R3i Editorials

Residual cardiovascular risk: is apolipoprotein B the preferred marker?
Prof. Michel Hermans, Prof. Pierre Amarenco

Beyond LDL-C, guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (apo)B as key secondary targets 4. These parameters can remain elevated even when LDL-C goal is attained. For example, in one analysis using data from the National Health and Nutrition Examination Survey and Very Large Database of Lipids study, between one in seven and one in 12 high-risk patients at LDL-C at goal (<70 mg/dL) had elevated non-HDL-C and apoB levels, respectively 5. Thus, both have been proposed as potential markers to assess residual cardiovascular risk. However, in the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guidelines, it was concluded that apoB was a more accurate measure of cardiovascular risk and a better guide to the adequacy of lipid lowering than LDL-C or HDL-C 4.

Indeed, there is a firm scientific basis to support this proposal. ApoB is the major structural constituent of atherogenic lipoproteins including LDL, triglyceride-rich lipoproteins and their remnants. As there is only one apoB molecule in each apoB-containing lipoprotein particle, measurement of apoB provides a measure of the total number of atherogenic apoB-containing particles. Thus, apoB integrates conventional lipid markers – total cholesterol, triglycerides, LDL-C, and non-HDL-C – into a single index. Epidemiologic studies and Mendelian randomization studies demonstrate that apoB is a superior predictor of cardiovascular risk associated with atherogenic apoB-containing lipoproteins compared with either LDL-C or non-HDL-C 6-9. These findings imply that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the primary focus of therapeutic strategies to reduce lipoprotein-related risk.

Beyond its utility as a marker of residual cardiovascular risk, apoB can also guide therapeutic intervention. A recent analysis from ODYSSEY OUTCOMES highlighted both attributes 10. This trial randomized patients with a recent acute coronary syndrome and elevated atherogenic lipoprotein levels (LDL-C ≥70 mg/dL [1.81 mmol/L], non-HDL-C ≥100 mg/dL [2.59 mmol/L], or apoB ≥80 mg/dL) despite high-intensity statin therapy and treatment with alirocumab or placebo. Not only did the risk of a major adverse cardiovascular event (MACE) increase incrementally as baseline apoB levels increased (by 11% per 10 mg/dL increase in baseline apoB), but patients who attained lower on-treatment apoB levels at 4 months demonstrated greater relative and absolute reductions in MACE. This relationship between achieved apoB levels and absolute clinical benefit was superior to that for LDL-C or non–HDL-C levels 10.

Taken together, accumulating evidence establishes the prominence of apoB in the assessment of lipoprotein-related residual risk. From a clinician’s perspective, the question is how best to integrate this knowledge into routine practice. ApoB measurement is now readily available, inexpensive and well validated, does not require a fasting blood test, and can be routinely incorporated into clinical lipid panels 11. There is now a clear case for guidelines to recognise and respond to this evidence, so that apoB measurement can be routinely adopted in clinical practice.

References

  1. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017; 376:1713–22.
    2. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018 379:2097–107.
    3. Honda S, Puri R, Anderson T, Kastelein JJP, et al. Determinants of plaque progression despite very low Low-density lipoprotein-cholesterol levels with the PCSK9 inhibitor, evolocumab. JACC Cardiovasc Imaging 2021;doi: 10.1016/j.jcmg.2021.11.014.
    4. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
    5. Sathiyakumar V, Park J, Quispe R, et al. 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. Circulation 2018;138:244-54.
    6. Sniderman AD, Thanassoulis G, Glavinovic T, et al. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol 2019;4:1287-95.
    7. Johannesen CDL, Mortensen MB, Langsted A, Nordestgaard BG. Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J Am Coll Cardiol 2021;77:1439-50.
    8. Marston NA, Giugliano RP, Melloni GEM, et al. Association of Apolipoprotein B-containing lipoproteins and risk of myocardial infarction in individuals with and without atherosclerosis: distinguishing between particle concentration, type, and content. JAMA Cardiol 2022;7:250-6.
    9. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321:364-73.
    10. Hagström E, Steg PG, Szarek M, et al. Apolipoprotein B, residual cardiovascular risk after acute coronary syndrome, and effects of alirocumab. Circulation 2022 Jun 30:101161CIRCULATIONAHA121057807. doi: 10.1161/CIRCULATIONAHA.121.057807.
    11. Langlois MR, Nordestgaard BG, Langsted A, et al. Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM. Clin Chem Lab Med 2020;58:496-517.