Abstract
The HDL hypothesis has suffered damage in the past few years. Clinical trials have shown that raising HDL cholesterol levels does not improve cardiovascular disease (CVD) outcomes. In addition, Mendelian randomization studies have shown that DNA variants that alter HDL cholesterol levels in populations are unrelated to incident CVD events. Balancing this deluge of negative data are substantial basic science data supporting the concept that raising HDL cholesterol levels reduces CVD risk. Also, functionally relevant HDL subfractions might be more important determinants of risk than overall HDL cholesterol levels. But, while wobbly, the HDL hypothesis is still standing, seemingly too big to fail owing to past intellectual, economic and psychological investments in the idea.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Friedewald, V. E. Jr, Ballantyne, C. M., Davidson, M. H., Guyton, J. R. & Roberts, W. C. The editor's roundtable: lipid management beyond statins—reducing residual cardiovascular risk. Am. J. Cardiol 102, 559–567 (2008).
Brewer, H. B. Jr. Clinical review: The evolving role of HDL in the treatment of high-risk patients with cardiovascular disease. J. Clin. Endocrinol. Metab. 96, 1246–1257 (2011).
Barter, P. HDL-C: role as a risk modifier. Atheroscler. Suppl. 12, 267–270 (2011).
Emerging Risk Factors Collaboration et al. Lipid-related markers and cardiovascular disease prediction. JAMA 307, 2499–2506 (2012).
Barter, P. et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N. Engl. J. Med. 357, 1301–1310 (2007).
Rosenson, R. S. et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 125, 1905–1919 (2012).
Alwaili, K., Awan, Z., Alshahrani, A. & Genest, J. High-density lipoproteins and cardiovascular disease: 2010 update. Expert Rev. Cardiovasc. Ther. 8, 413–423 (2010).
Vucic, E. & Rosenson, R. S. Recombinant high-density lipoprotein formulations. Curr. Atheroscler Rep. 13, 81–87 (2011).
Tabet, F. & Rye, K. A. High-density lipoproteins, inflammation and oxidative stress. Clin. Sci. (Lond.) 116, 87–98 (2009).
Joy, T. & Hegele, R. A. Is raising HDL a futile strategy for atheroprotection? Nat. Rev. Drug Discov. 7, 143–155 (2008).
Duffy, D. & Rader, D. J. Update on strategies to increase HDL quantity and function. Nat. Rev. Cardiol. 6, 455–463 (2009).
Asztalos, B. F., Tani, M. & Schaefer, E. J. Metabolic and functional relevance of HDL subspecies. Curr. Opin. Lipidol. 22, 176–185 (2011).
Vaisar, T. et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J. Clin. Invest. 117, 746–756 (2007).
Mackness, B. & Mackness, M. Anti-inflammatory properties of paraoxonase-1 in atherosclerosis. Adv. Exp. Med. Biol. 660, 143–151 (2010).
Soran, H., Hama, S., Yadav, R. & Durrington, P. N. HDL functionality. Curr. Opin. Lipidol. 23, 353–366 (2012).
Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).
de la Llera-Moya, M. et al. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler. Thromb. Vasc. Biol. 30, 796–801 (2010).
Degoma, E. M. & Rader, D. J. Novel HDL-directed pharmacotherapeutic strategies. Nat. Rev. Cardiol. 8, 266–277 (2011).
Tardif, J. C., Heinonen, T. & Noble, S. High-density lipoprotein/apolipoprotein A-I infusion therapy. Curr. Atheroscler. Rep. 11, 58–63 (2009).
Calabresi, L., Simonelli, S., Gomaraschi, M. & Franceschini, G. Genetic lecithin: cholesterol acyltransferase deficiency and cardiovascular disease. Atherosclerosis 222, 299–306 (2012).
Iatan, I., Palmyre, A., Alrasheed, S., Ruel, I. & Genest, J. Genetics of cholesterol efflux. Curr. Atheroscler. Rep. 14, 235–246 (2012).
Ng, D. S. et al. Apolipoprotein A-I deficiency. Biochemical and metabolic characteristics. Arterioscler. Thromb. Vasc Biol. 15, 2157–2164 (1995).
Tietjen, I. et al. Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT. Biochim. Biophys. Acta 1821, 416–424 (2012).
Oliveira, H. C. & de Faria, E. C. Cholesteryl ester transfer protein: the controversial relation to atherosclerosis and emerging new biological roles. IUBMB Life 63, 248–257 (2011).
Vergeer, M. et al. Genetic variant of the scavenger receptor BI in humans. N. Engl. J. Med. 364, 136–145 (2011).
Hegele, R. A. et al. Hepatic lipase deficiency. Clinical, biochemical, and molecular genetic characteristics. Arterioscler. Thromb. 13, 720–728 (1993).
Frikke-Schmidt, R. et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. JAMA 299, 2524–2532 (2008).
Johannsen, T. H. et al. Hepatic lipase, genetically elevated high-density lipoprotein, and risk of ischemic cardiovascular disease. J. Clin. Endocrinol. Metab. 94, 1264–1273 (2009).
Haase, C. L. et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J. Clin. Endocrinol. Metab. 97, E248–E256 (2012).
Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380, 572–580 (2012).
Canner, P. L. et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J. Am. Coll. Cardiol. 8, 1245–1255 (1986).
Frick, M. H. et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N. Engl. J. Med. 317, 1237–1245 (1987).
Rubins, H. B. et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med. 341, 410–418 (1999).
ACCORD Study Group et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).
AIM-HIGH Investigators et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365, 2255–2267 (2011).
Goldenberg, I. et al. Long-term benefit of high-density lipoprotein cholesterol-raising therapy with bezafibrate: 16-year mortality follow-up of the bezafibrate infarction prevention trial. Arch. Intern. Med. 169, 508–514 (2009).
Jun, M. et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 375, 1875–1884 (2010).
Merck. Merck announces HPS2-THRIVE study of Tredaptive™ (Extended-Release Niacin/Laropiprant) did not achieve primary endpoint [online] (2012).
Tall, A. R., Yvan-Charvet, L., Terasaka, N., Pagler, T. & Wang, N. HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis. Cell Metab. 7, 365–375 (2008).
Hewing, B. & Fisher, E. A. Rationale for cholesteryl ester transfer protein inhibition. Curr. Opin. Lipidol. 23, 372–376 (2012).
Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).
Hu, X. et al. Torcetrapib induces aldosterone and cortisol production by an intracellular calcium-mediated mechanism independently of cholesteryl ester transfer protein inhibition. Endocrinology 150, 2211–2219 (2009).
Nissen, S. E. et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304–1316 (2007).
Vergeer, M. et al. Cholesteryl ester transfer protein inhibitor torcetrapib and off-target toxicity: a pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials. Circulation 118, 2515–2522 (2008).
Nicholls, S. J., Tuzcu, E. M., Brennan, D. M., Tardif, J. C. & Nissen, S. E. Cholesteryl ester transfer protein inhibition, high-density lipoprotein raising, and progression of coronary atherosclerosis: insights from ILLUSTRATE (Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation). Circulation 118, 2506–2514 (2008).
Barter, P. J. & Rye, K. A. Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J. Lipid Res. 53, 1755–1766 (2012).
Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).
Hooper, A. J. & Burnett, J. R. Dalcetrapib, a cholesteryl ester transfer protein modulator. Expert Opin. Investig. Drugs 21, 1427–1432 (2012).
Niesor, E. J. Different effects of compounds decreasing cholesteryl ester transfer protein activity on lipoprotein metabolism. Curr. Opin. Lipidol. 22, 288–295 (2011).
Acknowledgements
D. S. Ng is supported by an operating grant from the Canadian Institutes for Health Research (CIHR; MOP-275369) and a CIHR China–Canada Joint Health Research Initiative grant. R. A. Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G. Blackburn Chair in Cardiovascular Research, and operating grants from the CIHR (MOP-13430, MOP-79523, CTP-79853), the Heart and Stroke Foundation of Ontario (NA-6059, T-6018) and Genome Canada through the Ontario Genomics Institute.
Author information
Authors and Affiliations
Contributions
All authors researched data for the article, provided a substantial contribution to discussion of content, wrote the article, and reviewed and/or edited the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
R. A. Hegele declares associations with the following companies: Abbott (honoraria for speaking), Amgen (honoraria for speaking; advisory board), AstraZeneca (honoraria for speaking), Merck (honoraria for speaking; advisory board), Pfizer (honoraria for speaking), Tribute Pharmaceuticals (honoraria for speaking; advisory board) and Valeant (honoraria for speaking; advisory board). N. C. W Wong declares an association with the following company: Resverlogix. The other authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Ng, D., Wong, N. & Hegele, R. HDL—is it too big to fail?. Nat Rev Endocrinol 9, 308–312 (2013). https://doi.org/10.1038/nrendo.2012.238
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrendo.2012.238
This article is cited by
-
Genetics of Triglycerides and the Risk of Atherosclerosis
Current Atherosclerosis Reports (2017)
-
Association of KCTD10, MVK, and MMAB polymorphisms with dyslipidemia and coronary heart disease in Han Chinese population
Lipids in Health and Disease (2016)
-
Mendelian randomisation study of the associations of vitamin B12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three Danish population-based studies
European Journal of Clinical Nutrition (2016)
-
HDL as a Causal Factor in Atherosclerosis: Insights from Human Genetics
Current Atherosclerosis Reports (2016)
-
The effect of a low-fat, plant-based lifestyle intervention (CHIP) on serum HDL levels and the implications for metabolic syndrome status – a cohort study
Nutrition & Metabolism (2013)