Skip to main content
SpringerLink
Log in

HDL as a Treatment Target: Should We Abandon This Idea?

  • Review
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

High-density lipoproteins (HDL) have long been regarded as an antiatherogenic lipoprotein species by virtue of their role in reverse cholesterol transport (RCT), as well as their established anti-inflammatory and antioxidant properties. For decades, HDL have been an extremely appealing therapeutic target to combat atherosclerotic cardiovascular diseases (ASCVD).

Recent Findings

Unfortunately, neither increasing HDL with drugs nor direct infusions of reconstituted HDL have convincedly proven to be positive strategies for cardiovascular health, raising the question of whether we should abandon the idea of considering HDL as a treatment target.

Summary

The results of two large clinical trials, one testing the latest CETP inhibitor Obicetrapib and the other testing the infusion of patients post-acute coronary events with reconstituted HDL, are still awaited. If they prove negative, these trials will seal the fate of HDL as a direct therapeutic target. However, using HDL as a therapeutic agent still holds promise if we manage to optimize their beneficial properties for not only ASCVD but also outside the cardiovascular field.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Mahley RW, Innerarity TL, Rall SC, Weisgraber KH. Plasma lipoproteins: apolipoprotein structure and function. J Lipid Res. 1984;25:1277–94.

    Article  CAS  PubMed  Google Scholar 

  2. Rye K-A, Bursill CA, Lambert G, Tabet F, Barter PJ. The metabolism and anti-atherogenic properties of HDL. J Lipid Res. 2009;50:S195–200.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu Y, Xu Y, Chen J, Zhao M, Rye K-A. HDL and endothelial function. Adv Exp Med Biol. 2022;1377:27–47.

    Article  CAS  PubMed  Google Scholar 

  4. Wilson PW, Abbott RD, Castelli WP. High density lipoprotein cholesterol and mortality. The Framingham Heart Study. Arteriosclerosis. 1988;8:737–41.

    Article  CAS  PubMed  Google Scholar 

  5. Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The global burden of cardiovascular diseases and risk. J Am Coll Cardiol. 2022;80:2361–71.

    Article  PubMed  Google Scholar 

  6. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017;38:2478–86.

    Article  CAS  PubMed  Google Scholar 

  7. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375:2349–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1046–81.

    PubMed  Google Scholar 

  9. Muscella A, Stefàno E, Marsigliante S. The effects of exercise training on lipid metabolism and coronary heart disease. Am J Physiol Heart Circ Physiol. 2020;319:H76–88.

    Article  CAS  PubMed  Google Scholar 

  10. Santos HO, Lavie CJ. Weight loss and its influence on high-density lipoprotein cholesterol (HDL-C) concentrations: a noble clinical hesitation. Clin Nutr ESPEN. 2021;42:90–2.

    Article  PubMed  Google Scholar 

  11. 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 randomisation study. Lancet. 2012;380:572–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tan Y-D, Xiao P, Guda C. In-depth Mendelian randomization analysis of causal factors for coronary artery disease. Sci Rep. 2020;10:9208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Glomset JA, Janssen ET, Kennedy R, Dobbins J. Role of plasma lecithin:cholesterol acyltransferase in the metabolism of high density lipoproteins. J Lipid Res. 1966;7:639–48.

    Article  CAS  Google Scholar 

  14. Rader DJ, Hovingh GK. HDL and cardiovascular disease. Lancet. 2014;384:618–25.

    Article  CAS  PubMed  Google Scholar 

  15. Wang N, Silver DL, Thiele C, Tall AR. ATP-binding Cassette Transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J Biol Chem. 2001;276:23742–7.

    Article  CAS  PubMed  Google Scholar 

  16. Terasaka N, Yu S, Yvan-Charvet L, Wang N, Mzhavia N, Langlois R, et al. ABCG1 and HDL protect against endothelial dysfunction in mice fed a high-cholesterol diet. J Clin Invest. 2008;118:3701–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jonas A. Lecithin cholesterol acyltransferase. Biochim Biophys Acta-Mol Cell Biol Lipids. 2000;1529:245–56.

    Article  CAS  Google Scholar 

  18. Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, et al. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007;117:2216–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Settasatian N, Duong M, Curtiss LK, Ehnholm C, Jauhiainen M, Huuskonen J, et al. The mechanism of the remodeling of high density lipoproteins by phospholipid transfer protein. J Biol Chem. 2001;276:26898–905.

    Article  CAS  PubMed  Google Scholar 

  20. 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;271:518–20.

    Article  CAS  PubMed  Google Scholar 

  21. Martinez LO, Najib S, Perret B, Cabou C, Lichtenstein L. Ecto-F1-ATPase/P2Y pathways in metabolic and vascular functions of high density lipoproteins. Atherosclerosis. 2015;238:89–100.

    Article  CAS  PubMed  Google Scholar 

  22. Tall A. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993;34:1255–74.

    Article  CAS  PubMed  Google Scholar 

  23. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7:161–71.

    Article  CAS  PubMed  Google Scholar 

  24. Li AC, Glass CK. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res. 2004;45:2161–73.

    Article  CAS  PubMed  Google Scholar 

  25. Plump AS, Azrolan N, Odaka H, Wu L, Jiang X, Tall A, et al. ApoA-I knockout mice: characterization of HDL metabolism in homozygotes and identification of a post-RNA mechanism of apoA-I up-regulation in heterozygotes. J Lipid Res. 1997;38:1033–47.

    Article  CAS  PubMed  Google Scholar 

  26. Lambert G, Sakai N, Vaisman BL, Neufeld EB, Marteyn B, Chan CC, et al. Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice. J Biol Chem. 2001;276:15090–8.

    Article  CAS  PubMed  Google Scholar 

  27. Rigotti A, Trigatti BL, Penman M, Rayburn H, Herz J, Krieger M. A targeted mutation in the murine gene encoding the high density lipoprotein (HDL) receptor scavenger receptor class B type I reveals its key role in HDL metabolism. Proc Natl Acad Sci. 1997;94:12610–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Trigatti B, Rayburn H, Viñals M, Braun A, Miettinen H, Penman M, et al. Influence of the high density lipoprotein receptor SR-BI on reproductive and cardiovascular pathophysiology. Proc Natl Acad Sci. 1999;96:9322–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Marotti KR, Castle CK, Boyle TP, Lin AH, Murray RW, Melchior GW. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature. 1993;364:73–5.

    Article  CAS  PubMed  Google Scholar 

  30. Tanigawa H, Billheimer JT, Tohyama J, Zhang Y, Rothblat G, Rader DJ. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation. 2007;116:1267–73.

    Article  CAS  PubMed  Google Scholar 

  31. Mabuchi H, Haba T, Tatami R, Miyamoto S, Sakai Y, Wakasugi T, et al. Effects of an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase on serum lipoproteins and ubiquinone-10 levels in patients with familial hypercholesterolemia. N Engl J Med. 1981;305:478–82.

    Article  CAS  PubMed  Google Scholar 

  32. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.

    Article  CAS  PubMed  Google Scholar 

  33. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.

    Article  CAS  PubMed  Google Scholar 

  34. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.

    Article  CAS  PubMed  Google Scholar 

  35. Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL, Goldstein LB, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39:e38–81.

    Article  CAS  PubMed  Google Scholar 

  36. Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353–64.

    Article  PubMed  Google Scholar 

  37. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys. 1955;54:558–9.

    Article  CAS  PubMed  Google Scholar 

  38. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67.

    Article  Google Scholar 

  39. The HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients. N Engl J Med. 2014;371:203–12.

    Article  Google Scholar 

  40. Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P, et al. Helsinki heart study: primary-prevention trial with Gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med. 1987;317:1237–45.

    Article  CAS  PubMed  Google Scholar 

  41. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. N Engl J Med. 1999;341:410–8.

    Article  CAS  PubMed  Google Scholar 

  42. The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation. 2000;102:21–7.

    Article  Google Scholar 

  43. Tenenbaum A, Motro M, Fisman EZ, Tanne D, Boyko V, Behar S. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med. 2005;165:1154–60.

    Article  CAS  PubMed  Google Scholar 

  44. The FIELD study. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–61.

    Article  Google Scholar 

  45. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–74.

    Article  PubMed Central  Google Scholar 

  46. Das Pradhan A, Glynn RJ, Fruchart J-C, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med. 2022;387:1923–34.

    Article  PubMed  Google Scholar 

  47. Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547–58.

    Article  CAS  PubMed  Google Scholar 

  48. Silverman MG, Ference BA, Im K, Wiviott SD, Giugliano RP, Grundy SM, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316:1289–97.

    Article  CAS  PubMed  Google Scholar 

  49. Barter PJ, Hopkins GJ, Calvert GD. Transfers and exchanges of esterified cholesterol between plasma lipoproteins. Biochem J. 1982;208:1–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Inazu A, Brown ML, Hesler CB, Agellon LB, Koizumi J, Takata K, et al. Increased high-density lipoprotein levels caused by a common cholesteryl-ester transfer protein gene mutation. N Engl J Med. 1990;323:1234–8.

    Article  CAS  PubMed  Google Scholar 

  51. 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;357:2109–22.

    Article  CAS  PubMed  Google Scholar 

  52. 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;367:2089–99.

    Article  CAS  PubMed  Google Scholar 

  53. Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med. 2010;363:2406–15.

    Article  CAS  PubMed  Google Scholar 

  54. The 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;377:1217–27.

    Article  Google Scholar 

  55. Lincoff AM, Nicholls SJ, Riesmeyer JS, Barter PJ, Brewer HB, Fox KAA, et al. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933–42.

    Article  PubMed  Google Scholar 

  56. Nicholls SJ, Ditmarsch M, Kastelein JJ, Rigby SP, Kling D, Curcio DL, et al. Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial. Nat Med. 2022;28:1672–8. This phase 2 trial demonstrates the safety and efficacy of obicetrapib on top of statins in lowering atherogenic lipoproteins and apoB and increasing HDL and ApoA1, paving the way for a phase 3 trial to assess the potential clinical benefits of this novel CETP inhibitor.

    Article  CAS  PubMed  Google Scholar 

  57. Sacks FM, Rudel LL, Conner A, Akeefe H, Kostner G, Baki T, et al. Selective delipidation of plasma HDL enhances reverse cholesterol transport in vivo. J Lipid Res. 2009;50:894–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Waksman R, Torguson R, Kent KM, Pichard AD, Suddath WO, Satler LF, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol. 2010;55:2727–35.

    Article  PubMed  Google Scholar 

  59. Wolska A, Reimund M, Sviridov DO, Amar MJ, Remaley AT. Apolipoprotein mimetic peptides: potential new therapies for cardiovascular diseases. Cells. 2021;10:597. An excellent and comprehensive review on the potential of apolipoproteins mimetic peptides in cardiovascular health and beyond.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Di Bartolo BA, Cartland SP, Genner S, Manuneedhi Cholan P, Vellozzi M, Rye K-A, et al. HDL improves cholesterol and glucose homeostasis and reduces atherosclerosis in diabetes-associated atherosclerosis. J Diabetes Res. 2021;2021:e6668506.

    Article  Google Scholar 

  61. Tardif J-C, Ballantyne CM, Barter P, Dasseux J-L, Fayad ZA, Guertin M-C, et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J. 2014;35:3277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290:2292–300.

    Article  CAS  PubMed  Google Scholar 

  63. Nicholls SJ, Andrews J, Kastelein JJP, Merkely B, Nissen SE, Ray KK, et al. Effect of Serial infusions of CER-001, a Pre-β high-density lipoprotein mimetic, on coronary atherosclerosis in patients following acute coronary syndromes in the CER-001 atherosclerosis regression acute coronary syndrome trial: a randomized clinical trial. JAMA Cardiol. 2018;3:815. This clinical trial shows that infusions of reconstituted HDL do not promote regression of coronary atherosclerosis in statin-treated patients with ACS and high plaque burden.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Tardif J-C, Grégoire J, L’Allier PL, Ibrahim R, Lespérance J, Heinonen TM, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA. 2007;297:1675–82.

    Article  PubMed  Google Scholar 

  65. Lee JJ, Chi G, Fitzgerald C, Kazmi SHA, Kalayci A, Korjian S, et al. Cholesterol efflux capacity and its association with adverse cardiovascular events: a systematic review and meta-analysis. Front Cardiovasc Med. 2021;8:774418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Nelson AJ, Sniderman AD, Ditmarsch M, Dicklin MR, Nicholls SJ, Davidson MH, et al. Cholesteryl ester transfer protein inhibition reduces major adverse cardiovascular events by lowering apolipoprotein B levels. Int J Mol Sci. 2022;23:9417. A solid demonstration that the potential cardiovascular benefits of CETP inhibitors are caused by the reduction in atherogenic lipoproteins rather than an elevation in HDL concentrations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tanaka S, Begue F, Veeren B, Tran-Dinh A, Robert T, Tashk P, et al. First recombinant high-density lipoprotein particles administration in a severe ICU COVID-19 patient, a multi-omics exploratory investigation. Biomedicines. 2022;10:754.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tanaka S, Couret D, Tran-Dinh A, Duranteau J, Montravers P, Schwendeman A, et al. High-density lipoproteins during sepsis: from bench to bedside. Crit Care. 2020;24:134.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

FB is the recipient of a PhD fellowship awarded by the Région Réunion and funded by the European Union (Brussels, Belgium). MLA is the laureate of a PhD scholarship awarded by the Université de La Réunion and funded by the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche (Paris, France).

Author information

Author notes

  1. Floran Begue and Marie Laurine Apalama contributed equally to this work.

Authors and Affiliations

  1. Inserm, UMR 1188 Diabète Athérothrombose Thérapies Réunion Océan Indien (DéTROI), Université de La Réunion, 97410, Saint-Pierre, France

    Floran Begue, Marie Laurine Apalama, Gilles Lambert & Olivier Meilhac

  2. CHU de La Réunion, 97400, Saint-Denis, France

    Olivier Meilhac

Authors
  1. Floran Begue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marie Laurine Apalama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gilles Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Olivier Meilhac
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gilles Lambert.

Ethics declarations

Conflict of Interest

The authors declare no competing interests.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Begue, F., Apalama, M.L., Lambert, G. et al. HDL as a Treatment Target: Should We Abandon This Idea?. Curr Atheroscler Rep 25, 1093–1099 (2023). https://doi.org/10.1007/s11883-023-01176-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11883-023-01176-1

Keywords

Search

Navigation