Analysis of Lipid Profile as a Risk Factor for Ischemic Stroke Incidence : A Systematic Review
Keywords:
Ischemic stroke, lipid profile, LDL cholesterol, lipoprotein(a), triglyceride-glucose index, systematic reviewAbstract
Background: Ischemic stroke (IS) is a leading cause of death and disability worldwide, with a complex and incompletely understood relationship with lipid parameters. Unlike coronary heart disease, the association between lipids and IS shows heterogeneity across subtypes and populations.
Methods: This systematic review synthesized evidence from 80 sources, including RCT, etc. We focused on studies reporting quantitative associations between lipid profile components and IS incidence, emphasizing statistically significant positive risk factors.
Results: Genetically determined LDL-C showed a modest causal effect on IS (OR 1.09, 95% CI 1.07-1.12) (1), but this was driven entirely by the large artery atherosclerosis (LAA) subtype (OR 0.75 for lower LDL-C) with null effects on cardioembolic and small vessel stroke (3). Observational data confirmed increased IS risk with elevated LDL-C (HR up to 1.74) (20) and non-HDL-C (HR 2.45) (20). HDL-C demonstrated a U-shaped relationship, with both low (HR 1.29) and very high levels (HR 1.84) increasing risk (4). Lipoprotein(a) [Lp(a)] was a significant observational risk factor (RR 1.29 per 1SD) (7) and for stroke recurrence (OR 1.69) (47), though MR evidence was weaker (1). The triglyceride-glucose (TyG) index (HR up to 2.21) (11) and atherogenic index of plasma (AIP) (HR 1.12) (10) showed strong, significant positive associations. Lp-PLA2 activity was causally linked specifically to LAA stroke (OR 3.25) (15), while oxidized LDL increased both stroke (HR 1.39) and hemorrhagic events (HR 3.61) (14). Omega-3 fatty acids DHA and DPA were protective (HR 0.80 and 0.74, respectively) (12).
Discussion: The LDL-C-IS association is real but weaker than for coronary disease due to subtype heterogeneity. HDL-C is a complex marker where particle functionality supersedes total cholesterol. The discordance between observational and MR evidence for Lp(a) suggests conditional causality dependent on inflammatory and lipid milieu.
Conclusion: Significant positive risk markers for IS include LDL-C, non-HDL-C, Lp(a), TyG index, AIP, Lp-PLA2 (for LAA), and oxidized LDL. Lipid management for stroke prevention must be subtype-specific and move beyond traditional LDL-C targeting.
References
Guo Y, Guo Z, Zhu Y, et al (2026) Associations between lipoproteins and risk of ischemic stroke: a systematic review and meta-analysis of Mendelian randomization studies. Frontiers in Neurology. https://doi.org/10.3389/fneur.2025.1694731
Angelantonio E di, Sarwar N, Perry P, et al (2009) Major lipids, apolipoproteins, and risk of vascular disease. Journal of the American Medical Association (JAMA). https://doi.org/10.1001/jama.2009.1619
Hopewell J, Stiby A, Ibrahim M, Valdés‐Márquez E (2020) Differential impact of life-long lower LDL-C levels on ischaemic stroke subtypes and coronary heart disease risk among 1 million individuals. European Heart Journal. https://doi.org/10.1093/ehjci/ehaa946.2410
Li H, Qian F, Zuo Y, et al (2022) U-Shaped Relationship of High-Density Lipoprotein Cholesterol and Incidence of Total, Ischemic and Hemorrhagic Stroke: A Prospective Cohort Study. Stroke. https://doi.org/10.1161/STROKEAHA.121.034393
Harshfield E, Markus H (2023) Association of Baseline Metabolomic Profiles With Incident Stroke and Dementia and With Imaging Markers of Cerebral Small Vessel Disease. Neurology. https://doi.org/10.1212/WNL.0000000000207458
Erqou S, Kaptoge S, Perry P, et al (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. Journal of the American Medical Association (JAMA). https://doi.org/10.1001/jama.2009.1063
Nave A, Lange KS, Leonards C, et al (2015) Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis. Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2015.08.021
Huang Y, Zhang R, Han L, et al (2023) Lipoprotein(a) and stroke: a two-sample Mendelian randomization study. Frontiers in Aging Neuroscience. https://doi.org/10.3389/fnagi.2023.1178079
Xu J, Hao X, Zhan R, et al (2022) Effect of Lipoprotein(a) on Stroke Recurrence Attenuates at Low LDL-C (Low-Density Lipoprotein) and Inflammation Levels. Stroke. https://doi.org/10.1161/STROKEAHA.121.034924
Zhang Y, Chen S, Tian X, et al (2024) Elevated atherogenic index of plasma associated with stroke risk in general Chinese. Endocrine. https://doi.org/10.1007/s12020-023-03677-0
Huang Z, Ding X, Yue Q, et al (2022) Triglyceride-glucose index trajectory and stroke incidence in patients with hypertension: a prospective cohort study. Cardiovascular Diabetology. https://doi.org/10.1186/s12933-022-01577-7
Saber H, Yakoob M, Shi P, et al (2017) Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. Stroke. https://doi.org/10.1161/STROKEAHA.117.018235
Xu Z, Chen W, Wang X, et al (2026) Association between Free Fatty Acid and 3-Month Prognosis of acute ischemic stroke. Journal of Stroke & Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2026.108589
Ding Y, Jiang L-N, Wang T, et al (2025) Oxidised low-density lipoprotein and adverse outcome in patients with acute mild ischaemic stroke or high-risk TIA: a secondary analysis of the INSPIRES randomised clinical trial. Stroke and vascular neurology. https://doi.org/10.1136/svn-2024-003664
Zhang Y, Jiang M, Gao Y, et al (2023) Causal Effect of Lipoprotein-Associated Phospholipase A2 Activity on Ischemic Stroke: A Mendelian Randomization Study. Cerebrovascular Diseases. https://doi.org/10.1159/000535286
Liu Y, Jin X, Fu K, et al (2023) Non-traditional lipid profiles and the risk of stroke: A systematic review and meta-analysis. NMCD Nutrition Metabolism and Cardiovascular Diseases. https://doi.org/10.1016/j.numecd.2023.01.003
Dong H, Chen W, Wang X, et al (2015) Apolipoprotein A1, B levels, and their ratio and the risk of a first stroke: a meta-analysis and case–control study. Metabolic brain disease. https://doi.org/10.1007/s11011-015-9732-7
Hopewell J, Malik R, Valdés‐Márquez E, et al (2017) Differential effects of PCSK9 variants on risk of coronary disease and ischaemic stroke. European Heart Journal. https://doi.org/10.1093/eurheartj/ehx373
Nordestgaard AT, Moorthy M, Cook NR, et al (2025) High-sensitivity C-reactive protein, LDL cholesterol, lipoprotein(a) and 30-year risk of stroke in healthy women: a prospective, longitudinal cohort study. Lancet Neurology. https://doi.org/10.1016/s1474-4422(25)00306-0
Kurth T, Everett BM, Buring J, et al (2007) Lipid levels and the risk of ischemic stroke in women. Neurology. https://doi.org/10.1212/01.wnl.0000254472.41810.0d
Gong X, Chen L, Song B, et al (2022) Associations of lipid profiles with the risk of ischemic and hemorrhagic stroke: A systematic review and meta-analysis of prospective cohort studies. Frontiers in Cardiovascular Medicine. https://doi.org/10.3389/fcvm.2022.893248
Rexrode K, Hu J, Li J, Balasubramanian R (2020) Abstract TMP59: Metabolomic Profiles Are Associated With Incident Ischemic Stroke in Women. Stroke. https://doi.org/10.1161/STR.51.SUPPL_1.TMP59
Qie R, Liu L, Zhang D, et al (2021) Dose–Response Association Between High-Density Lipoprotein Cholesterol and Stroke: A Systematic Review and Meta-Analysis of Prospective Cohort Studies. Preventing Chronic Disease. https://doi.org/10.5888/pcd18.200278
Wei C, Huang Y-Q, Yu C (2025) Relationship between longitudinal changes in lipid composition and ischemic stroke among hypertensive patients. World Journal of Clinical Cases. https://doi.org/10.12998/wjcc.v13.i4.95803
Leonards C, Ebinger M, Batluk J, et al (2010) The Role of Fasting Versus Non-Fasting Triglycerides in Ischemic Stroke: A Systematic Review. Front Neur. https://doi.org/10.3389/fneur.2010.000133
Riva P de la, Zubikarai M, Sarasqueta C, et al (2017) Nontraditional Lipid Variables Predict Recurrent Brain Ischemia in Embolic Stroke of Undetermined Source. Journal of Stroke & Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.03.024
Amarenco P, Goldstein L, Szarek M, et al (2007) Effects of Intense Low-Density Lipoprotein Cholesterol Reduction in Patients With Stroke or Transient Ischemic Attack: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial. Stroke. https://doi.org/10.1161/STROKEAHA.107.493106
Wang C, Sun T, Li H, et al (2011) Lipoprotein lipase Ser447Ter polymorphism associated with the risk of ischemic stroke: a meta-analysis. Thrombosis Research. https://doi.org/10.1016/j.thromres.2011.07.016
Zhang W, Zhou F, Huang H, et al (2020) Biomarker of dietary linoleic acid and risk for stroke: A systematic review and meta-analysis. Nutrition (Burbank, Los Angeles County, Calif). https://doi.org/10.1016/j.nut.2020.110953
Hattori Y, Noda K, Hori M, et al (2026) Ischemic stroke and intracranial large-artery disease risk in familial hypercholesterolemia: A prospective Japanese study. Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2026.120674
Hu G, Liu D, Tong H, et al (2019) Lipoprotein-Associated Phospholipase A2 Activity and Mass as Independent Risk Factor of Stroke: A Meta-Analysis. BioMed Research International. https://doi.org/10.1155/2019/8642784
Vaisar T, Miller RG, Kalani R, et al (2022) Abstract 551: HDL Particle Concentration And Incident Ischemic Stroke In Type 1 Diabetes. Arteriosclerosis, Thrombosis and Vascular Biology. https://doi.org/10.1161/atvb.42.suppl_1.551
Khan F, Kalani R, Bartz TM, et al (2024) Abstract 47: Estimated Remnant Lipoprotein Particle Cholesterol, Very Low-Density Lipoprotein Cholesterol, and Incident Ischemic Stroke Risk - The Cardiovascular Health Study. Stroke. https://doi.org/10.1161/str.55.suppl_1.47
Mokhayeri Y, Hashemi-Nazari S, Khodakarim S, et al (2019) Effects of Hypothetical Interventions on Ischemic Stroke Using Parametric G-Formula. Stroke. https://doi.org/10.1161/STROKEAHA.119.025749
Pan Y, Wangqin R, Li H, et al (2022) LDL-C levels, lipid-lowering treatment and recurrent stroke in minor ischaemic stroke or TIA. Stroke and vascular neurology. https://doi.org/10.1136/svn-2021-001317
Liu Q, Wu S, Shao J, et al (2024) Metabolic syndrome parameters' variability and stroke incidence in hypertensive patients: evidence from a functional community cohort. Cardiovascular Diabetology. https://doi.org/10.1186/s12933-024-02282-3
Al-shoaibi A, Li Y, Chiang C, et al (2022) Abstract EP32: Low Density Lipoprotein Cholesterol Associations With The Risk Of Coronary Heart Disease And Stroke Among Middle-aged Japanese Workers: Analysis Using Inverse Probability Weighting. Circulation. https://doi.org/10.1161/circ.145.suppl_1.ep32
Al-shoaibi A, Li Y, Song Z, et al (2022) Association of Low-Density Lipoprotein Cholesterol with Risk of Coronary Heart Disease and Stroke among Middle-Aged Japanese Workers: An Analysis using Inverse Probability Weighting. Journal of atherosclerosis and thrombosis. https://doi.org/10.5551/jat.63519
Spence J (2006) Lipoprotein(a): involved in events, but not burden of atherosclerotic disease? Stroke. https://doi.org/10.1161/01.STR.0000222979.34697.BF
Fatumo S, Karhunen V, Chikowore T, et al (2021) Metabolic Traits and Stroke Risk in Individuals of African Ancestry: Mendelian Randomization Analysis. Stroke. https://doi.org/10.1161/STROKEAHA.121.034747
Yang B, Ren X, Huang H, et al (2017) Circulating long-chain n-3 polyunsaturated fatty acid and incidence of stroke: a meta-analysis of prospective cohort studies. OncoTarget. https://doi.org/10.18632/oncotarget.19530
Kim M, Lee KN, Han K, Lee S-H (2024) Diabetes Duration, Cholesterol Levels, and Risk of Cardiovascular Diseases in Individuals With Type 2 Diabetes. Journal of Clinical Endocrinology and Metabolism. https://doi.org/10.1210/clinem/dgae092
Pawar S, Turan T, Lynn M, et al (2014) Abstract T P144: Association Between Lipoprotein (a) Levels and Vascular Events in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. Stroke. https://doi.org/10.1161/str.45.suppl_1.tp144
Saber H, Yakoob M, Shi P, et al (2016) Abstract MP98: Circulating Phospholipid n-3 Polyunsaturated Fatty Acids and Incident Atherothrombotic and Cardioembolic Ischemic Stroke in 3 Large US Cohorts. Circulation. https://doi.org/10.1161/circ.133.suppl_1.mp98
Maj B, Pruc M, Momot K, et al (2025) Lipoprotein(a) and Risk of Ischemic Stroke in Atrial Fibrillation: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine. https://doi.org/10.3390/jcm14217851
Vojinovic D, Kalaoja M, Trompet S, et al (2020) Association of circulating metabolites in plasma or serum and risk of stroke: Meta-analysis from seven prospective cohorts. Neurology. https://doi.org/10.1212/WNL.0000000000011236
Palaiodimou L, Melanis K, Stefanou M-I, et al (2025) The Association of Lipoprotein(a) and Stroke Recurrence: A Systematic Review and Meta-Analysis. Journal of Stroke. https://doi.org/10.5853/jos.2024.04623
Prabhakaran S, Liebeskind D, Cotsonis G, et al (2021) Lipid Levels and Short-Term Risk of Recurrent Brain Infarcts in Symptomatic Intracranial Stenosis. Journal of Stroke & Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2021.106141
Kumar P, Swarnkar P, Misra S, Nath M (2021) Lipoprotein (a) level as a risk factor for stroke and its subtype: A systematic review and meta-analysis. Scientific Reports. https://doi.org/10.1038/s41598-021-95141-0
Khan T, Shah T, Prieto D, et al (2013) Apolipoprotein E genotype, cardiovascular biomarkers and risk of stroke: systematic review and meta-analysis of 14,015 stroke cases and pooled analysis of primary biomarker data from up to 60,883 individuals. International Journal of Epidemiology. https://doi.org/10.1093/ije/dyt034
Erqou S, Thompson A, Angelantonio E, et al (2010) Focus Issue: Biomarkers in Cardiovascular DiseaseClinical Research: Biomarkers in Vascular Disease and HypertensionApolipoprotein(a) Isoforms and the Risk of Vascular Disease: Systematic Review of 40 Studies Involving 58,000 Participants. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2009.10.080
Deng Q, Li S, Zhang H-Q, et al (2019) Association of serum lipids with clinical outcome in acute ischaemic stroke: A systematic review and meta-analysis. Journal of clinical neuroscience. https://doi.org/10.1016/j.jocn.2018.09.003
Sarrafzadegan N, Gharipour M, Sadeghi M, et al (2017) Metabolic Syndrome and the Risk of Ischemic Stroke. Journal of Stroke & Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.09.019
Li D, Wei W, Ran X, et al (2017) Lipoprotein-associated phospholipase A2 and risks of coronary heart disease and ischemic stroke in the general population: A systematic review and meta-analysis. Clinica chimica acta; international journal of clinical chemistry. https://doi.org/10.1016/j.cca.2017.05.017
Tian Y, Tang X, Liu Y, Liu S (2024) Mendelian randomization studies of lifestyle-related risk factors for stroke: a systematic review and meta-analysis. Frontiers in Endocrinology. https://doi.org/10.3389/fendo.2024.1379516
Nakaya N, Kita T, Mabuchi H, et al (2005) Large-scale cohort study on the relationship between serum lipid concentrations and risk of cerebrovascular disease under low-dose simvastatin in Japanese patients with hypercholesterolemia: sub-analysis of the Japan Lipid Intervention Trial (J-LIT). Circulation Journal. https://doi.org/10.1253/CIRCJ.69.1016
Akioyamen L, Tu J, Genest J, et al (2019) Risk of Ischemic Stroke and Peripheral Arterial Disease in Heterozygous Familial Hypercholesterolemia: A Meta-Analysis. Angiology. https://doi.org/10.1177/0003319719835433
Melissano G, Chiesa R (2009) The "other revolution" in stroke prevention. European Journal of Vascular and Endovascular Surgery. https://doi.org/10.1016/j.ejvs.2009.04.016
Xia W, Hu Z, Song Z (2017) [Meta-analysis for the relationship between lipoprotein-associated phospholipase A2 and ischemic stroke]. Zhong nan da xue xue bao Yi xue ban = Journal of Central South University Medical sciences. https://doi.org/10.11817/j.issn.1672-7347.2017.02.015
Pi Y, Zhang L, Yang Q, et al (2012) Apolipoprotein A5 Gene Promoter Region-1131T/C Polymorphism Is Associated with Risk of Ischemic Stroke and Elevated Triglyceride Levels: A Meta-Analysis. Cerebrovascular Diseases. https://doi.org/10.1159/000338781
Yang W, Jin J, Xie M, Ai C (2024) Association of circulating adiponectin levels with the incidence of ischemic stroke: a meta-analysis. Journal of Neurorestoratology. https://doi.org/10.1016/j.jnrt.2024.100119
Wangqin R, Pan Y, Xian Y, et al (2022) Abstract WP194: Ldlc Levels, Lipid Lowering Treatment And Recurrent Stroke In Minor Ischemic Stroke Or Tia. Stroke. https://doi.org/10.1161/str.53.suppl_1.wp194
Wu Y, Xiong Y, Wang P, et al (2022) Risk factors of cardiovascular and cerebrovascular diseases in young and middle-aged adults: A meta-analysis. Medicine. https://doi.org/10.1097/MD.0000000000032082
Monguillon V, Kelly P, O'Donoghue ML, et al (2025) Efficacy and Safety of Very Low Achieved LDL-Cholesterol in Patients with Prior Ischemic Stroke. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.125.077549
Quek A, Teng O, Park J-H, et al (2025) Lipoprotein disruption following ischemic stroke across subtypes and over time: Findings from NMR-based metabolomic analysis. Free Radical Biology & Medicine. https://doi.org/10.1016/j.freeradbiomed.2025.07.041
Hosomi N, Kitagawa K, Nagai Y, et al (2018) Desirable Low-Density Lipoprotein Cholesterol Levels for Preventing Stroke Recurrence: A Post Hoc Analysis of the J-STARS Study (Japan Statin Treatment Against Recurrent Stroke). Stroke. https://doi.org/10.1161/STROKEAHA.117.018870
Chemello K, Guedon AF, Techer R, et al (2025) Apolipoprotein E Plasma Concentrations Are Predictive of Recurrent Strokes: Insights From the SPARCL Trial. Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease. https://doi.org/10.1161/JAHA.124.036630
Si S, Hou L, Chen X, et al (2021) Exploring the Causal Roles of Circulating Remnant Lipid Profile on Cardiovascular and Cerebrovascular Diseases: Mendelian Randomization Study. Journal of Epidemiology. https://doi.org/10.2188/jea.JE20200305
Cheng P, Wang J, Shao W (2016) Monounsaturated Fatty Acid Intake and Stroke Risk: A Meta-analysis of Prospective Cohort Studies. Journal of Stroke & Cerebrovascular Diseases. https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.02.017
Erqou S (2010) Lipoprotein(a) and the risk of vascular disease. Nature Reviews Cardiology. https://doi.org/10.17863/CAM.16247
Ao L, Heemst D, Jukema J, et al (2025) Potential causal evidence for an ApoB-independent and HDL-related risk profile associated with coronary artery disease. Journal of Lipid Research. https://doi.org/10.1016/j.jlr.2025.100778
Yuan S, Huang X, Ma W, et al (2022) Associations of HDL-C/LDL-C with myocardial infarction, all-cause mortality, haemorrhagic stroke and ischaemic stroke: a longitudinal study based on 384 093 participants from the UK Biobank. Stroke and vascular neurology. https://doi.org/10.1136/svn-2022-001668
Ma X, Han Y, Jiang L, Li M-Y (2022) Triglyceride-Glucose Index and the Prognosis of Patients with Acute Ischemic Stroke: A Meta-Analysis. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. https://doi.org/10.1055/a-1853-9889
Yang H-M, Park CS, Han K-D (2023) Abstract 18219: J-Shaped Association Between LDL-Cholesterol Level and Cardiovascular Events: A Longitudinal Follow-Up Study Over 2.4 Million Nationwide Primary Prevention Cohort. Circulation. https://doi.org/10.1161/circ.148.suppl_1.18219
Thakare S, Badani R, Bhagat H, Nikalje M (2025) Analysis of Lipid Values In Patients of Acute Ischemic Stroke And Initiate Aggressive Lipid Management. Indian Journal of Critical Care Medicine. https://doi.org/10.5005/jaypee-journals-10071-24933.63
Yaghi S, Elkind M (2015) Lipids and Cerebrovascular Disease: Research and Practice. Stroke. https://doi.org/10.1161/STROKEAHA.115.011164
Cui Q, Naikoo NA (2019) Modifiable and non-modifiable risk factors in ischemic stroke: a meta-analysis. African Health Sciences. https://doi.org/10.4314/ahs.v19i2.36
Smolders B, Lemmens R, Thijs V (2007) Lipoprotein (a) and Stroke: A Meta-Analysis of Observational Studies. Stroke. https://doi.org/10.1161/STROKEAHA.106.480657
Barkas F, Elisaf M, Milionis H (2015) Statins decrease the risk of stroke in individuals with heterozygous familial hypercholesterolemia: A systematic review and meta-analysis. Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2015.08.038
Carvalho LSF de (2018) Total cholesterol and the risk of stroke: A double-edged sword or a blunt knife? Atherosclerosis. https://doi.org/10.1016/j.atherosclerosis.2018.01.016
Downloads
Published
Issue
Section
License
Copyright (c) 2026 Febriana Intan Diatri (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors publishing here keep copyright but grant the journal first publication rights, under a Creative Commons Attribution-NonCommercial 4.0 License. They can distribute their work non-exclusively elsewhere with an acknowledgment of its first publication in this journal. Posting the work online before and during submission for earlier and greater citation is encouraged, reflecting Open Access benefits.
