differences, recent guidelines worldwide provide largely concordant recommendations for diagnosing and managing dyslipidemia with general consensus regarding the need for optimal control of low-density lipoprotein cholesterol and ApoB-containing lipoproteins to prevent cardiovascular events and improve patient care.

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The joint consensus panel of the European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) recently addressed present and future challenges in the laboratory diagnostics of atherogenic lipoproteins. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), LDL cholesterol (LDLC), and calculated non-HDLC (=total - HDLC) constitute the primary lipid panel for estimating risk of atherosclerotic cardiovascular disease (ASCVD) and can be measured in the nonfasting state. LDLC is the primary target of lipid-lowering therapies. For on-treatment follow-up, LDLC shall be measured or calculated by the same method to attenuate errors in treatment decisions due to marked between-method variations. Lipoprotein(a) [Lp(a)]-cholesterol is part of measured or calculated LDLC and should be estimated at least once in all patients at risk of ASCVD, especially in those whose LDLC declines poorly upon statin treatment. Residual risk of ASCVD even under optimal LDL-lowering treatment should be also assessed by non-HDLC or apolipoprotein B (apoB), especially in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L). Non-HDLC includes the assessment of remnant lipoprotein cholesterol and shall be reported in all standard lipid panels. Additional apoB measurement can detect elevated LDL particle (LDLP) numbers often unidentified on the basis of LDLC alone. Reference intervals of lipids, lipoproteins, and apolipoproteins are reported for European men and women aged 20-100 years. However, laboratories shall flag abnormal lipid values with reference to therapeutic decision thresholds.

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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.
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).
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.
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.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01698489.

BACKGROUND: Canadian and European treatment guidelines identify low-density lipoprotein cholesterol (LDL-C) as a primary treatment target for hypercholesterolaemia.
OBJECTIVE: This post hoc analysis compared ezetimibe 10 mg (ezetimibe) added to atorvastatin vs. doubling the atorvastatin dose on achievement of the 2009 Canadian Cardiovascular Society (CCS) and the 2007 Joint European Prevention Guidelines primary and optional secondary lipid targets and high-sensitivity C-reactive protein (hs-CRP) levels.
METHODS: After stabilisation on atorvastatin, hypercholesterolaemic patients at moderately high risk (MHR) for coronary heart disease (CHD) not at LDL-C < 2.6 mmol/l were randomised to atorvastatin 20 mg vs. doubling their atorvastatin dose to 40 mg; and patients at high risk (HR) for CHD not at LDL-C < 1.8 mmol/l were randomised to atorvastatin 40 mg plus ezetimibe vs. doubling their atorvastatin dose to 80 mg for 6 weeks.
RESULTS: When treated with atorvastatin plus ezetimibe, MHR and HR patients had greater attainment of LDL-C, most lipids and lipoproteins and/or hs-CRP targets compared with doubling their atorvastatin dose. More MHR and HR patients achieved dual targets of LDL-C and: Apolipoprotein (Apo) B, total cholesterol (total-C), total-C/high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglycerides, Apo B/Apo A-I or hs-CRP with ezetimibe + atorvastatin treatment compared with doubling their atorvastatin dose.
CONCLUSIONS: These results demonstrated greater achievement of single/dual treatment targets as set by Canadian and European treatment guidelines with ezetimibe added to atorvastatin 20 mg or 40 mg compared with doubling the atorvastatin dose to 40 mg or 80 mg in MHR and HR patients, respectively.

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The extent to which atorvastatin treatment affects LDL size, LDL subfraction levels and remnant-like particle cholesterol (RLP-C) was determined in type 2 diabetes. We also compared LDL size and RLP-C in relation to guideline cut-off values for LDL cholesterol, non-HDL cholesterol and apolipoprotein (apo) B. Changes in LDL size and RLP-C were determined in fasting plasma from type 2 diabetic patients after 30 weeks administration of atorvastatin (10 mg daily, n=65; 80 mg daily, n=62) or placebo (n=58). LDL subfraction cholesterol was measured in 74 participants. Atorvastatin lowered LDL cholesterol, non-HDL cholesterol, triglycerides, apo B and RLP-C (P<0.001 for all at each dose) and LDL mean peak particle diameter remained unchanged. Atorvastatin treatment decreased cholesterol concentrations in all LDL subfractions (P<0.001 for each dose). RLP-C at follow-up was lower in those patients achieving the non-HDL cholesterol or the apo B guideline targets (P<0.01), but the LDL cholesterol cut-off value failed to discriminate. In conclusion, atorvastatin lowers fasting RLP-C and LDL subfraction cholesterol in diabetes. The proposed guideline cut-off levels for non-HDL cholesterol and apo B may be superior to the LDL cholesterol target in discriminating between higher and lower RLP-C levels.