Opinion | Published:

HDL—is it too big to fail?

Nature Reviews Endocrinology volume 9, pages 308312 (2013) | Download Citation


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.

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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


  1. Keenan Research Centre, Li Ka Shing Knowledge Institute, St Michael's Hospital, Shuter Wing, Room 3-041, 30 Bond Street, Toronto, ON M5B 1W8, Canada

    • Dominic S. Ng
  2. Department of Medicine, Faculty of Medicine at University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada

    • Norman C. W. Wong
  3. Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, 4288A-100 Perth Drive, London, ON N6A 5K8, Canada

    • Robert A. Hegele


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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.

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.

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Correspondence to Robert A. Hegele.

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