LDL cholesterol: controversies and future therapeutic directions

Ridker, Paul M

doi:10.1016/s0140-6736(14)61009-6

Cited by 276Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismDiabetes, Cardiovascular Risks, and Lipoproteins

LDL cholesterol: controversies and future therapeutic directions

Ridker, Paul M·2014·The Lancet

DOI 10.1016/s0140-6736(14)61009-6

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Abstract

Lifelong exposure to raised concentrations of LDL cholesterol increases cardiovascular event rates, and the use of statin therapy as an adjunct to diet, exercise, and smoking cessation has proven highly effective in reducing the population burden associated with hyperlipidaemia. Yet, despite consistent biological, genetic, and epidemiological data, and evidence from randomised trials, there is controversy among national guidelines and clinical practice with regard to LDL cholesterol, its measurement, the usefulness of population-based screening, the net benefit-to-risk ratio for different LDL-lowering drugs, the benefit of treatment targets, and whether aggressive lowering of LDL is safe. Several novel therapies have been introduced for the treatment of people with genetic defects that result in loss of function within the LDL receptor, a major determinant of inherited hyperlipidaemias. Moreover, the usefulness of monoclonal antibodies that extend the LDL-receptor lifecycle (and thus result in substantial lowering of LDL cholesterol below the levels achieved with statins alone) is being assessed in phase 3 trials that will enrol more than 60,000 at-risk patients worldwide. These trials represent an exceptionally rapid translation of genetic observations into clinical practice and will address core questions of how low LDL cholesterol can be safely reduced, whether the mechanism of LDL-cholesterol lowering matters, and whether ever more aggressive lipid-lowering provides a safe, long-term mechanism to prevent atherothrombotic complications.

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Genetic Determinants of Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: The Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Trial
Chasman, D. I., Giulianini, F., MacFadyen, J., Barratt, B. J., Nyberg, F., & Ridker, P. M. (2012) · Circulation: Cardiovascular Genetics · doi:10.1161/circgenetics.111.961144 · Cited by 285 · see citing works
Self-citation
Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL-related measures and future coronary events
Mora, S., Buring, J. E., & Ridker, P. M. (2014) · Circulation · doi:10.1161/circulationaha.113.005873 · Cited by 255 · see citing works
Self-citation
High-Density Lipoprotein Cholesterol, Size, Particle Number, and Residual Vascular Risk After Potent Statin Therapy
Mora, S., Glynn, R. J., & Ridker, P. M. (2013) · Circulation · doi:10.1161/circulationaha.113.002671 · Cited by 238 · see citing works
Self-citation
Mechanisms for the anti-inflammatory effects of statins
Bu, D.-X., Griffin, G. K., & Lichtman, A. H. (2011) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283453e41 · Cited by 235 · see citing works
Cardiovascular Event Reduction and Adverse Events Among Subjects Attaining Low-Density Lipoprotein Cholesterol <50 mg/dl With Rosuvastatin
Hsia, J., MacFadyen, J. G., Monyak, J., & Ridker, P. M. (2011) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.09.082 · Cited by 231 · see citing works
Self-citation
Randomized, Placebo-Controlled Trial of Mipomersen in Patients with Severe Hypercholesterolemia Receiving Maximally Tolerated Lipid-Lowering Therapy
McGowan, M. P., Tardif, J., Češka, R., Burgess, L. J., Soran, H., Gouni‐Berthold, I., Wagener, G., & Chasan-Taber, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049006 · Cited by 222 · see citing works
More Than a Billion People Taking Statins?
Ioannidis, J. P. A. (2013) · JAMA · doi:10.1001/jama.2013.284657 · Cited by 187 · see citing works
AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy
Desai, N. R., Kohli, P., Giugliano, R. P., O’Donoghue, M. L., Somaratne, R. M., Zhou, J., Hoffman, E. B., Huang, F., Rogers, W. J., Wasserman, S. M., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.001969 · Cited by 179 · see citing works
The Severe Hypercholesterolemia Phenotype
Sniderman, A. D., Tsimikas, S., & Fazio, S. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.01.060 · Cited by 177 · see citing works
Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27,331 women
Mora, S., Rifai, N., Buring, J. E., & Ridker, P. M. (2009) · Clinical Chemistry · doi:10.1373/clinchem.2008.117929 · Cited by 176 · see citing works
Self-citation
Efficacy and Safety of a Novel Dual Modulator of Adenosine Triphosphate-Citrate Lyase and Adenosine Monophosphate-Activated Protein Kinase in Patients With Hypercholesterolemia
Ballantyne, C. M., Davidson, M. H., MacDougall, D. E., Bays, H. E., DiCarlo, L. A., Rosenberg, N. L., Margulies, J., & Newton, R. S. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.05.050 · Cited by 175 · see citing works
Efficacy and Safety of ETC-1002, a Novel Investigational Low-Density Lipoprotein-Cholesterol–Lowering Therapy for the Treatment of Patients With Hypercholesterolemia and Type 2 Diabetes Mellitus
Gutierrez, M. J., Rosenberg, N. L., MacDougall, D. E., Hanselman, J. C., Margulies, J. R., Strange, P., Milad, M. A., McBride, S. J., & Newton, R. S. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.113.302677 · Cited by 170 · see citing works
MBX-8025, A Novel Peroxisome Proliferator Receptor-δ Agonist: Lipid and Other Metabolic Effects in Dyslipidemic Overweight Patients Treated with and without Atorvastatin
Bays, H. E., Schwartz, S. L., Littlejohn, T. W., Kerzner, B., Krauss, R. M., Karpf, D. B., Choi, Y., Wang, X., Naim, S., & Roberts, B. K. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-1061 · Cited by 151 · see citing works
Discordance analysis of apolipoprotein B and non-high density lipoprotein cholesterol as markers of cardiovascular risk in the INTERHEART study
Sniderman, A. D., Islam, S., Yusuf, S., & McQueen, M. J. (2012) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2012.08.039 · Cited by 138 · see citing works
C-Reactive Protein, but not Low-Density Lipoprotein Cholesterol Levels, Associate With Coronary Atheroma Regression and Cardiovascular Events After Maximally Intensive Statin Therapy
Puri, R., Nissen, S. E., Libby, P., Shao, M., Ballantyne, C. M., Barter, P. J., Chapman, M. J., Erbel, R. M., Raichlen, J. S., Uno, K., et al. (2013) · Circulation · doi:10.1161/circulationaha.113.004243 · Cited by 124 · see citing works
Three Reasons to Abandon Low-Density Lipoprotein Targets
Hayward, R. A., & Krumholz, H. M. (2012) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.111.964676 · Cited by 118 · see citing works
Screening for Future Cardiovascular Disease Using Age Alone Compared with Multiple Risk Factors and Age
Wald, N., Simmonds, M. C., & Morris, J. K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018742 · Cited by 114 · see citing works
New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs
Norata, G. D., Ballantyne, C. M., & Catapano, A. L. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht088 · Cited by 99 · see citing works
Mipomersen (kynamro): a novel antisense oligonucleotide inhibitor for the management of homozygous familial hypercholesterolemia.
Wong, E., & Goldberg, T. (2014) · PubMed · Cited by 81 · see citing works
Effects of the PPAR-δ agonist MBX-8025 on atherogenic dyslipidemia
Choi, Y., Roberts, B. K., Wang, X., Geaney, J. C., Naim, S., Wojnoonski, K., Karpf, D. B., & Krauss, R. M. (2011) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2011.10.029 · Cited by 78 · see citing works
Lipoprotein disorders and cardiovascular risk
Genest, J. J. (2003) · Journal of Inherited Metabolic Disease · doi:10.1023/a:1024449603891 · Cited by 73 · see citing works
Personalized cardiovascular disease prevention by applying individualized prediction of treatment effects
van der Leeuw, J., Ridker, P. M., van der Graaf, Y., & Visseren, F. L. J. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu004 · Cited by 68 · see citing works
Self-citation
Future of Cholesteryl Ester Transfer Protein Inhibitors
Rader, D. J., & deGoma, E. M. (2014) · Annual Review of Medicine · doi:10.1146/annurev-med-050311-163305 · Cited by 66 · see citing works
Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials
D, E. B. M. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr310 · Cited by 64 · see citing works
Measurement of LDL-C after treatment with the CETP inhibitor anacetrapib
Davidson, M., Liu, S. X., Barter, P., Brinton, E. A., Cannon, C. P., Gotto, A. M., Leary, E. T., Shah, S., Stepanavage, M., Mitchel, Y., et al. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m032615 · Cited by 56 · see citing works
A Trial-Based Approach to Statin Guidelines
Ridker, P. M., & Wilson, P. W. F. (2013) · JAMA · doi:10.1001/jama.2013.276529 · Cited by 51 · see citing works
Self-citation
Lomitapide for homozygous familial hypercholesterolaemia
Raal, F. J. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61845-5 · Cited by 37 · see citing works
Lipoprotein Disorders and Cardiovascular Disease
Genest, J. J., & Libby, P. (2012) · Elsevier eBooks · doi:10.1016/b978-1-4377-0398-6.00047-0 · Cited by 36 · see citing works
Evaluation of C-Reactive Protein Before and On-Treatment as a Predictor of Benefit of Atorvastatin
Sever, P., Poulter, N. R., Chang, C. L., Thom, S., Hughes, A. D., Welsh, P. I., & Sattar, N. A. (2013) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.02.098 · Cited by 29 · see citing works
Agreement Between Fasting and Postprandial LDL Cholesterol Measured with 3 Methods in Patients with Type 2 Diabetes Mellitus
Lund, S. S., Petersen, M., Frandsen, M., Smidt, U., Parving, H., Vaag, A. A., & Jensen, T. J. (2010) · Clinical Chemistry · doi:10.1373/clinchem.2009.133868 · Cited by 22 · see citing works
Two New Drugs for Homozygous Familial Hypercholesterolemia
Smith, R. J., & Hiatt, W. R. (2013) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2013.6624 · Cited by 15 · see citing works
Limitations of Direct Methods and the Reference Method for Measuring HDL and LDL Cholesterol
Schaefer, E. J., Otokozawa, S., & Ai, M. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.159483 · Cited by 14 · see citing works
What Is the Role of the Clinical Laboratory in the New ACC/AHA Guidelines for the Treatment of Blood Cholesterol in Adults?
Jialal, I. (2014) · American Journal of Clinical Pathology · doi:10.1309/ajcped9x7rnmyaeq · Cited by 4 · see citing works
Normal levels of inflammatory markers in treated patients with familial hypercholesterolaemia: a cross-sectional study
Seed, M., Betteridge, D. J., Cooper, J. A., CASLAKE, M. J., Durrington, P. N., Thompson, G. R., Sattar, N. A., Humphries, S. E., & Neil, H. A. W. (2012) · JRSM Cardiovascular Disease · doi:10.1258/cvd.2012.012011 · Cited by 2 · see citing works

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Strategies to increase nitric oxide signalling in cardiovascular disease
Lundberg, J. O., Gladwin, M. T., & Weitzberg, E. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4623 · Cited by 576 · see citing works
Saturated Fat Consumption and Risk of Coronary Heart Disease and Ischemic Stroke: A Science Update
Nettleton, J. A., Brouwer, I. A., Geleijnse, J. M., & Hornstra, G. (2017) · Annals of Nutrition and Metabolism · doi:10.1159/000455681 · Cited by 511 · see citing works
Effects of aerobic exercise on lipids and lipoproteins
Wang, Y., & Xu, D. (2017) · Lipids in Health and Disease · doi:10.1186/s12944-017-0515-5 · Cited by 436 · see citing works
“However, their hepatotoxicity, high cost, inconvenience, and a general lack of availability outside the tertiary referral centers imply that their use is limited [10].”
Background
Dyslipidemia and cardiovascular disease risk among the MASHAD study population
Hedayatnia, M., Asadi, Z., Zare‐Feyzabadi, R., Yaghooti‐Khorasani, M., Ghazizadeh, H., Zirak, R. G., Tirkani, A. N., Mohammadi‐Bajgiran, M., Rohban, M., Sadabadi, F., et al. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-01204-y · Cited by 368 · see citing works
Effects of Vegetarian Diets on Blood Lipids: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Wang, F., Zheng, J., Yang, B., Jiang, J., Fu, Y., & Li, D. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.115.002408 · Cited by 340 · see citing works
Causal associations of blood lipids with risk of ischemic stroke and intracerebral hemorrhage in Chinese adults
on behalf of the China Kadoorie Biobank Collaborative Group, Sun, L., Clarke, R., Bennett, D., Yu, C., Walters, R. G., Hill, M., Parish, S., Millwood, I. Y., Bian, Z., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0366-x · Cited by 316 · 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
Pathophysiological mechanisms of increased cardiometabolic risk in people with schizophrenia and other severe mental illnesses
Henderson, D. C., Vincenzi, B., Andrea, N. V., Ulloa, M., & Copeland, P. M. (2015) · The Lancet Psychiatry · doi:10.1016/s2215-0366(15)00115-7 · Cited by 288 · see citing works
Quantifying Atherogenic Lipoproteins: Current and Future Challenges in the Era of Personalized Medicine and Very Low Concentrations of LDL Cholesterol. A Consensus Statement from EAS and EFLM
Langlois, M. R., Chapman, M. J., Cobbaert, C., Mora, S., Remaley, A. T., Ros, E., Watts, G. F., Borén, J., Baum, H., Bruckert, E., et al. (2018) · Clinical Chemistry · doi:10.1373/clinchem.2018.287037 · Cited by 260 · see citing works
“with PCSK9 inhibitors), are now available (11, 12).”
Background
Quantitative Lipoprotein Subclass and Low Molecular Weight Metabolite Analysis in Human Serum and Plasma by 1 H NMR Spectroscopy in a Multilaboratory Trial
Jiménez, B., Holmes, E. C., Heude, C., Tolson, R. F., Harvey, N. E., Lodge, S., Chetwynd, A. J., Cannet, C., Fang, F., Pearce, J. T. M., et al. (2018) · Analytical Chemistry · doi:10.1021/acs.analchem.8b02412 · Cited by 231 · see citing works
Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase
Würtz, P., Wang, Q., Soininen, P., Kangas, A. J., Fatemifar, G., Tynkkynen, T., Tiainen, M., Perola, M., Tillin, T., Hughes, A. D., et al. (2016) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2015.12.060 · Cited by 188 · see citing works
“GlycA, a measure of systemic inflammation and a biomarker for CVD and all-cause mortality (5,6,32,33,39), was modestly lowered, in accordance with the proposed anti-inflammatory properties of statins (7,8).”
Background
ABCA1 and ABCG1 as potential therapeutic targets for the prevention of atherosclerosis
Matsuo, M. (2021) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2021.11.005 · Cited by 174 · see citing works
Results of Bococizumab, A Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, from a Randomized, Placebo-Controlled, Dose-Ranging Study in Statin-Treated Subjects With Hypercholesterolemia
Ballantyne, C. M., Neutel, J., Cropp, A., Duggan, W. T., Wang, E. Q., Plowchalk, D. R., Sweeney, K., Kaila, N., Vincent, J., & Bays, H. E. (2015) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2015.02.006 · Cited by 170 · see citing works
“LDL-C levels of 25 mg/dl were not associated with harm in this study and do not appear to be associated with harm in trials of other PCSK9 inhibitors conducted to date.(5,7,14) Hence, future studies may need to consider lowering the LDL-C threshold at which dose reduction is initiated (e.”
Background
Trajectories of Blood Lipid Concentrations Over the Adult Life Course and Risk of Cardiovascular Disease and All‐Cause Mortality: Observations From the Framingham Study Over 35 Years
Duncan, M. S., Vasan, R. S., & Xanthakis, V. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.118.011433 · Cited by 157 · see citing works
Relevance of Multi-Omics Studies in Cardiovascular Diseases
León‐Mimila, P., Wang, J., & Huertas‐Vázquez, A. (2019) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2019.00091 · Cited by 152 · see citing works
The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk
Nayor, M. G., Brown, K., & Vasan, R. S. (2021) · Circulation Research · doi:10.1161/circresaha.120.315890 · Cited by 147 · see citing works
Endogenous Allosteric Modulators of G Protein–Coupled Receptors
van der Westhuizen, E. T., Valant, C., Sexton, P. M., & Christopoulos, A. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.221606 · Cited by 144 · see citing works
“Given that cholesterol levels can vary dramatically in and contribute directly to disease (Vance, 2012; Ridker, 2014), their ability to influence GPCR biology may play role in”
Background
Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment
Frambach, S. J. C. M., de Haas, R., Smeitink, J. A. M., Rongen, G. A. P. J. M., Rüssel, F. G. M., & Schirris, T. J. J. (2019) · Pharmacological Reviews · doi:10.1124/pr.119.017897 · Cited by 145 · see citing works
“Consequently, these lipid-loaded macrophages can result in atherosclerotic plaque formation, contributing to an increased risk of CVD (Levine et al., 1995; Kwiterovich, 2000; De Backer et al., 2003; Guyton and Hall, 2011; Taylor et al., 2011; Ridker, 2014; Piepoli et al., 2016).”
Background
Genetic association of lipids and lipid-lowering drug target genes with non-alcoholic fatty liver disease
Li, Z., Zhang, B., Liu, Q., Tao, Z., Ding, L., Guo, B., Zhang, E., Zhang, H., Meng, Z., Guo, S., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104543 · Cited by 137 · see citing works
Macrophage Apoptosis and Necrotic Core Development in Atherosclerosis: A Rapidly Advancing Field with Clinical Relevance to Imaging and Therapy
González, L., & Trigatti, B. L. (2016) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2016.12.010 · Cited by 130 · see citing works
Plasma proprotein convertase subtilisin/kexin type 9 levels and the risk of first cardiovascular events
Ridker, P. M., Rifai, N., Bradwin, G., & Rose, L. M. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv568 · Cited by 111 · see citing works
“Monoclonal antibodies that functionally inhibit PCSK9 have already proved capable of markedly reducing LDL cholesterol both as monotherapy(6) and as adjuncts to statin treatment,(7) and are now under investigation in multiple large-scale event reduction trials.(8) Substantive LDL reduction is also seen with PCSK9 inhi…”
BackgroundSelf-citation
Metabolomic Consequences of Genetic Inhibition of PCSK9 Compared With Statin Treatment
Sliz, E., Kettunen, J., Holmes, M. V., Williams, C. O., Boachie, C., Wang, Q., Männikkö, M., Sebert, S., Walters, R., Lin, K., et al. (2018) · Circulation · doi:10.1161/circulationaha.118.034942 · Cited by 109 · see citing works
The effects of a nutraceutical combination on plasma lipids and glucose: A systematic review and meta -analysis of randomized controlled trials
Pirro, M., Mannarino, M. R., Bianconi, V., Simental‐Mendía, L. E., Bagaglia, F., Mannarino, E., & Sahebkar, A. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2016.04.021 · Cited by 104 · see citing works
Cardiovascular injury induced by tobacco products: assessment of risk factors and biomarkers of harm. A Tobacco Centers of Regulatory Science compilation
Conklin, D. J., Schick, S. F., Blaha, M. J., Carll, A. P., DeFilippis, A. P., Ganz, P., Hall, M. E., Hamburg, N. M., O’Toole, T. E., Reynolds, L. M., et al. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00591.2018 · Cited by 98 · see citing works
Serum Apolipoprotein A-I and Large High-Density Lipoprotein Particles Are Positively Correlated with FEV1 in Atopic Asthma
Barochia, A. V., Kaler, M. M., Cuento, R. A., Gordon, E. M., Weir, N. A., Sampson, M. L., Fontana, J. R., MacDonald, S. D., Moss, J., Manganiello, V., et al. (2015) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201411-1990oc · Cited by 83 · see citing works
“LDL particles and their associated apoB molecules are the primary carriers of cholesterol to tissues where the cholesterol cargo is internalized into cells via LDLR (1, 35).”
BackgroundInfluential
Cardiovascular risk in rheumatoid arthritis: assessment, management and next steps
Zegkos, T., Kitas, G. D., & Dimitroulas, T. (2016) · Therapeutic Advances in Musculoskeletal Disease · doi:10.1177/1759720x16643340 · Cited by 81 · see citing works
“2014; Ridker, 2014].”
Background
Atherosclerosis and Coronary Artery Disease
Zaromitidou, M., Siasos, G., Παπαγεωργίου, Ν., Oikonomou, E. K., & Tousoulis, D. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-803312-8.00002-1 · Cited by 80 · see citing works
Prevention of cardiovascular disease in rheumatoid arthritis
Hollan, I., Dessein, P. H., Ronda, N., Wasko, M. C., Svenungsson, E., Agewall, S., Tervaert, J.-W. C., Maki-Petaja, K. M., Grundtvig, M., Karpouzas, G. A., et al. (2015) · Autoimmunity Reviews · doi:10.1016/j.autrev.2015.06.004 · Cited by 72 · see citing works
“It has been proposed that the cardioprotective effect of statins may be partly due to immunomodulation, inhibition of inflammation (including vascular inflammation), plaque stabilization, improvement of endothelial and HDL function, reduction of sympathetic activity, and anti-oxidative and antithrombotic effects [59,7…”
BackgroundInfluential
The protective effects of Chinese yam polysaccharide against obesity-induced insulin resistance
Cheng, Z., Hu, M., Tao, J., Yang, H., Yan, P., An, G., & Wang, H. (2019) · Journal of Functional Foods · doi:10.1016/j.jff.2019.02.023 · Cited by 68 · see citing works
Protective effect of the new prepared Atractylodes macrocephala Koidz polysaccharide on fatty liver hemorrhagic syndrome in laying hens
Miao, Y. F., Gao, X., Xu, D., Li, M. C., Gao, Z., Tang, Z. H., Mhlambi, N. H., Wang, W. J., Fan, W., Shi, X. Z., et al. (2020) · Poultry Science · doi:10.1016/j.psj.2020.11.036 · Cited by 68 · see citing works
“Low-density lipoprotein cholesterol abnormalities were considered to be a highly risk factor for atherosclerosis, contributing to the development of cardiovascular disease (Ridker, 2014).”
Background
Visceral adiposity and metabolic syndrome after very high–fat and low-fat isocaloric diets: a randomized controlled trial
Veum, V. L., Laupsa‐Borge, J., Eng, Ø., Rostrup, E., Larsen, T. H., Nordrehaug, J. E., Nygard, O. K., Sagen, J. V., Gudbrandsen, O. A., Dankel, S. N., et al. (2016) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.123463 · Cited by 69 · see citing works
National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio: a pooled analysis of 458 population-based studies in Asian and Western countries
Taddei, C., Jackson, R., Zhou, B., Bixby, H., Danaei, G., Cesare, M. D., Kuulasmaa, K., Hajifathalian, K., Bentham, J., Bennett, J. E., et al. (2019) · International Journal of Epidemiology · doi:10.1093/ije/dyz099 · Cited by 64 · see citing works
Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials
Ridker, P. M., Amarenco, P., Brunell, R., Glynn, R. J., Jukema, J. W., Kastelein, J. J. P., Köenig, W., Nissen, S. E., Revkin, J. H., Santos, R. D., et al. (2016) · American Heart Journal · doi:10.1016/j.ahj.2016.05.010 · Cited by 62 · see citing works
Self-citation
Triglyceride Rich Lipoprotein -LPL-VLDL Receptor and Lp(a)-VLDL Receptor Pathways for Macrophage Foam Cell Formation
Takahashi, S. (2017) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.rv17004 · Cited by 61 · see citing works
Serum selenium and lipid levels: Associations observed in the National Health and Nutrition Examination Survey (NHANES) 2011–2012
Christensen, K. L. Y., Werner, M., & Malecki, K. M. C. (2015) · Environmental Research · doi:10.1016/j.envres.2015.03.020 · Cited by 60 · see citing works
Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab
Ridker, P. M., Rose, L. M., Kastelein, J. J. P., Santos, R. D., Wei, C., Revkin, J. H., Yunis, C., Tardif, J., & Shear, C. L. (2018) · Journal of clinical lipidology · doi:10.1016/j.jacl.2018.03.088 · Cited by 60 · see citing works
Self-citation
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
“There is still concern for regular monitoring of hepatic function is requested in the patients receiving mipomersen [6].”
BackgroundInfluential
Associations between age and dyslipidemia are differed by education level: The Cardiovascular and Metabolic Diseases Etiology Research Center (CMERC) cohort
Cho, S. M. J., Lee, H. J., Shim, J., Song, B., & Kim, H. C. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-1189-y · Cited by 57 · see citing works
Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raisingA systematic review and meta-analysis of relevant preclinical studies and clinical trials
Kühnast, S., Fiocco, M. F., van der Hoorn, J. W. A., Princen, H. M. G., & Jukema, J. W. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.03.089 · Cited by 55 · see citing works
“Low density lipoprotein (LDL)-cholesterol is recognized as a primary causal risk factor in cardiovascular disease as evidenced from experimental, epidemiological and genetic studies (Ridker, 2014).”
Background
Saturated fats, dairy foods and health: A curious paradox?
Givens, D. I. (2017) · Nutrition Bulletin · doi:10.1111/nbu.12283 · Cited by 56 · see citing works
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Authors: Ridker, P. M.
Affiliations: Brigham and Women's Hospital (US)
Corresponding author: Ridker, Paul M
ORCID: Ridker, Paul M
Venue: The Lancet
Publisher: Elsevier BV
Published: 2014-08
Volume: 384
Issue: 9943
Pages: 607-617
ISSN: 0099-5355 (ISSN-L)
0140-6736
DOI: 10.1016/s0140-6736(14)61009-6
OpenAlex: W2058652637
Cited by: 274
References: 104
Citations by year: 2026: 7 · 2025: 23 · 2024: 13 · 2023: 20 · 2022: 13 · 2021: 14 · 2020: 25 · 2019: 22 · 2018: 31 · 2017: 29 · 2016: 35 · 2015: 38 · 2014: 4
FWCI: 6.67
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: The Lancet (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords: LDL cholesterol, hyperlipidemia, statin therapy, LDL receptor, PCSK9 inhibitors, monoclonal antibodies, LDL cholesterol measurement, mass screening, treatment goals, cardiovascular risk, atherothrombotic complications
MeSH terms: Animals, Hypolipidemic Agents, Humans, Hypercholesterolemia, Cholesterol, LDL, Risk Factors, Risk Assessment, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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LDL cholesterol: controversies and future therapeutic directions

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