By Michael H. Crawford, MD
Synopsis: In U.K. Biobank participants without known atherosclerotic cardiovascular disease or diabetes or taking lipid-lowering therapy, the risk of developing coronary artery disease is best determined by apolipoprotein B particle number, but elevated lipoprotein(a) adds significant risk, so both should be considered.
Source: Morze J, Melloni GEM, Wittenbecher C, et al. ApoB-containing lipoproteins: Count, type, size, and risk of coronary artery disease. Eur Heart J. 2025;46(27):2691-2701.
Apolipoprotein B-containing lipoprotein particles (apoB-P) are the main drivers of atherosclerotic coronary artery disease (CAD) and contain, among other things, low-density lipoproteins (LDL) and lipoprotein(a) (Lp[a]). However, the exact role of Lp(a)-containing apoB-P compared to all apoB-P is unclear. Thus, these investigators studied a random sample of 274,353 of the roughly 500,000 subjects in the U.K. Biobank (UKB) enrolled between 2006 and 2010, by proton nuclear magnetic resonance (NMR) spectroscopy, which allows for direct measurement of lipoprotein particle count, size, and lipid fractions.
After excluding those with known CAD, peripheral arterial disease, stroke, or diabetes or taking lipid-lowering medications, 207,368 subjects (mean age 56 years, 57% women, 94% white) were included. NMR measured 14 biomarkers related to apoB except for Lp(a), which was measured by immunoassay. The primary outcome was the development of CAD adjusted for other clinical risk factors. Median non-Lp(a) apoB-P was 1,688 nmol/L and Lp(a) was 19 nmol/L. On average, very low-density lipoprotein (VLDL) represented 9% and intermediate-density lipoprotein (IDL) and LDL represented 91% of apoB-P.
A one standard deviation increase in apoB-P increased CAD risk by 33% (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.30-1.36). Although VLDL carried a higher per particle risk of CAD than LDL, because of the relative abundance of LDL it had a higher risk per one standard deviation elevation (HR, 1.24 vs. 1.09). After apoB-P adjustment, particle size was not associated with CAD. Lp(a) was robustly associated with higher CAD risk even after adjustment for apoB-P (HR, 1.18; 95% CI, 1.16 to 1.20) and added independent prognostic value to the 10-year risk of CAD (area under the curve, 0. 0.774 vs. 0.769; P < 0.001). The authors concluded that apoB-P count is the most accurate for estimating the risk of CAD and is not affected by particle type, count, or size. However, Lp(a) adds significant risk, so both should be considered.
Commentary
ApoB particles contain LDL, IDL, VLDL, chylomicrons, and Lp(a), and they are a better measure of lipoprotein-associated CAD risk than LDL cholesterol or triglycerides. Also, Lp(a), which is genetically determined, also is independently predictive of CAD, probably because it also has pro-inflammatory and enhanced arterial retention properties.
Currently, there are drugs in development for reducing Lp(a). Until they are on the market (if ever), drugs that reduce LDL production by the liver (e.g., statins, PCSK9 inhibitors) will remain the standard of care for reducing CAD risk. Also, the incremental value of considering ApoB over LDL or non-HDL cholesterol is modest, but it should be incorporated in risk prediction models, as well as Lp(a). Currently, there are no established risk categories for apoB and Lp(a), so current therapy still will focus on established LDL cholesterol reduction targets. Specific targets will have to be developed if drugs to lower apoB and Lp(a) become a reality.
There are limitations to this UKB study. It is observational, so residual confounding cannot be ignored, which limits causal interpretations. Also, UKB is not representative of the general population. It is comprised of mostly younger Northern European individuals and may suffer from the healthy volunteer effect. In addition, it does not necessarily apply to those with serious risk factors for CAD, such as diabetes and those with known atherosclerotic cardiovascular disease. Finally, apoB-P was measured by NMR and Lp(a) was measured by immunoassay, so we do not know the particle number for Lp(a). In addition, the size of apoB particles did not add any predictive value, which suggests that NMR is not necessary for assessing apoB and conventional measurements are adequate.
Recently, laboratories in my area have begun offering an expanded lipid panel, which includes apoB and Lp(a) in addition to inflammatory biomarkers. Now I better understand what to do with this information. However, these additional lipoprotein entities are not included in the current risk prediction formulae. Therefore, currently, they can only be used to fine-tune the risk assessments from the pooled cohort equation and the PREVENT algorithm equations.
Michael H. Crawford, MD, is Professor Emeritus of Medicine and Consulting Cardiologist, UCSF Health, San Francisco.
In U.K. Biobank participants without known atherosclerotic cardiovascular disease or diabetes or taking lipid-lowering therapy, the risk of developing coronary artery disease is best determined by apolipoprotein B particle number, but elevated lipoprotein(a) adds significant risk, so both should be considered.
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