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Discordance Among ApoB, non–HDL-C, and Triglycerides for CV Prevention
Quick Takes
- Non–HDL-C represents total cholesterol minus cholesterol from HDL particles. ApoB represents the total number of atherogenic particles. Since one apoB molecule is found on each LDL, very low–density lipoprotein, intermediate-density lipoprotein, and lipoprotein(a) particle, apoB represents the total number of atherogenic particles.
- Atherosclerosis is more closely associated with the number of apoB–containing lipoprotein particles than with the sum of cholesterol concentration in the atherogenic particles (non–HDL-C).
- High variability of apoB at specific levels of LDL-C, non–HDL-C, and triglycerides coupled with meaningful differences in 10-year ASCVD rates demonstrate that serum lipids and various ratios are not adequate surrogates for apoB in the clinical care of individual patients.
- Clinical practice should include a fasting lipid profile and apoB and nonfasting apoB as the standard for follow-up unless there is an indication for treating triglycerides per se in addition to statins.
Study Questions:
Does apolipoprotein B (apoB) have a utility in atherosclerotic cardiovascular disease (ASCVD) or are low-density lipoprotein cholesterol (LDL-C), non–high-density lipoprotein cholesterol (non–HDL-C), and triglycerides sufficient for routine cardiovascular (CV) care?
Methods:
A sample of 293,876 UK Biobank adults (aged 40–73 years; 42% men), free of CVD, with a median follow-up for new-onset ASCVD of 11 years was included. Distribution of apoB at prespecified levels of LDL-C, non–HDL-C, and triglycerides was examined graphically, and 10-year ASCVD event rates were compared for high vs. low apoB. Residuals of apoB were constructed after regressing apoB on LDL-C, non–HDL-C, and log-transformed triglycerides and used as predictors in a proportional hazards regression model for new-onset ASCVD adjusted for standard risk factors, including HDL-C.
Results:
ApoB was highly correlated with LDL-C and non–HDL-C (Pearson’s r = 0.96, p < 0.001 for both) but less so with log triglycerides (r = 0.42, p < 0.001). However, apoB ranges necessary to capture 95% of all observations at prespecified levels of LDL-C, non–HDL-C, or triglycerides were wide, spanning 85.8–108.8 mg/dL when LDL-C was 130 mg/dL, 88.3–112.4 mg/dL when non–HDL-C was 160 mg/dL, and 67.8–147.4 mg/dL when triglycerides were 115 mg/dL. At these levels (±10 mg/dL), 10-year ASCVD rates for apoB above mean + 1 standard deviation (SD) vs. below mean – 1 SD were 7.3 vs. 4.0 for LDL-C, 6.4 vs. 4.6 for non–HDL-C, and 7.0 vs. 4.6 for triglycerides (all p < 0.001). With 19,982 new-onset ASCVD events on follow-up, in the adjusted model, residual apoB remained statistically significant after accounting for LDL-C and HDL-C (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.0–1.07), after accounting for non–HDL-C and HDL-C (HR, 1.04; 95% CI, 1.03–1.06), and after accounting for triglycerides and HDL-C (HR, 1.13; 95% CI, 1.12–1.15). None of the residuals of LDL-C, non–HDL-C, or of log triglycerides remained significant when apoB was included in the model.
Conclusions:
High variability of apoB at individual levels of LDL-C, non–HDL-C, and triglycerides coupled with meaningful differences in 10-year ASCVD rates and significant residual information contained in apoB for prediction of new-onset ASCVD events demonstrate that LDL-C, non–HDL-C, and triglycerides are not adequate proxies for apoB in clinical care.
Perspective:
Despite extremely high correlations between apoB and LDL-C or non–HDL-C, at the individual patient level, there remains significant variability in values for apoB at any given level of LDL-C or non–HDL-C.
There are strong recommendations to use non–HDL-C, which can be obtained nonfasting and represents atherogenic lipid particle risk, but it is not used much clinically. The same can be said for apoB, which is highly recommended by the European and Canadian lipid guidelines but not the US guidelines. Having the initial lipids and apoB done fasting will provide the triglyceride level that is necessary for lipid diagnosis and selecting lipid-lowering treatment and lipid targets. Subsequent monitoring of fasting triglycerides is needed to prescribe and monitor the appropriate diet (e.g., low glycemic index diet for weight loss and to reduce triglycerides in diabetes, metabolic syndrome, familial mixed dyslipidemias); in addition, to prescribe FDA approved icosapent ethyl as an add-on to maximally tolerated statins to reduce CV events in diabetes with two or more risk factors and triglycerides >150 mg/dL to <500 mg/dL and in ASCVD with triglycerides >150 to <500 mg/dL.
Most importantly, while there is controversy whether apoB or non–HDL-C is the best biomarker for risk of ASCVD, in clinical trials of statins, ezetimibe and PCSK9 inhibitor levels of apoB more accurately predicted risk of myocardial infarction (MI) than levels of LDL-C or non–HDL-C for primary prevention as well as persons with ASCVD on statins (Marston NA, et al., JAMA Cardiol 2022;7:250-6). The risk of CV events associated with apoB is greater in younger persons, arguing for earlier treatment. That apoB can be used independent of country of origin was suggested in the worldwide study of risk factors for MI in the INTERHEART study (Yusuf S, et al., Lancet 2004;364:937-52), but there is evidence that apoB gene polymorphisms may affect coronary artery disease/MI susceptibility, which can be increased or decreased among populations (Xiao D, et al., Genes Genom 2015;37:621-32).
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Prevention
Keywords: Apolipoproteins, Cholesterol, Triglycerides
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