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Low HDL-The Challenge.

Authors: Shereif H Rezkalla|||Robert A Kloner

Journal: Clinical medicine & research

Publication Type: Journal Article

Date: 2025

DOI: PMC12352915

ID: 40813253

Affiliations:

Affiliations

    Emeritus Physician, Marshfield Clinic Health System, 1000 North Oak Avenue, Marshfield, WI 54449, and Adjunct Professor of Medicine, University of Wisconsin, School of Medicine; E-mail: rezkalla.shereif@marshfieldclinic.org rezkalla.shereif@marshfieldclinic.org.|||Chief Science Officer, Scientific Director of Cardiovascular Research Institute, Huntington Medical Research Institutes, Pasadena, CA; and Professor of Medicine (Clinical Scholar), Cardiovascular Division, Dept. of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA; Email: robert.kloner@hmri.org.

Abstract

The main function of high-density lipoprotein (HDL) is to remove low-density lipoprotein (LDL) from blood vessels through reverse cholesterol transport. In addition, HDL has anti-inflammatory and antioxidant properties. Low HDL level is an independent risk factor for development of coronary artery disease. To manage patients with low HDL levels, general measures such as lifestyle modification, controlling acute metabolic syndrome, and participating in regular endurance exercise are essential. Smoking cessation is a must, and it will often improve HDL levels by 5% to 10%. While statin therapy is the backbone therapy for controlling LDL levels, it also results in elevation of HDL levels by at least 5%. Specific pharmacologic interventions to improve HDL level and function have been disappointing. Cholesteryl ester transfer protein (CETP) is the key metabolic pathway to transfer HDL to LDL; thus, CETP inhibitors result in elevation of HDL levels. Several products were tested in large controlled studies, such as dalcetrapib and evacetrapib; neither resulted in any clinical benefit. Anacetrapib only resulted in very limited benefit and is no longer under active development. The most recent study utilized apolipoprotein A1 infusion in high-risk patients shortly after acute myocardial infarction. There was no benefit in the primary end point of myocardial infarction, stroke, or death. In patients with low HDL, a strategy of having LDL as low as can be possibly achieved may be the most appropriate approach.


Chemical List

    Cholesterol Ester Transfer Proteins|||Lipoproteins, HDL|||Anticholesteremic Agents|||Cholesterol, HDL|||Hydroxymethylglutaryl-CoA Reductase Inhibitors

Reference List

    Kuijpers PMJC. History in medicine: the story of cholesterol, lipids and cardiology. European Society of Cardiology. E-Journal of Cardiology Practice. 2021;19(9). https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-19/history-in-medicine-the-story-of-cholesterol-lipids-and-cardiology|||McGill HC Jr. The relationship of dietary cholesterol to serum cholesterol concentration and to atherosclerosis in man. Am J Clin Nutr. 1979;32(12 Suppl):2664-2702. doi: 10.1093/ajcn/32.12.2664|||Andersson C, Johnson AD, Benjamin EJ, Levy D, Vasan RS.. 70-year legacy of the Framingham Heart Study. Nat Rev Cardiol. 2019;16(11):687-698. doi: 10.1038/s41569-019-0202-5|||Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J 3rd.. Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:33-50. doi: 10.7326/0003-4819-55-1-33|||Walton KW. Hyperlipidaemia and the pathogenesis of atherosclerosis. Adv Drug Res. 1974;9:55-67.|||Goldstein JL, Brown MS.. The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977;46:897-930. doi: 10.1146/annurev.bi.46.070177.004341|||Vergeer M, Holleboom AG, Kastelein JJ, Kuivenhoven JA.. The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?. J Lipid Res. 2010;51(8):2058-2073. doi: 10.1194/jlr.R001610|||Berger GM. High-density lipoproteins in the prevention of atherosclerotic heart disease. Part I. Epidemiological and family studies. S Afr Med J. 1978;54(17):689-693.|||Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335(14):1001-1009. doi: 10.1056/NEJM199610033351401|||Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group . Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339(19):1349-1357. doi: 10.1056/NEJM199811053391902|||Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes [published correction appears in N Engl J Med. 2006 Feb 16;354(7):778]. N Engl J Med. 2004;350(15):1495-1504. doi: 10.1056/NEJMoa040583|||Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387-2397. doi: 10.1056/NEJMoa1410489|||Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713-1722. doi: 10.1056/NEJMoa1615664|||Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 2018;379(22):2097-2107. doi: 10.1056/NEJMoa1801174|||Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med. 2017;376(15):1430-1440. doi: 10.1056/NEJMoa1615758|||Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. doi: 10.1056/NEJMoa1913805|||Blumenthal RS, Shay Martin S.. Bempedoic acid for LDL-C lowering: what do we know? American College of Cardiology. August 10, 2020. Available at: https://www.acc.org/Latest-in-Cardiology/Articles/2020/08/10/08/21/Bempedoic-Acid-for-LDL-C-Lowering. Accessed 9/30/2024.|||von Eckardstein A, Nordestgaard BG, Remaley AT, Catapano AL.. High-density lipoprotein revisited: biological functions and clinical relevance. Eur Heart J. 2023;44(16):1394-1407. doi: 10.1093/eurheartj/ehac605|||Bonilha I, Luchiari B, Nadruz W, Sposito AC.. Very low HDL levels: clinical assessment and management. Arch Endocrinol Metab. 2023;67(1):3-18. doi: 10.20945/2359-3997000000585|||Sposito AC. HDL metrics, let’s call the number thing off?. Atherosclerosis. 2016;251:525-527. doi: 10.1016/j.atherosclerosis.2016.06.044|||Rothblat GH, Phillips MC.. High-density lipoprotein heterogeneity and function in reverse cholesterol transport. Curr Opin Lipidol. 2010;21(3):229-238. doi: 10.1097/mol.0b013e328338472d|||Chen XF, Xiang YF, Cai XL, et al. A V-shaped association between high-density lipoprotein cholesterol levels and poor outcomes in patients after percutaneous coronary intervention. Int J Cardiol. 2024;400:131773. doi: 10.1016/j.ijcard.2024.131773|||Zakai NA, Minnier J, Safford MM, et al. Race-Dependent Association of High-Density Lipoprotein Cholesterol Levels With Incident Coronary Artery Disease. J Am Coll Cardiol. 2022;80(22):2104-2115. doi: 10.1016/j.jacc.2022.09.027|||Ayyobi AF, McGladdery SH, Chan S, John Mancini GB, Hill JS, Frohlich JJ.. Lecithin: cholesterol acyltransferase (LCAT) deficiency and risk of vascular disease: 25 year follow-up. Atherosclerosis. 2004;177(2):361-366. doi: 10.1016/j.atherosclerosis.2004.07.018|||Pirillo A, Norata GD, Catapano AL.. High-density lipoprotein subfractions--what the clinicians need to know. Cardiology. 2013;124(2):116-125. doi: 10.1159/000346463|||González-Pacheco H, Amezcua-Guerra LM, Vazquez-Rangel A, et al. Levels of High-Density Lipoprotein Cholesterol are Associated With Biomarkers of Inflammation in Patients With Acute Coronary Syndrome. Am J Cardiol. 2015;116(11):1651-1657. doi: 10.1016/j.amjcard.2015.09.009|||Kontush A, Chapman MJ.. Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities. Curr Opin Lipidol. 2010;21(4):312-318. doi: 10.1097/MOL.0b013e32833bcdc1|||Mazidi M, Mikhailidis DP, Banach M.. Associations between risk of overall mortality, cause-specific mortality and level of inflammatory factors with extremely low and high high-density lipoprotein cholesterol levels among American adults. Int J Cardiol. 2019;276:242-247. doi: 10.1016/j.ijcard.2018.11.095|||Couillard C, Després JP, Lamarche B, et al. Effects of endurance exercise training on plasma HDL cholesterol levels depend on levels of triglycerides: evidence from men of the Health, Risk Factors, Exercise Training and Genetics (HERITAGE) Family Study. Arterioscler Thromb Vasc Biol. 2001;21(7):1226-1232. doi: 10.1161/hq0701.092137|||Kodama S, Tanaka S, Saito K, et al. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis. Arch Intern Med. 2007;167(10):999-1008. doi: 10.1001/archinte.167.10.999|||Ruiz-Ramie JJ, Barber JL, Sarzynski MA.. Effects of exercise on HDL functionality. Curr Opin Lipidol. 2019;30(1):16-23. doi: 10.1097/MOL.0000000000000568|||De Oliveira E Silva ER, Foster D, McGee Harper M, et al. Alcohol consumption raises HDL cholesterol levels by increasing the transport rate of apolipoproteins A-I and A-II. Circulation. 2000;102(19):2347-2352. doi: 10.1161/01.cir.102.19.2347|||Clofibrate and niacin in coronary heart disease. JAMA. 1975;231(4):360-381.|||AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy [published correction appears in N Engl J Med. 2012 Jul 12;367(2):189]. N Engl J Med. 2011;365(24):2255-2267. doi: 10.1056/NEJMoa1107579|||McTaggart F, Jones P.. Effects of statins on high-density lipoproteins: a potential contribution to cardiovascular benefit. Cardiovasc Drugs Ther. 2008;22(4):321-338. doi: 10.1007/s10557-008-6113-z|||Jones PH, Davidson MH, Stein EA, et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92(2):152-160. doi: 10.1016/s0002-9149(03)00530-7|||Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ.. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database. J Lipid Res. 2010;51(6):1546-1553. doi: 10.1194/jlr.P002816|||Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089-2099. doi: 10.1056/NEJMoa1206797|||Lincoff AM, Nicholls SJ, Riesmeyer JS, et al. Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. N Engl J Med. 2017;376(20):1933-1942. doi: 10.1056/NEJMoa1609581|||HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC, et al. Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease. N Engl J Med. 2017;377(13):1217-1227. doi: 10.1056/NEJMoa1706444|||Gibson CM, Duffy D, Korjian S, et al. Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction. N Engl J Med. 2024;390(17):1560-1571. doi: 10.1056/NEJMoa2400969|||Szarek M, Bhatt DL, Miller M, et al. Lipoprotein(a) Blood Levels and Cardiovascular Risk Reduction With Icosapent Ethyl. J Am Coll Cardiol. 2024;83(16):1529-1539. doi: 10.1016/j.jacc.2024.02.016