Apolipoprotein B Discordance with Low-Density Lipoprotein Cholesterol and Risk of Atherosclerotic Cardiovascular Events and Mortality: A Systematic Review and Meta-Analysis
DOI:
https://doi.org/10.19166/med.v15i3.11631Keywords:
apolipoprotein B, atherosclerotic cardiovascular disease, low-density lipoprotein cholesterol, meta-analysisAbstract
Background:
Apolipoprotein B (apoB) reflects the burden of atherogenic lipoprotein particles and may identify residual cardiovascular risk when low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol appears controlled. This review evaluated whether elevated apoB discordance is associated with cardiovascular events and mortality.
Methods:
PubMed, Scopus, ScienceDirect, and Google Scholar were searched through 23 May 2026. Eligible studies enrolled adults, assessed apoB discordance using residual-, percentile-, or median-based definitions, and reported adjusted estimates for clinical outcomes. Risk of bias was assessed using the Newcastle-Ottawa Scale. Random-effects meta-analysis used restricted maximum likelihood estimation with Hartung-Knapp-Sidik-Jonkman adjustment.
Result:
Four studies (128,103 participants) were included. In the cohort-only analysis, the pooled estimate was HR 1.28 (95% CI 0.31-5.25; I² = 67.7%). For all-cause mortality, the pooled estimate was HR 1.12 (95% CI 1.02-1.23; I² = 0%). The residual-based excess apoB-only analysis showed HR 1.11 (95% CI 1.04-1.17; I² = 0%).
Conclusions:
ApoB discordance may identify residual risk beyond LDL-C, with the most consistent evidence observed for all-cause mortality. Evidence for atherosclerotic cardiovascular events and cardiovascular mortality remains suggestive but limited by heterogeneity and few eligible studies.
References
1. Sniderman AD, Thanassoulis G, Glavinovic T, Navar AM, Pencina M, Catapano A, et al. Apolipoprotein B particles and cardiovascular disease: a narrative review. JAMA Cardiol. 2019;4(12):1287-1295. doi:10.1001/jamacardio.2019.3780
2. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38(32):2459-2472. doi:10.1093/eurheartj/ehx144
3. Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330. doi:10.1093/eurheartj/ehz962
4. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-188. doi:10.1093/eurheartj/ehz455
5. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Bäck M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021;42(34):3227-3337. doi:10.1093/eurheartj/ehab484
6. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
7. Welsh C, Celis-Morales CA, Brown R, Mackay DF, Lewsey J, Mark PB, et al. Comparison of conventional lipoprotein tests and apolipoproteins in the prediction of cardiovascular disease. Circulation. 2019;140(7):542-552. doi:10.1161/CIRCULATIONAHA.119.041149
8. Soffer DE, Michos ED, Orringer CE, Brown AS, Jacobson TA, McConnell JP, et al. Role of apolipoprotein B in the clinical management of cardiovascular risk in adults: an expert clinical consensus from the National Lipid Association. J Clin Lipidol. 2024;18(5):e1-e33. doi:10.1016/j.jacl.2024.08.013
9. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993-2000. doi:10.1001/jama.2009.1619
10. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4(3):337-345. doi:10.1161/CIRCOUTCOMES.110.959247
11. Ahmad M, Sniderman AD, Hegele RA. Apolipoprotein B in cardiovascular risk assessment. CMAJ. 2023;195(33):E1124. doi:10.1503/cmaj.230048
12. Sayed A, Peterson ED, Virani SS, Sniderman AD, Navar AM. Individual variation in the distribution of apolipoprotein B levels across the spectrum of LDL-C or non-HDL-C levels. JAMA Cardiol. 2024;9(8):741-747. doi:10.1001/jamacardio.2024.1310
13. Sniderman AD, Dufresne L, Pencina KM, Bilgic S, Thanassoulis G, Pencina MJ. Discordance among apoB, non-high-density lipoprotein cholesterol, and triglycerides: implications for cardiovascular prevention. Eur Heart J. 2024;45(27):2410-2418. doi:10.1093/eurheartj/ehae258
14. Wilkins JT, Li RC, Sniderman A, Chan C, Lloyd-Jones DM. Discordance between apolipoprotein B and LDL-cholesterol in young adults predicts coronary artery calcification: the CARDIA study. J Am Coll Cardiol. 2016;67(2):193-201. doi:10.1016/j.jacc.2015.10.055
15. Mora S, Glynn RJ, Boekholdt SM, Nordestgaard BG, Kastelein JJ, Ridker PM. On-treatment non-high-density lipoprotein cholesterol, apolipoprotein B, triglycerides, and lipid ratios in relation to residual vascular risk after treatment with potent statin therapy. J Am Coll Cardiol. 2012;59(17):1521-1528. doi:10.1016/j.jacc.2011.12.035
16. 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(11):1439-1450. doi:10.1016/j.jacc.2021.01.027
17. Sniderman AD, Islam S, Yusuf S, McQueen MJ. Discordance analysis of apolipoprotein B and non-high-density lipoprotein cholesterol as markers of cardiovascular risk in the INTERHEART study. Atherosclerosis. 2012;225(2):444-449. doi:10.1016/j.atherosclerosis.2012.08.039
18. Johannesen CDL, Langsted A, Nordestgaard BG, Mortensen MB. Excess apolipoprotein B and cardiovascular risk in women and men. J Am Coll Cardiol. 2024;83(23):2262-2273. doi:10.1016/j.jacc.2024.03.423
19. Lyu L, Kao C, Su J, Yu Y, Zhang X, Lyu J, et al. Association of apolipoprotein B and excess apolipoprotein B with cardiovascular risk in type 2 diabetes: a prospective cohort study of the UK Biobank. Lipids Health Dis. 2026;25(1):55. doi:10.1186/s12944-025-02852-8
20. Pan W, Lu X, Zhou Z, Liu J, Zhang S, Huang H, et al. Excess apolipoprotein B predicts long-term survival in statin-treated CAD irrespective of achieved LDL-C levels: a pooled cohort analysis. Lipids Health Dis. 2026;25(1):124. doi:10.1186/s12944-026-02928-z
21. Contois JH, Langlois MR, Cobbaert C, Sniderman AD. Standardization of apolipoprotein B, LDL-cholesterol, and non-HDL-cholesterol. J Am Heart Assoc. 2023;12(19):e030405. doi:10.1161/JAHA.123.030405
22. Sehayek D, Cole J, Bjornson E, Wilkins JT, Mortensen MB, Dufresne L, Pencina KM, Pencina MJ, Thanassoulis G, Sniderman AD. ApoB, LDL-C, and non-HDL-C as markers of cardiovascular risk. J Clin Lipidol. 2025;19(4):844-859. doi:10.1016/j.jacl.2025.05.024
23. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71
24. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.5. Cochrane; 2024.
25. Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa Hospital Research Institute; 2000.
26. Qu G, Zhou G, Zhang Z, Wang H, Tong X, Wang X. Discordance between apolipoprotein B or non-HDL cholesterol and LDL-cholesterol in middle-aged and elderly Chinese patients predicts arterial stiffness. Lipids Health Dis. 2021;20(1):60. doi:10.1186/s12944-021-01509-6
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 Adinda Wafdani Putri, Jessica Adrya, Srigita Varsha, Muhammad Ferhat, Stella Pangestika, Natania Eliadi, Alan Dharmasaputra
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Authors who publish with this journal agree to the following terms:
1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC-BY-SA 4.0) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website). The final published PDF should be used and bibliographic details that credit the publication in this journal should be included.
