Review Article

Is a high concentration of high-density lipoprotein cholesterol still relevant?

Hanselim Hanselim

Hanselim Hanselim
Rumah Sakit Umum Daerah Abdoel Wahab Sjahranie, Samarinda, Kalimantan Timur, Indonesia. Email:
Online First: August 31, 2021 | Cite this Article
Hanselim, H. 2021. Is a high concentration of high-density lipoprotein cholesterol still relevant?. Intisari Sains Medis 12(2): 660-665. DOI:10.15562/ism.v12i2.1036

The importance of cholesterol management, particularly high-density lipoprotein (HDL) cholesterol, has always been believed to be essential in preventing and managing cardiovascular disease (CVD). While HDL has long been accepted as the 'good' cholesterol, various studies have started to challenge this paradigm. Most of these studies found that HDL cholesterol concentrations did not linearly translate into a reduction in CVD risk. There is a suspicion of dysfunctional HDL particles leading to the loss of HDL's cardioprotective function. Some of these dysfunctions were caused by changes in the structure of HDL particles due to an underlying disease or genetic mutations, causing defects in the reverse cholesterol transport (RCT) mechanism and vascular inflammation inhibition. Therefore, therapies that focus on these two mechanisms are expected to be one of the new cornerstones in reducing CVD. Simultaneously, cholesterol efflux capacity (CEC) assay could become the new therapeutic target as it has an inverse correlation with CVD risk regardless of HDL cholesterol concentration, increasing the accuracy in stratifying CVD risk in patients. However, standardization and a more thorough study on CEC assay and various subcellular cholesterol metabolism should be conducted before stepping further.


WHO CVD Risk Chart Working Group. World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health. 2019;7(10):e1332–45.

Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596–646. Available from:

Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020;41(1):111–88. Available from:

Huang Y-C, Lin C-Y, Lan C-C, Wu Y-K, Lim C-S, Huang C-Y, et al. Comparison of cardiovascular comorbidities and CPAP use in patients with positional and non-positional mild obstructive sleep apnea. BMC Pulm Med. 2014;14:153–153. Available from:

Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arterioscler Off J Am Heart Assoc Inc. 1988;8(6):737–41. Available from:

Ko DT, Alter DA, Guo H, Koh M, Lau G, Austin PC, et al. High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in Individuals Without Previous Cardiovascular Conditions. J Am Coll Cardiol. 2016;68(19):2073–83. Available from:

Nordestgaard BG, Madsen CM, Varbo A. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: Two prospective cohort studies. Atherosclerosis. 2017;263:e89. Available from:

Hirata A, Sugiyama D, Watanabe M, Tamakoshi A, Iso H, Kotani K, et al. Association of extremely high levels of high-density lipoprotein cholesterol with cardiovascular mortality in a pooled analysis of 9 cohort studies including 43,407 individuals: The EPOCH–JAPAN study. J Clin Lipidol. 2018;12(3):674-684.e5. Available from:

Li X, Guan B, Wang Y, Tse G, Zou F, Khalid BW, et al. Association between high-density lipoprotein cholesterol and all-cause mortality in the general population of northern China. Sci Rep. 2019;9(1):14426–14426. Available from:

Wang HH, Garruti G, Liu M, Portincasa P, Wang DQ-H. Cholesterol and Lipoprotein Metabolism and Atherosclerosis: Recent Advances in Reverse Cholesterol Transport. Ann Hepatol. 2017;16:S27–42. Available from:

Lüscher TF, Landmesser U, von Eckardstein A, Fogelman AM. High-Density Lipoprotein. Circ Res. 2014;114(1):171–82. Available from:

Davidson MH. Update on CETP inhibition. J Clin Lipidol. 2010;4(5):394–8. Available from:

Johns DG, Duffy J, Fisher T, Hubbard BK, Forrest MJ. On- and Off-Target Pharmacology of Torcetrapib. Drugs. 2012;72(4):491–507. Available from:

Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJP, Komajda M, et al. Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med. 2007;357(21):2109–22. Available from:

Clerc RG, Stauffer A, Weibel F, Hainaut E, Perez A, Hoflack J-C, et al. Mechanisms underlying off-target effects of the cholesteryl ester transfer protein inhibitor torcetrapib involve L-type calcium channels. J Hypertens. 2010;28(8):1676–86. Available from:

Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, et al. Effects of Dalcetrapib in Patients with a Recent Acute Coronary Syndrome. N Engl J Med. 2012;367(22):2089–99. Available from:

HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med. 2017;377(13):1217–27.

Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet Lond Engl. 2010/11/08 ed. 2010;376(9753):1670–81. Available from:

Barter PJ, Rye K-A. HDL cholesterol concentration or HDL function: which matters? Eur Heart J. 2017;38(32):2487–9. Available from:

Filippatos TD, Elisaf MS. High density lipoprotein and cardiovascular diseases. World J Cardiol. 2013;5(7):210–4. Available from:

Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor. Science. 1996;271(5248):518–20. Available from:

Samadi S, Farjami Z, Hosseini ZS, Ferns GA, Mohammadpour A hooshang, Tayefi M, et al. Rare P376L variant in the SR-BI gene associates with HDL dysfunction and risk of cardiovascular disease. Clin Biochem. 2019;73:44–9. Available from:

Zanoni P, Khetarpal SA, Larach DB, Hancock-Cerutti WF, Millar JS, Cuchel M, et al. Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease. Science. 2016;351(6278):1166–71. Available from:

Silbernagel G, Pagel P, Pfahlert V, Genser B, Scharnagl H, Kleber ME, et al. High-Density Lipoprotein Subclasses, Coronary Artery Disease, and Cardiovascular Mortality. Clin Chem. 2017;63(12):1886–96. Available from:

Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomization study. Lancet Lond Engl. 2012;380(9841):572–80.

Zhao H, Hu S, Rong J. Gene polymorphism associated with Angiotensinogen(M235T), Endothelial lipase (584C/T) and susceptibility to coronary artery disease: A meta-analysis. 2020; Available from:

Wang Q, Zhou S-B, Wang L-J, Lei M-M, Wang Y, Miao C, et al. Seven functional polymorphisms in the CETP gene and myocardial infarction risk: a meta-analysis and meta-regression. PloS One. 2014;9(2):e88118–e88118. Available from:

Riwanto M, Rohrer L, Roschitzki B, Besler C, Mocharla P, Mueller M, et al. Altered Activation of Endothelial Anti- and Proapoptotic Pathways by High-Density Lipoprotein from Patients with Coronary Artery Disease. Circulation. 2013;127(8):891–904. Available from:

Brinck JW, Thomas A, Lauer E, Jornayvaz FR, Brulhart-Meynet M-C, Prost J-C, et al. Diabetes Mellitus Is Associated With Reduced High-Density Lipoprotein Sphingosine-1-Phosphate Content and Impaired High-Density Lipoprotein Cardiac Cell Protection. Arterioscler Thromb Vasc Biol. 2016;36(5):817–24. Available from:

Morgantini C, Natali A, Boldrini B, Imaizumi S, Navab M, Fogelman AM, et al. Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes. Diabetes. 2011/08/18 ed. 2011;60(10):2617–23. Available from:

Tölle M, Huang T, Schuchardt M, Jankowski V, Prüfer N, Jankowski J, et al. High-density lipoprotein loses its anti-inflammatory capacity by accumulation of pro-inflammatory-serum amyloid A. Cardiovasc Res. 2012;94(1):154–62. Available from:

Levkau B. HDL-S1P: cardiovascular functions, disease-associated alterations, and therapeutic applications. Front Pharmacol. 2015;6:243–243. Available from:

Galvani S, Sanson M, Blaho VA, Swendeman SL, Obinata H, Conger H, et al. HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal. 2015;8(389):ra79–ra79. Available from:

Takaeko Y, Matsui S, Kajikawa M, Maruhashi T, Kishimoto S, Hashimoto H, et al. Association of extremely high levels of high-density lipoprotein cholesterol with endothelial dysfunction in men. J Clin Lipidol. 2019;13(4):664-672.e1. Available from:

Holzer M, Birner-Gruenberger R, Stojakovic T, El-Gamal D, Binder V, Wadsack C, et al. Uremia alters HDL composition and function. J Am Soc Nephrol JASN. 2011/07/29 ed. 2011;22(9):1631–41. Available from:

Mangaraj M, Nanda R, Panda S. Apolipoprotein A-I: A Molecule of Diverse Function. Indian J Clin Biochem IJCB. 2015/07/16 ed. 2016;31(3):253–9. Available from:

Fisher EA, Feig JE, Hewing B, Hazen SL, Smith JD. High-density lipoprotein function, dysfunction, and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2012;32(12):2813–20. Available from:

Vaisar T, Tang C, Babenko I, Hutchins P, Wimberger J, Suffredini AF, et al. Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity. J Lipid Res. 2015/05/20 ed. 2015;56(8):1519–30. Available from:

Anastasius M, Kockx M, Jessup W, Sullivan D, Rye K-A, Kritharides L. Cholesterol efflux capacity: An introduction for clinicians. Am Heart J. 2016;180:54–63. Available from:

Qiu C, Zhao X, Zhou Q, Zhang Z. High-density lipoprotein cholesterol efflux capacity is inversely associated with cardiovascular risk: a systematic review and meta-analysis. Lipids Health Dis. 2017;16(1):212–212. Available from:

Ritsch A, Duerr A, Kahler P, Hunjadi M, Stojakovic T, Silbernagel G, et al. Cholesterol Efflux Capacity and Cardiovascular Disease: The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Biomedicines. 2020;8(11):524. Available from:

Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014;371(25):2383–93.

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