Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Spotlight on HDL-raising therapies: insights from the torcetrapib trials

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 329–336 (2008)Cite this article

Abstract

Subnormal levels of HDL cholesterol constitute a major cardiovascular risk factor. Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent HDL-raising agents. Torcetrapib was the first CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial, which was prematurely terminated in December 2006 because of excess cardiovascular and noncardiovascular mortality in the active treatment group. Therapy with torcetrapib was associated with considerable increases in aldosterone level and blood pressure and changes in serum electrolytes indicative of mineralocorticoid excess. These findings indicate that torcetrapib has off-target toxic effects unrelated to HDL raising that involve the activation of mineralocorticoid receptors by aldosterone and result in the induction of hypertension. In contrast with torcetrapib, other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation which discounts a class effect. The available data do not, however, exclude potential adverse effects of CETP inhibition such as the generation of HDL particles that have deficient biological activities and a deleterious impact on reverse cholesterol transport and steroid metabolism. Normalization of both defective HDL function and diminished HDL levels should, therefore, be the focus of pharmacological HDL raising in future studies.

Key Points

  • Inhibitors of cholesteryl ester transfer protein (CETP) are presently the most potent agents for raising HDL cholesterol

  • Torcetrapib, the first CETP inhibitor to enter a large-scale, prospective, placebo-controlled interventional trial (ILLUMINATE), was associated with excess cardiovascular and noncardiovascular mortality in the active-treatment group

  • Torcetrapib treatment resulted in significantly increased aldosterone levels, altered serum electrolytes indicative of mineralocorticoid excess, and elevated blood pressure, indicating an off-target mechanism of torcetrapib-related toxic effects involving activation of mineralocorticoid receptors by aldosterone with subsequent induction of hypertension

  • Other CETP inhibitors such as JTT-705 and MK-825 do not increase blood pressure in humans, an observation that tends to discount a class effect

  • Potential adverse effects of CETP inhibition cannot, however, be excluded; CETP inhibition could result in the generation of HDL particles that have deficient antiatherogenic activities and a deleterious impact on reverse cholesterol transport and steroid metabolism

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Intravascular HDL metabolism and potential targets for therapeutic normalization of abnormal metabolism and deficient biological activities of HDL.

Similar content being viewed by others

References

  1. Chapman MJ (2005) Beyond LDL-cholesterol reduction: the way ahead in managing dyslipidaemia. Eur Heart J Suppl 7: F56–F62

    Article  CAS  Google Scholar 

  2. Yusuf S et al.; INTERHEART Study Investigators (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet 364: 937–952

    Article  Google Scholar 

  3. Barter P et al.; Treating to New Targets Investigators (2007) HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 357: 1301–1310

    Article  CAS  Google Scholar 

  4. Dullens SP et al. (2007) Increasing apoA-I production as a target for CHD risk reduction. Nutr Metab Cardiovasc Dis 17: 616–628

    Article  CAS  Google Scholar 

  5. Kontush A and Chapman MJ (2006) Functionally defective HDL: a new therapeutic target at the crossroads of dyslipidemia, inflammation and atherosclerosis. Pharmacol Rev 3: 342–374

    Article  Google Scholar 

  6. Kontush A and Chapman MJ (2006) Antiatherogenic small, dense HDL—guardian angel of the arterial wall? Nat Clin Pract Cardiovasc Med 3: 144–153

    Article  CAS  Google Scholar 

  7. Ansell BJ et al. (2007) The paradox of dysfunctional high-density lipoprotein. Curr Opin Lipidol 18: 427–434

    Article  CAS  Google Scholar 

  8. Navab M et al. (2006) Potential clinical utility of high-density lipoprotein-mimetic peptides. Curr Opin Lipidol 17: 440–444

    Article  CAS  Google Scholar 

  9. Shah PK (2007) High-density lipoprotein mimetics: focus on synthetic high-density lipoprotein. Am J Cardiol 100: S62–S67

    Article  Google Scholar 

  10. Barter PJ and Kastelein JJ (2006) Targeting cholesteryl ester transfer protein for the prevention and management of cardiovascular disease. J Am Coll Cardiol 47: 492–499

    Article  CAS  Google Scholar 

  11. Lewis GF and Rader DJ (2005) New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 96: 1221–1232

    Article  CAS  Google Scholar 

  12. Barter PJ et al.; ILLUMINATE Investigators (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357: 2109–2122

    Article  CAS  Google Scholar 

  13. Chapman MJ (2006) Therapeutic elevation of HDL-cholesterol to prevent atherosclerosis and coronary heart disease. Pharmacol Ther 111: 893–908

    Article  CAS  Google Scholar 

  14. Rader DJ (2007) Illuminating HDL—is it still a viable therapeutic target? N Engl J Med 357: 2180–2183

    Article  CAS  Google Scholar 

  15. Guérin M et al. (1994) Preferential cholesteryl ester acceptors among the LDL subspecies of subjects with familial hypercholesterolemia. Arterioscler Thromb 14: 679–685

    Article  Google Scholar 

  16. Millar JS et al. (2006) Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on apolipoprotein B100 metabolism in humans. Arterioscler Thromb Vasc Biol 26: 1350–1356

    Article  CAS  Google Scholar 

  17. Guérin M et al. (2008) Inhibition of CETP by torcetrapib attenuates the atherogenicity of postprandial TG-rich lipoproteins in type IIB hyperlipidemia. Arterioscler Thromb Vasc Biol 28: 148–154

    Article  Google Scholar 

  18. Brousseau ME et al. (2005) Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol 25: 1057–1064

    Article  CAS  Google Scholar 

  19. Yvan-Charvet L et al. (2007) Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 27: 1132–1138

    Article  CAS  Google Scholar 

  20. Thuahnai ST et al. (2004) Scavenger receptor class B type I-mediated cholesteryl ester-selective uptake and efflux of unesterified cholesterol: influence of high density lipoprotein size and structure. J Biol Chem 279: 12448–12455

    Article  CAS  Google Scholar 

  21. Rhainds D et al. (2003) The role of human and mouse hepatic scavenger receptor class B type I (SR-BI) in the selective uptake of low-density lipoprotein-cholesteryl esters. Biochemistry 42: 7527–7538

    Article  CAS  Google Scholar 

  22. Greene DJ et al. (2001) Elevated triglyceride content diminishes the capacity of high density lipoprotein to deliver cholesteryl esters via the scavenger receptor class B type I (SR-BI). J Biol Chem 276: 4804–4811

    Article  CAS  Google Scholar 

  23. Kastelein JJ et al.; RADIANCE 1 Investigators (2007) Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 356: 1620–1630

    Article  CAS  Google Scholar 

  24. Nissen SE et al.; ILLUSTRATE Investigators (2007) Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 356: 1304–1316

    Article  CAS  Google Scholar 

  25. Nicholls SJ et al. (2007) Changes in levels of high density lipoprotein cholesterol predict the impact of torcetrapib on progression of coronary atherosclerosis: insights from ILLUSTRATE [abstract 684]. Circulation 116 (Suppl 16): II–127

    Google Scholar 

  26. Zilversmit DB (1979) Atherogenesis: a postprandial phenomenon. Circulation 60: 473–485

    Article  CAS  Google Scholar 

  27. Cohn JS et al. (1999) Detection, quantification, and characterization of potentially atherogenic triglyceride-rich remnant lipoproteins. Arterioscler Thromb Vasc Biol 19: 2474–2486

    Article  CAS  Google Scholar 

  28. Guérin M et al. (2002) Cholesteryl ester flux from HDL to VLDL-1 is preferentially enhanced in type IIB hyperlipidemia in the postprandial state. J Lipid Res 43: 1652–1660

    Article  Google Scholar 

  29. Vaisar T et al. (2007) Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 117: 746–756

    Article  CAS  Google Scholar 

  30. Genest J (2008) The yin and yang of high-density lipoprotein cholesterol. J Am Coll Cardiol 51: 643–644

    Article  Google Scholar 

  31. Krishna R et al. (2007) Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 370: 1907–1914

    Article  CAS  Google Scholar 

  32. van der Steeg WA et al. (2007) Role of the apolipoprotein B-apolipoprotein A-I ratio in cardiovascular risk assessment: a case-control analysis in EPIC-Norfolk. Ann Intern Med 146: 640–648

    Article  Google Scholar 

  33. Walldius G and Jungner I (2007) Apolipoprotein A-I versus HDL cholesterol in the prediction of risk for myocardial infarction and stroke. Curr Opin Cardiol 22: 359–367

    Article  Google Scholar 

  34. Ingelsson E et al. (2007) Clinical utility of different lipid measures for prediction of coronary heart disease in men and women. JAMA 298: 776–785

    Article  CAS  Google Scholar 

  35. Watson KE et al. (2007) HDL function as a target of lipid-modifying therapy. Rev Cardiovasc Med 8: 1–8

    Article  Google Scholar 

  36. Kontush A and Chapman MJ (2008) Why is HDL functionally deficient in Type 2 diabetes? Curr Diabetes Rep 8: 51–59

    Article  CAS  Google Scholar 

  37. Lai E et al. (2007) Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther 81: 849–857

    Article  CAS  Google Scholar 

  38. Kamanna VS and Kashyap ML (2007) Nicotinic acid (niacin) receptor agonists: will they be useful therapeutic agents? Am J Cardiol 100: S53–S61

    Article  Google Scholar 

  39. Sviridov D et al. (2007) Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin. Atherosclerosis [10.1016/j.atherosclerosis.2007.07.007]

  40. Charles-Schoeman C et al. (2007) Effects of high-dose atorvastatin on antiinflammatory properties of high density lipoprotein in patients with rheumatoid arthritis: a pilot study. J Rheumatol 34: 1459–1464

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

  1. A Kontush is a Research Director, M Guérin is a Senior Investigator, and MJ Chapman is Director, in the Dyslipidemia and Atherosclerosis Research Unit (UMR S.551) of the National Institute of Health and Medical Research (INSERM) at the Hôpital de la Pitié, and Université Pierre et Marie Curie, Paris, France.,

    Anatol Kontush, Maryse Guérin & M John Chapman

Authors
  1. Anatol Kontush
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maryse Guérin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M John Chapman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anatol Kontush.

Ethics declarations

Competing interests

Anatol Kontush has been a consultant for, and has received speaker honoraria and grant/research support from Pfizer.

Maryse Guérin has received grant/research support from Pfizer.

M John Chapman has been a consultant for, and has received speaker honoraria and grant/research support from Pfizer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kontush, A., Guérin, M. & Chapman, M. Spotlight on HDL-raising therapies: insights from the torcetrapib trials. Nat Rev Cardiol 5, 329–336 (2008). https://doi.org/10.1038/ncpcardio1191

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1191

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing