Residual Cardiovascular Risk Despite Optimal LDL Cholesterol Reduction with Statins: The Evidence, Etiology, and Therapeutic Challenges

Sampson, Uchechukwu K.; Fazio, Sergio; Linton, MacRae F.

doi:10.1007/s11883-011-0219-7

Cited by 439Lipoproteins and Cardiovascular HealthDiabetes, Cardiovascular Risks, and LipoproteinsLipid metabolism and disorders

Residual Cardiovascular Risk Despite Optimal LDL Cholesterol Reduction with Statins: The Evidence, Etiology, and Therapeutic Challenges

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Sampson, Uchechukwu K., Fazio, Sergio, Linton, MacRae F.·2012·Current Atherosclerosis Reports

DOI 10.1007/s11883-011-0219-7PMC PMC3697085

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Abstract

This review captures the existence, cause, and treatment challenges of residual cardiovascular risk (CVR) after aggressive low-density lipoprotein cholesterol (LDL-C) reduction. Scientific evidence implicates low high-density lipoprotein cholesterol (HDL-C) and high triglycerides (TG) in the CVR observed after LDL-C lowering. However, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial with fenofibrate, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) study with torcetrapib, and the recently terminated Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study with niacin, do not clearly attribute risk reduction value to HDL-C/TG modulation. The optimum approach to long-term lipid-modifying therapies for CVR reduction remains uncertain. Consequently, absolute risk modulation via lifestyle changes remains the centerpiece of a strategy addressing the physiologic drivers of CVR associated with HDL-C/TG, especially in the context of diabetes/metabolic syndrome.

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Residual risk persists in many individuals, especially those with features of metabolic syndrome or diabetes mellitus.
“Residual risk persists in many individuals, especially those with features of metabolic syndrome (MetS) or diabetes mellitus (DM), suggesting the need to address additional lipoprotein abnormalities such as elevated triglycerides (TGs) and TG-rich lipoproteins (TRLs) [6, 7].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [7]

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The Forgotten Majority
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Non-HDL Cholesterol and Apolipoprotein B Predict Cardiovascular Disease Events Among Men With Type 2 Diabetes
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Statins and diabetes – Authors' reply
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A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis
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Prognostic Utility of ApoB/AI, Total Cholesterol/HDL, Non-HDL Cholesterol, or hs-CRP as Predictors of Clinical Risk in Patients Receiving Statin Therapy After Acute Coronary Syndromes
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Is There a Role for Fibrates in the Management of Dyslipidemia in the Metabolic Syndrome?
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Cholesteryl Ester Transfer Protein Inhibitor Torcetrapib and Off-Target Toxicity
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Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention
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Meta-analysis: Statin Therapy Does Not Alter the Association Between Low Levels of High-Density Lipoprotein Cholesterol and Increased Cardiovascular Risk
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Efficacy of Extended-Release Niacin With Lovastatin for Hypercholesterolemia
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Apolipoprotein A-I Therapy
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Flagged first, then by citations

1 of the 117 references couldn’t be matched to a known paper.

Sorted by citations

High-Density Lipoprotein Subfractions - What the Clinicians Need to Know
Pirillo, A., Norata, G. D., & Catapano, A. L. (2013) · Cardiology · doi:10.1159/000346463 · Cited by 749 · see citing works
The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk
Sandesara, P. B., Virani, S. S., Fazio, S., & Shapiro, M. D. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00184 · Cited by 626 · see citing works
Self-citation
How the immune system shapes atherosclerosis: roles of innate and adaptive immunity
Roy, P., Orecchioni, M., & Ley, K. F. (2021) · Nature reviews. Immunology · doi:10.1038/s41577-021-00584-1 · Cited by 584 · see citing works
Diabetic dyslipidemia
Li-ya, W., & Parhofer, K. G. (2014) · Metabolism · doi:10.1016/j.metabol.2014.08.010 · Cited by 523 · see citing works
“This residual cardiovascular risk in individuals receiving an adequate statin therapy has been attributed to elevated triglycerides and low HDL [76].”
Background
Inflammation and cardiovascular disease: From mechanisms to therapeutics
Alfaddagh, A., Martin, S. S., Leucker, T. M., Michos, E. D., Blaha, M. J., Lowenstein, C. J., Jones, S. R., & Toth, P. P. (2020) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2020.100130 · Cited by 473 · see citing works
“ence residual cardiovascular (CV) risk [1].”
The Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio as a Risk Marker for Metabolic Syndrome and Cardiovascular Disease
Kosmas, C. E., Polanco, S. R., Bousvarou, M. D., Papakonstantinou, E. J., Genao, E. P., Guzman, E., & Kostara, C. E. (2023) · Diagnostics · doi:10.3390/diagnostics13050929 · Cited by 327 · see citing works
“Nevertheless, a noteworthy subset of patients remains in peril for CVD events, in spite of optimal LDL-C control [14].”
Background
Mechanisms and Consequences of Defective Efferocytosis in Atherosclerosis
Yurdagul, A., Doran, A. C., Cai, B., Fredman, G., & Tabas, I. A. (2018) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2017.00086 · Cited by 300 · see citing works
Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target
Behbodikhah, J., Ahmed, S., Elyasi, A., Kasselman, L. J., Leon, J. D., Glass, A. D., & Reiss, A. B. (2021) · Metabolites · doi:10.3390/metabo11100690 · Cited by 284 · see citing works
Effects of statins on mitochondrial pathways
Mollazadeh, H., Tavana, E., Fanni, G., Bo, S., Banach, M., Pirro, M., von Haehling, S., Jamialahmadi, T., & Sahebkar, A. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12654 · Cited by 259 · see citing works
“CVD risk is reduced by ~22% per each 1 mmol/L LDL cholesterol decrease.(3) There is overwhelming evidence showing an increasing clinical benefit when greater and earlier LDL cholesterol reductions are achieved.”
Background
Hypertriglyceridemia and atherosclerosis
Peng, J., Luo, F., Ruan, G., Peng, R., & Li, X. (2017) · Lipids in Health and Disease · doi:10.1186/s12944-017-0625-0 · Cited by 262 · see citing works
“However, the substantial residual risk of ASCVD often remains after adjustment for the certain risk factors such as LDL-C [1] or intensive LDL-C lowering with statins and other optimal therapies [2].”
Background
Coronary heart disease risk: Low-density lipoprotein and beyond
Shaya, G. E., Leucker, T. M., Jones, S. R., Martin, S. S., & Toth, P. P. (2021) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2021.04.002 · Cited by 243 · see citing works
Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease
Toth, P. (2016) · Vascular Health and Risk Management · doi:10.2147/vhrm.s104369 · Cited by 237 · see citing works
“Despite significant LDL-C lowering with statin therapy, substantial residual cardiovascular risk often remains.(5) This residual risk is thought to be due, in part, to inadequate reduction of LDL-C for a given level of risk, low levels of Vascular Health and Risk Management”
Background
Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease
Jepsen, A.-M. K., Langsted, A., Varbo, A., Bang, L. E., Kamstrup, P. R., & Nordestgaard, B. G. (2016) · Clinical Chemistry · doi:10.1373/clinchem.2015.253757 · Cited by 218 · see citing works
Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study
Bhanpuri, N. H., Hallberg, S. J., Williams, P. T., McKenzie, A. L., Ballard, K. D., Campbell, W. W., McCarter, J. P., Phinney, S. D., & Volek, J. S. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0698-8 · Cited by 190 · see citing works
“Inflammation is often observed in T2D concurrent with atherogenic dyslipidemia [34] and represents an additional CVD risk even in individuals with low to normal LDL-C [35, 36].”
Background
Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement
Banach, M., Stulc, T., Dent, R., & Toth, P. P. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.09.075 · Cited by 197 · see citing works
Prevalence and risk factors for dyslipidemia among adults in rural and urban China: findings from the China National Stroke Screening and prevention project (CNSSPP)
Opoku, S., Gan, Y., Fu, W., Chen, D., Addo‐Yobo, E. O. D., Trofimovitch, D., Yue, W., Yan, F., Wang, Z., & Lu, Z. (2019) · BMC Public Health · doi:10.1186/s12889-019-7827-5 · Cited by 197 · see citing works
Non-HDL-cholesterol and apolipoprotein B compared with LDL-cholesterol in atherosclerotic cardiovascular disease risk assessment
Carr, S. S., Hooper, A. J., SULLIVAN, D. R., & Burnett, J. R. (2018) · Pathology · doi:10.1016/j.pathol.2018.11.006 · Cited by 197 · see citing works
Management of Statin Intolerance in 2018: Still More Questions Than Answers
Toth, P. P., Patti, A. M., Giglio, R. V., Nikolić, D., Castellino, G., Rizzo, M., & Banach, M. (2018) · American Journal of Cardiovascular Drugs · doi:10.1007/s40256-017-0259-7 · Cited by 188 · see citing works
“city can lead to poor adherence to statin therapy or discontinuation [15, 22] despite the highly established benefits of LDL-C reduction [68, 69].”
Background
Relationship of the triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio to the remainder of the lipid profile: The Very Large Database of Lipids-4 (VLDL-4) study
Quispe, R., Manalac, R. J., Faridi, K. F., Blaha, M. J., Toth, P. P., Kulkarni, K. R., Nasir, K., Virani, S. S., Banach, M., Blumenthal, R. S., et al. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.06.057 · Cited by 172 · see citing works
Lipids in Atherosclerosis: Pathophysiology and the Role of Calculated Lipid Indices in Assessing Cardiovascular Risk in Patients with Hyperlipidemia
Gaggini, M., Gorini, F., & Vassalle, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010075 · Cited by 183 · see citing works
“, TC/HDL beyond non-HDL) may better predict CV risk when compared to LDL, and they could serve as auxiliary tools to assess residual risk in cardiometabolic patients [9,40,44,116,117].”
Background
Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009–2016
Araújo, J., Cai, J., & Stevens, J. (2018) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2018.0105 · Cited by 157 · see citing works
HDL Function and Atherosclerosis: Reactive Dicarbonyls as Promising Targets of Therapy
Linton, M. F., Yancey, P. G., Tao, H., & Davies, S. S. (2023) · Circulation Research · doi:10.1161/circresaha.123.321563 · Cited by 155 · see citing works
Self-citation
Prevention of Cardiovascular Events with Omega-3 Polyunsaturated Fatty Acids and the Mechanism Involved
Watanabe, Y., & Tatsuno, I. (2019) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.50658 · Cited by 132 · see citing works
Impact of Excessive Weight Gain on Cardiovascular Outcomes in Type 1 Diabetes: Results From the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study
Purnell, J. Q., Braffett, B. H., Zinman, B., Gubitosi-Klug, R. A., Sivitz, W., Bantle, J. P., Ziegler, G., Cleary, P. A., Brunzell, J. D., DCCT/EDIC Research Group, et al. (2017) · Diabetes Care · doi:10.2337/dc16-2523 · Cited by 120 · see citing works
“proinflammatory factors that are thought to contribute to the 50–60% “residual risk” for cardiac events despite optimal LDL cholesterol lowering reported in statin trials (19).”
Background
Association of small, dense LDL-cholesterol concentration and lipoprotein particle characteristics with coronary heart disease: A systematic review and meta-analysis
Liou, L., & Kaptoge, S. (2020) · PLoS ONE · doi:10.1371/journal.pone.0241993 · Cited by 118 · see citing works
“CHD is primarily caused by atherosclerosis and the resulting inflammation of the coronary arteries [3].”
Background
The atherogenic index of plasma and carotid atherosclerosis in a community population: a population-based cohort study in China
Huang, Q., Liu, Z., Wei, M., Huang, Q. Y., Feng, J., Liu, Z., & Xia, J. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-01839-y · Cited by 115 · see citing works
“However, substantial residual risk persists with the majority of predicted first and recurrent CVD events not being averted despite reductions in LDL-C levels to the recommended levels [17].”
Background
The Role of Lipids and Lipoproteins in Atherosclerosis
Linton, M. F., Yancey, P. G., Davies, S. S., Jerome, W. G., Linton, E. F., Song, W., Doran, A. C., & Vickers, K. C. (2015) · Europe PMC (PubMed Central) · Cited by 108 · see citing works
Self-citation
Independent Causal Effect of Remnant Cholesterol on Atherosclerotic Cardiovascular Outcomes: A Mendelian Randomization Study
Navarese, E. P., Vine, D., Proctor, S., Grzelakowska, K., Berti, S., Kubica, J., & Raggi, P. (2023) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.123.319297 · Cited by 107 · see citing works
Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management
Johnston, T. P., Короленко, Т. А., Pirro, M., & Sahebkar, A. (2017) · Pharmacological Research · doi:10.1016/j.phrs.2017.04.008 · Cited by 102 · see citing works
Ephs and ephrins resurface in inflammation, immunity, and atherosclerosis
Funk, S. D., & Orr, A. W. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.10.008 · Cited by 95 · see citing works
Effect of Eicosapentaenoic and Docosahexaenoic Acids Added to Statin Therapy on Coronary Artery Plaque in Patients With Coronary Artery Disease: A Randomized Clinical Trial
Alfaddagh, A., Elajami, T. K., Ashfaque, H., Saleh, M. A., Bistrian, B. R., & Welty, F. K. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006981 · Cited by 95 · see citing works
Fibrates Revisited: Potential Role in Cardiovascular Risk Reduction
Kim, N. H., & Kim, S. G. (2020) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2020.0001 · Cited by 96 · see citing works
Omega-3 polyunsaturated fatty acids for cardiovascular diseases: present, past and future
Watanabe, Y., & Tatsuno, I. (2017) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2017.1333902 · Cited by 93 · see citing works
“Despite significant LDL-C lowering with statin, substantial residual CV risk remains [98], and several risk factors such as low level of HDL-C and high level of TGs have attracted attention.”
Background
Use of fenofibrate on cardiovascular outcomes in statin users with metabolic syndrome: propensity matched cohort study
Kim, N. H., Han, K. H., Choi, J., Lee, J., & Kim, S. G. (2019) · BMJ · doi:10.1136/bmj.l5125 · Cited by 95 · see citing works
LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins
Wei, W., Li, X., Feng, Q., Kubo, M., Kullo, I. J., Peissig, P. L., Karlson, E. W., Jarvik, G. P., Lee, M. T. M., Shang, N., et al. (2018) · Circulation · doi:10.1161/circulationaha.117.031356 · Cited by 93 · see citing works
The Importance of Lipoprotein Lipase Regulation in Atherosclerosis
Kumari, A., Kristensen, K. K., Ploug, M., & Winther, A.-M. L. (2021) · Biomedicines · doi:10.3390/biomedicines9070782 · Cited by 95 · see citing works
“Although the mechanistic insights of ApoC-II and its association with atherosclerosis are not yet fully elucidated, further investigations in this field may lead to new therapeutic potentials aimed at ASCVD.”
BackgroundInfluential
Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study
Penson, P. E., Long, D. L., Howard, G., Toth, P. P., Muntner, P., Howard, V. J., Safford, M. M., Jones, S. R., Martin, S. S., Mazidi, M., et al. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy533 · Cited by 88 · see citing works
Small Dense Low-Density Lipoprotein Cholesterol and the Risk of Coronary Heart Disease in a Japanese Community
Higashioka, M., Sakata, S., Honda, T., Hata, J., Yoshida, D., Hirakawa, Y., Shibata, M., Gotō, K., Kitazono, T., Osawa, H., et al. (2019) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.51961 · Cited by 88 · see citing works
Triglyceride to high-density lipoprotein cholesterol ratio and cardiovascular events in the general population: A systematic review and meta-analysis of cohort studies
Chen, Y., Chang, Z., Liu, Y., Zhao, Y., Fu, J., Zhang, Y., Liu, Y., & Fan, Z. (2021) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2021.11.005 · Cited by 86 · see citing works
Discovery and Optimization of Imidazopyridine-Based Inhibitors of Diacylglycerol Acyltransferase 2 (DGAT2)
Futatsugi, K., Kung, D. W., Orr, S. T. M., Cabral, S., Hepworth, D., Aspnes, G., Bader, S., Bian, J., Boehm, M., Carpino, P. A., et al. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01006 · Cited by 88 · see citing works
The Role of High Triglycerides Level in Predicting Cognitive Impairment: A Review of Current Evidence
Dimache, A.-M., Șalaru, D. L., Sascău, R. A., & Stătescu, C. (2021) · Nutrients · doi:10.3390/nu13062118 · Cited by 84 · see citing works
“Nevertheless, it was observed that after optimal treatment and the achievement of lower LDL-cholesterol levels, there is still a considerable residual risk [18].”
Background
New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins
Kim, K., Ginsberg, H. N., & Choi, S. H. (2022) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2022.0198 · Cited by 85 · see citing works
“However, despite optimal statin therapy, a significant residual ASCVD risk remains [6,7].”
Background
Novel Diagnostic Biomarkers Related to Oxidative Stress and Macrophage Ferroptosis in Atherosclerosis
Li, M., Xin, S., Gu, R., Zheng, L., Hu, J., Zhang, R., & Dong, H. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/8917947 · Cited by 81 · see citing works
“These therapies, however, have not been effective in reducing levels of MACESs [4].”
Resistin: Potential biomarker and therapeutic target in atherosclerosis
Zhou, L., Li, J., He, P., Yu, X.-H., & Tang, C. (2020) · Clinica Chimica Acta · doi:10.1016/j.cca.2020.11.010 · Cited by 74 · see citing works
Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis
Zhang, B., Yin, F., Qiao, Y.-N., & Guo, S. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.909151 · Cited by 79 · see citing works
Lipid-modifying activity of curcuminoids: A systematic review and meta-analysis of randomized controlled trials
Simental‐Mendía, L. E., Pirro, M., Gotto, A. M., Banach, M., Atkin, S. L., Majeed, M. A., & Sahebkar, A. (2017) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2017.1396201 · Cited by 72 · see citing works
“Increased plasma triglycerides and reduced HDL-C may contribute to this residual CV risk in statin-treated individuals, and those lipid indices are not effectively modulated by statins (Sampson et al. 2012, Sirimarco et al. 2014).”
Background
Erectile Dysfunction Is a Hallmark of Cardiovascular Disease: Unavoidable Matter of Fact or Opportunity to Improve Men’s Health?
Yannas, D., Frizza, F., Vignozzi, L., Corona, G., Maggi, M., & Rastrelli, G. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10102221 · Cited by 68 · see citing works
“As with hypertension, this is a continuous relationship without a clear threshold [26].”
Background
Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities
Stroope, C., Nettersheim, F. S., Coon, B. G., Finney, A. C., Schwartz, M. A., Ley, K. F., Rom, O., & Yurdagul, A. (2024) · Nature Metabolism · doi:10.1038/s42255-024-01015-w · Cited by 72 · see citing works
“Despite this, numerous individuals with normal LDL cholesterol levels still suffer from major cardiovascular events 344,345 , emphasizing the importance of other metabolic pathways.”
Triglyceride-Rich Lipoproteins and Coronary Artery Disease Risk
Khetarpal, S. A., & Rader, D. J. (2015) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.305172 · Cited by 69 · see citing works
Current and future trends in the lipid lowering therapy
Okopień, B., Bułdak, Ł., & Bołdys, A. (2016) · Pharmacological Reports · doi:10.1016/j.pharep.2016.03.016 · Cited by 69 · see citing works
“This specific risk is called the residual risk [2] and it is thought to be still modifiable with further reduction in the level of currently known risk factors (e.”
Background
Reducing residual cardiovascular risk in Europe: Therapeutic implications of European medicines agency approval of icosapent ethyl/eicosapentaenoic acid
Chapman, M. J., Zamorano, J. L., & Parhofer, K. G. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108172 · Cited by 68 · see citing works
Small, Dense LDL Particles Predict Changes in Intima Media Thickness and Insulin Resistance in Men with Type 2 Diabetes and Prediabetes – A Prospective Cohort Study
Gerber, P. A., Thalhammer, C., Schmied, C. M., Spring, S., Amann-Vesti, B. R., Spinas, G. A., & Berneis, K. K. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072763 · Cited by 70 · see citing works
“Of interest, changes in flow mediated dilation were only predicted by the LDL-C concentration, but neither by sdLDL levels or other lipid parameters nor by age, BMI or HbA1c, whereas changes in IMT were only predicted by the proportion of sdLDL particles, but not by LDL-C levels.”
Background
Cardiovascular risk in patients achieving low-density lipoprotein cholesterol and particle targets
Toth, P. P., Grabner, M., Punekar, R. S., Quimbo, R. A., Cziraky, M. J., & Jacobson, T. A. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.05.914 · Cited by 62 · see citing works
DNA methylation and gene expression integration in cardiovascular disease
Palou-Márquez, G., Subirana, I., Nonell, L., Fernández‐Sanlés, A., & Elosúa, R. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01064-y · Cited by 61 · see citing works
“Moreover, despite pharmacological success in reducing cardiovascular morbidity and mortality, the search for new pathogenic pathways and therapeutic targets is important because residual cardiovascular risk remains a major concern [5].”
Background
Scavenging of reactive dicarbonyls with 2-hydroxybenzylamine reduces atherosclerosis in hypercholesterolemic Ldlr−/− mice
Tao, H., Huang, J., Yancey, P. G., Yermalitsky, V. N., Blakemore, J. L., Zhang, Y., Ding, L., Zagol-Ikapitte, I. A., Ye, F., Amarnath, V., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17915-w · Cited by 61 · see citing works
Self-citation
Novel therapeutic targets and emerging treatments for atherosclerotic cardiovascular disease
Zheng, W. C., Chan, W., Dart, A. M., & Shaw, J. A. (2023) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvad074 · Cited by 61 · see citing works
AtheroSpectrum Reveals Novel Macrophage Foam Cell Gene Signatures Associated With Atherosclerotic Cardiovascular Disease Risk
Li, C., Qu, L., Matz, A., Murphy, P. A., Liu, Y., Manichaikul, A. W., Aguiar, D., Rich, S. S., Herrington, D. M., Vu, D., et al. (2021) · Circulation · doi:10.1161/circulationaha.121.054285 · Cited by 59 · see citing works
New Drugs for Treating Dyslipidemia: Beyond Statins
Ahn, C. H., & Choi, S. H. (2015) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2015.39.2.87 · Cited by 58 · see citing works
“These remaining ASCVD risk has been considered as causing the major vascular event in about 20% of patients with coronary heart disease even under the optimal statin treatment [4].”
Background
Residual Risk Factors to Predict Major Adverse Cardiovascular Events in Atherosclerotic Cardiovascular Disease Patients with and without Diabetes Mellitus
Lin, F., Tseng, W.-K., Yin, W., Yeh, H., Chen, J., & Wu, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-08741-0 · Cited by 56 · see citing works
Regression of human coronary artery plaque is associated with a high ratio of (18‐hydroxy‐eicosapentaenoic acid + resolvin E1) to leukotriene B 4
Welty, F. K., Schulte, F., Alfaddagh, A., Elajami, T. K., Bistrian, B. R., & Hardt, M. (2021) · The FASEB Journal · doi:10.1096/fj.202002471r · Cited by 57 · see citing works
Clinical and economic burden associated with cardiovascular events among patients with hyperlipidemia: a retrospective cohort study
Fox, K. M., Wang, L., Gandra, S. R., Quek, R. G. W., Li, L., & Başer, O. (2016) · BMC Cardiovascular Disorders · doi:10.1186/s12872-016-0190-x · Cited by 56 · see citing works
“Although statins are widely prescribed for elevated LDL-C levels, 9 %–20 % of treated patients, especially highrisk patients, continue to have elevated LDL-C and remain at risk for new CV events [38].”
Background
Discordance of Low-Density Lipoprotein and High-Density Lipoprotein Cholesterol Particle Versus Cholesterol Concentration for the Prediction of Cardiovascular Disease in Patients With Metabolic Syndrome and Diabetes Mellitus (from the Multi-Ethnic Study of Atherosclerosis [MESA])
Tehrani, D. M., Zhao, Y., Blaha, M. J., Mora, S., Mackey, R. H., Michos, E. D., Budoff, M. J., Cromwell, W. C., Otvos, J. D., Rosenblit, P. D., et al. (2016) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2016.03.040 · Cited by 56 · see citing works
“We show that LDL-P is predictive of CHD and CVD in those with MetS and HDL-P is protective of CHD and CVD in those with DM, even when adjusting for each other, HDL-C, and LDL-C.”
BackgroundInfluential
Apolipoprotein B compared with low-density lipoprotein cholesterol in the atherosclerotic cardiovascular diseases risk assessment
Galimberti, F., Casula, M., & Olmastroni, E. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106873 · Cited by 63 · see citing works
Nicotinic acid as a lipid-modifying drug – A review
Julius, U., & Fischer, S. (2013) · Atherosclerosis Supplements · doi:10.1016/j.atherosclerosissup.2012.10.036 · Cited by 54 · see citing works
Benefits and risks of the treatment with fibrates––a comprehensive summary
Okopień, B., Bułdak, Ł., & Bołdys, A. (2018) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2018.1537780 · Cited by 55 · see citing works
“On the other hand, in the case of coinciding low level of HDL-C [HR = 1.74 (1.28–2.37; p = 0.0005)] or high level of LDL-C [1.52 (1.12–2.07; p = 0.0073)] the risk was significantly elevated [38].”
BackgroundInfluential
Legacy effect of fibrate add-on therapy in diabetic patients with dyslipidemia: a secondary analysis of the ACCORDION study
Zhu, L., Hayen, A. D., & Bell, K. (2020) · Cardiovascular Diabetology · doi:10.1186/s12933-020-01002-x · Cited by 54 · see citing works
Atherosclerosis is a major human killer and non-resolving inflammation is a prime suspect
Fredman, G., & MacNamara, K. C. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab309 · Cited by 52 · see citing works
Evaluating bempedoic acid for the treatment of hyperlipidaemia
Penson, P. E., McGowan, M. P., & Banach, M. (2017) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2017.1280458 · Cited by 52 · see citing works
“a number of factors, including poor adherence to statin therapy, statin discontinuation [13] and statin intolerance [14] and residual risk despite achieving therapeutic LDL-C targets [6, 15].”
Background
Recent advances in targeted delivery of non-coding RNA-based therapeutics for atherosclerosis
Li, X., Qi, H., Cui, W., Wang, Z., Fu, X., Li, T., Ma, H., Yang, Y., & Yu, T. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.07.018 · Cited by 51 · see citing works
The predictive value of atherogenic index of plasma for cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention with LDL-C below 1.8mmol/L
Wang, Y., Wang, S., Sun, S., Li, F., Zhao, W., Yang, H., & Wu, X. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-01888-3 · Cited by 51 · see citing works
“This is particularly evident in patients with atherogenic dyslipidemia, characterized by elevated TG levels or low HDL-C levels [4, 18].”
Background
Causal associations of remnant cholesterol with cardiometabolic diseases and risk factors: a mendelian randomization analysis
Guan, B., Wang, A., & Xu, H. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-01927-z · Cited by 50 · see citing works
“Moreover, despite treated with LDL-C-lowering agents, most of the predicted first or recurrent CVDs events are not avoided due to substantial residual risks [9].”
Background
High residual cardiovascular risk after lipid-lowering: prime time for Predictive, Preventive, Personalized, Participatory, and Psycho-cognitive medicine
Reijnders, E., van der Laarse, A., Jukema, J. W., & Cobbaert, C. M. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1264319 · Cited by 50 · see citing works
The Effect of Bergamot-Derived Polyphenolic Fraction on LDL Small Dense Particles and Non Alcoholic Fatty Liver Disease in Patients with Metabolic Syndrome
Gliozzi, M., Carresi, C., Musolino, V., Palma, E., Muscoli, C., Vitale, C., Gratteri, S., Muscianisi, G., Janda, E., Muscoli, S., et al. (2014) · Advances in Biological Chemistry · doi:10.4236/abc.2014.42017 · Cited by 50 · see citing works
“Numerous studies demonstrated an increased cardiovascular risk in patients with MS prior to the development of overt hyperglycemia [5] [6].”
Background
LDL Receptor and ApoE Are Involved in the Clearance of ApoM-associated Sphingosine 1-Phosphate
Kurano, M., Tsukamoto, K., Hara, M., Ohkawa, R., Ikeda, H., & Yatomi, Y. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.596445 · Cited by 50 · see citing works
“eliminate ischemic heart diseases (35).”
An omega-3 fatty acid plasma index ≥4% prevents progression of coronary artery plaque in patients with coronary artery disease on statin treatment
Alfaddagh, A., Elajami, T. K., Saleh, M. A., Mohebali, D., Bistrian, B. R., & Welty, F. K. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.04.213 · Cited by 53 · see citing works
Defining preventive cardiology: A clinical practice statement from the American Society for Preventive Cardiology
German, C. A., Baum, S. J., Ferdinand, K. C., Gulati, M., Polonsky, T. S., Toth, P. P., & Shapiro, M. D. (2022) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2022.100432 · Cited by 53 · see citing works
“cant LDL-C lowering led to the realization that a more comprehensive view on prevention is necessary [38].”
Background
Ceruloplasmin and Coronary Heart Disease—A Systematic Review
Larriva, A. P. A.-D., Pérez, L. L., Alcala-Diaz, J. F., Alonso, Á., López‐Miranda, J., & Delgado‐Lista, J. (2020) · Nutrients · doi:10.3390/nu12103219 · Cited by 49 · see citing works
Plant-Based Diets and Lipid, Lipoprotein, and Inflammatory Biomarkers of Cardiovascular Disease: A Review of Observational and Interventional Studies
Elliott, P. S., Kharaty, S. S., & Phillips, C. M. (2022) · Nutrients · doi:10.3390/nu14245371 · Cited by 51 · see citing works
“Despite the significant reductions in CVD risk observed with aggressive lowering of LDL-C concentration, patients with established CVD still experience residual risk [142], which may, at least in part, be due to a range of risk factors, including inflammation [143].”
Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia
Moon, J. H., Kim, K., & Choi, S. H. (2022) · Endocrinology and Metabolism · doi:10.3803/enm.2022.402 · Cited by 49 · see citing works
“Despite this success, recent studies have pointed out that high levels of triglycerides (TGs) and triglyceride-rich lipoproteins (TGRLs) confer substantial residual risk after optimal LDL-C-lowering therapy [3].”
Background
Targeting pro-inflammatory T cells as a novel therapeutic approach to potentially resolve atherosclerosis in humans
Fan, L., Liu, J., Hu, W., Chen, Z., Lan, J., Zhang, T., Zhang, Y., Wu, X., Zhong, Z., Zhang, D., et al. (2024) · Cell Research · doi:10.1038/s41422-024-00945-0 · Cited by 47 · see citing works
Redox markers and inflammation are differentially affected by atorvastatin, pravastatin or simvastatin administered before endotoxin-induced acute lung injury
Melo, A. C., Valença, S. S., de Brito‐Gitirana, L., Santos, J. C., Ribeiro, M. L., Machado, M. N., Magalhães, C. B., Zin, W. A., & Pôrto, L. C. (2013) · International Immunopharmacology · doi:10.1016/j.intimp.2013.05.016 · Cited by 45 · see citing works
Clinical implications of the IMPROVE-IT trial in the light of current and future lipid-lowering treatment options
Șerban, M.-C., Banach, M., & Mikhailidis, D. P. (2015) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2016.1118055 · Cited by 44 · see citing works
“benefits of statin use in many trials,[17,18] there is a residual CV risk even when statin-induced LDL-C goals, according to the current guidelines, are achieved.[19]”
Background
Long-term prognostic value of LDL-C, HDL-C, lp(a) and TG levels on cardiovascular disease incidence, by body weight status, dietary habits and lipid-lowering treatment: the ATTICA epidemiological cohort study (2002–2012)
Georgoulis, M., Chrysohoou, C. A., Georgousopoulou, E. N., Damigou, E., Skoumas, I., Pitsavos, C. S., & Panagiotakos, D. B. (2022) · Lipids in Health and Disease · doi:10.1186/s12944-022-01747-2 · Cited by 51 · see citing works
“For example, LDL-C has been shown to have a lower predictive value for CVD development among individuals with obesity or metabolic syndrome who present with low HDL-C levels, fasting and postprandial hypertriglyceridemia, elevated small and dense apo B lipoproteins, and thus a high residual CVD risk [4].”
Background
Omega-3 polyunsaturated fatty acids focusing on eicosapentaenoic acid and docosahexaenoic acid in the prevention of cardiovascular diseases: a review of the state-of-the-art
Watanabe, Y., & Tatsuno, I. (2020) · Expert Review of Clinical Pharmacology · doi:10.1080/17512433.2021.1863784 · Cited by 42 · see citing works
Targeting macrophages with multifunctional nanoparticles to detect and prevent atherosclerotic cardiovascular disease
Nankivell, V. A., Vidanapathirana, A. K., Hoogendoorn, A., Tan, J. T. M., Verjans, J. W. H., Psaltis, P. J., Hutchinson, M. R., Gibson, B. C., Lu, Y., Goldys, E. M., et al. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae099 · Cited by 42 · see citing works
Current and Emerging Reconstituted HDL-apoA-I and HDL-apoE Approaches to Treat Atherosclerosis
Valanti, E.-K., Dalakoura-Karagkouni, K., & Sanoudou, D. (2018) · Journal of Personalized Medicine · doi:10.3390/jpm8040034 · Cited by 41 · see citing works
Association of the triglyceride–glucose index with all-cause and cause-specific mortality: a population-based cohort study of 3.5 million adults in China
He, G., Zhang, Z., Wang, C., Wang, W., Bai, X., He, L., Chen, S., Li, G., Yang, Y., Zhang, X., et al. (2024) · The Lancet Regional Health - Western Pacific · doi:10.1016/j.lanwpc.2024.101135 · Cited by 39 · see citing works
“49,50 We found that the association between the TyG index and mortality is independent of conventional CVD risk factors, such as LDL-C and diabetes.”
Background
Alteration of HDL functionality and PON1 activities in acute coronary syndrome patients
Bounafaa, A., Berrougui, H., Ikhlef, S., Essamadi, A., Nasser, B., Bennis, A., Yamoul, N., Ghalim, N., & Khalil, A. (2014) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2014.09.001 · Cited by 39 · see citing works
“001 LDL reduction, residual annual risk that approximates 9% in patients with established coronary artery disease remains a reality, which prompted questions about etiology and a therapeutic course of action [3].”
Background
Antioxidant and hypolipidemic effects of soymilk fermented via Lactococcus acidophilus MF204
Chen, J., Wu, Y., Yang, C., Xu, X., & Meng, Y. (2017) · Food & Function · doi:10.1039/c7fo00701a · Cited by 38 · see citing works
The Effect of Three Mediterranean Diets on Remnant Cholesterol and Non-Alcoholic Fatty Liver Disease: A Secondary Analysis
Campanella, A., Iacovazzi, P. A., Misciagna, G., Bonfiglio, C., Mirizzi, A., Franco, I., Bianco, A., Sorino, P., Caruso, M. G., Cisternino, A. M., et al. (2020) · Nutrients · doi:10.3390/nu12061674 · Cited by 38 · see citing works
“However, even after a reduction of LDL-C to the recommended concentrations, there is still a considerable residual risk of recurrent cardiovascular events, so lowering LDL-C levels alone is insufficient [8].”
Background
Alirocumab for the treatment of hypercholesterolemia
Tomlinson, B., Hu, M., Zhang, Y., Chan, P., & Liu, Z.-M. (2017) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2017.1305354 · Cited by 37 · see citing works
“risk may be ameliorated by more intensive reduction of LDL-C below current therapeutic targets [5].”
Background
Trehalose administration attenuates atherosclerosis in rabbits fed a high‐fat diet
Sahebkar, A., Hatamipour, M., & Tabatabaei, S. A. (2018) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28221 · Cited by 37 · see citing works
“This issue is of particular importance as cholesterol‐ lowering medications are the cornerstone of pharmacotherapy for ACVD but these drugs, despite their documented efficacy, cannot achieve a complete risk reduction and many patients carry a considerable residual CVD risk despite being at target LDL‐C levels.(19) Hen…”
Background
Cholesterol Transport Dysfunction and Its Involvement in Atherogenesis
Poznyak, A. V., Kashirskikh, D. A., Sukhorukov, V. N., Kalmykov, V. A., Omelchenko, A. V., & Orekhov, A. N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031332 · Cited by 38 · see citing works
“It is worth noting that no aggressive statin therapy is able to cause a reduction in CHD or stroke risk [18].”
Background
Efficacy and safety of fixed dose combination of atorvastatin and hydroxychloroquine: a randomized, double-blind comparison with atorvastatin alone among Indian patients with dyslipidemia
Pareek, A. K., Chandurkar, N. B., Thulaseedharan, N. K., Legha, R., Agarwal, M., Mathur, S., Salkar, H. R., Pednekar, S., Pai, V., Sriram, U., et al. (2015) · Current Medical Research and Opinion · doi:10.1185/03007995.2015.1087989 · Cited by 36 · see citing works
Inflammatory therapeutic targets in coronary atherosclerosis—from molecular biology to clinical application
Linden, F., Domschke, G., Erbel, C., Akhavanpoor, M., Katus, H. A., & Gleissner, C. A. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00455 · Cited by 36 · see citing works
“atherosclerosis—from molecular biology to clinical application”
Background
C1q tumor necrosis factor-related protein 9 in atherosclerosis: Mechanistic insights and therapeutic potential
Yu, X., Zhang, D., Zheng, X., & Tang, C. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.07.022 · Cited by 36 · see citing works
Peptide Amphiphile Supramolecular Nanostructures as a Targeted Therapy for Atherosclerosis
Mansukhani, N. A., Peters, E. B., So, M. M., Albaghdadi, M. S., Wang, Z., Karver, M. R., Clemons, T. D., Laux, J. P., Tsihlis, N. D., Stupp, S. I., et al. (2019) · Macromolecular Bioscience · doi:10.1002/mabi.201900066 · Cited by 36 · see citing works
Role of Sp1 in atherosclerosis
Jiang, J.-F., Zhou, Z., Liu, Y.-Z., Wu, L., Nie, B.-B., Huang, L., & Zhang, C. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07516-9 · Cited by 37 · see citing works
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Authors: Sampson, U. K., Fazio, S., & Linton, M. F.
Affiliations: Vanderbilt University Medical Center (US)
Corresponding author: Linton, MacRae F.
ORCID: Fazio, Sergio
Linton, MacRae F.
Venue: Current Atherosclerosis Reports
Publisher: Springer Science and Business Media LLC
Published: 2011-11-19
Volume: 14
Issue: 1
Pages: 1-10
ISSN: 1523-3804 (ISSN-L)
1534-6242
DOI: 10.1007/s11883-011-0219-7
PMC: PMC3697085
OpenAlex: W2079979713
Cited by: 439
References: 117
Citations by year: 2026: 37 · 2025: 36 · 2024: 38 · 2023: 50 · 2022: 43 · 2021: 36 · 2020: 34 · 2019: 36 · 2018: 33 · 2017: 25 · 2016: 19 · 2015: 18 · 2014: 15 · 2013: 11 · 2012: 7
FWCI: 1.91
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springer.com/tdm (tdm)
Locations: Current Atherosclerosis Reports (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL065709, R01HL086988, HL086988, HL105375, HL65709, R01HL105375)
Topics: Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords: residual cardiovascular risk, LDL cholesterol lowering, statins, HDL cholesterol, triglycerides, fenofibrate, torcetrapib, nicotinic acid, AIM-HIGH trial, ILLUMINATE trial, diabetes mellitus, metabolic syndrome, lifestyle modification, lipid therapy
MeSH terms: Cardiovascular Diseases, Humans, Life Style, Cholesterol, LDL, Morbidity, Risk Factors, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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Residual Cardiovascular Risk Despite Optimal LDL Cholesterol Reduction with Statins: The Evidence, Etiology, and Therapeutic Challenges

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