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

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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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1 retracted

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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 58
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
“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
“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
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
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
“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 58
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 55
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
“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 52
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
“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 51
“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 55
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
“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 51
“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
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 55
“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
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 53
“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 53
“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
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
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 43
“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
“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 43
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 44
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
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
“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 40
“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
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
“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
“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
“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
“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
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 35
“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
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
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 39
“[4] It means that other better therapeutic strategies need to be explored.”
Background
An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis
Yi, S., Karabin, N. B., Zhu, J. Y., Bobbala, S. K. R., Lyu, H., Li, S., Liu, Y., Frey, M. A., Vincent, M. P., & Scott, E. A. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.00542 · Cited by 35
“Many patients with reduced low-density lipoprotein (LDL) cholesterol levels still have a high risk of heart attack and stroke (Hu et al., 2003; Sampson et al., 2012; Fernández-Friera et al., 2017).”
Background
Atherosclerosis: Pathogenesis and Key Cellular Processes, Current and Emerging Therapies, Key Challenges, and Future Research Directions
Chan, Y., & Ramji, D. P. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-1924-7_1 · Cited by 41

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 › Cardiology and Cardiovascular Medicine › 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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