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Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis

BMJ 2009; 338 doi: (Published 16 February 2009) Cite this as: BMJ 2009;338:b92
  1. Matthias Briel, senior researcher 12,
  2. Ignacio Ferreira-Gonzalez, senior researcher3,
  3. John J You, assistant professor14,
  4. Paul J Karanicolas, senior researcher5,
  5. Elie A Akl, assistant professor6,
  6. Ping Wu, research associate7,
  7. Boris Blechacz, instructor in medicine8,
  8. Dirk Bassler, senior researcher9,
  9. Xinge Wei, physician1,
  10. Asheer Sharman, physician4,
  11. Irene Whitt, physician8,
  12. Suzana Alves da Silva, senior researcher10,
  13. Zahira Khalid, physician4,
  14. Alain J Nordmann, senior researcher2,
  15. Qi Zhou, statistician1,
  16. Stephen D Walter, professor1,
  17. Noah Vale, junior researcher1,
  18. Neera Bhatnagar, librarian1,
  19. Christopher O’Regan, research associate11,
  20. Edward J Mills, assistant professor12,
  21. Heiner C Bucher, professor2,
  22. Victor M Montori, associate professor13,
  23. Gordon H Guyatt, professor14
  1. 1Department of Clinical Epidemiology and Biostatistics, McMaster University, 1200 Main Street West, Hamilton, ON, Canada
  2. 2Basel Institute for Clinical Epidemiology, University Hospital Basel, Basel, Switzerland
  3. 3Department of Cardiology, Vall d’Hebron Hospital, Barcelona, and CIBER de Epidemiologia y Salud Pública (CIBERESP), Spain
  4. 4Department of Medicine, McMaster University
  5. 5Department of Surgery, University of Western Ontario, London, ON
  6. 6Department of Medicine, State University of New York at Buffalo, Buffalo, NY, USA
  7. 7Canadian College of Naturopathic Medicine, Toronto, ON
  8. 8Department of Medicine, Mayo Clinic, Rochester, MN, USA
  9. 9Department of Neonatology, University Children’s Hospital, Tuebingen, Germany
  10. 10Department of Research, Teaching and Research Center of Pro-Cardiaco/PROCEP, Rio de Janeiro, Brazil
  11. 11Pfizer Ltd, Walton on the Hill, Surrey
  12. 12British Columbia Centre for Excellence in HIV/AIDS, St Paul’s Hospital, Vancouver, BC, Canada
  13. 13Division of Endocrinology and Knowledge and Encounter Research Unit, Mayo Clinic
  1. Correspondence to: M Briel brielm{at}
  • Accepted 30 October 2008


Objective To investigate the association between treatment induced change in high density lipoprotein cholesterol and total death, coronary heart disease death, and coronary heart disease events (coronary heart disease death and non-fatal myocardial infarction) adjusted for changes in low density lipoprotein cholesterol and drug class in randomised trials of lipid modifying interventions.

Design Systematic review and meta-regression analysis of randomised controlled trials.

Data sources Medline, Embase, Central, CINAHL, and AMED to October 2006 supplemented by contact with experts in the field.

Study selection In teams of two, reviewers independently determined eligibility of randomised trials that tested lipid modifying interventions to reduce cardiovascular risk, reported high density lipoprotein cholesterol and mortality or myocardial infarctions separately for treatment groups, and treated and followed participants for at least six months.

Data extraction and synthesis Using standardised, pre-piloted forms, reviewers independently extracted relevant information from each article. The change in lipid concentrations for each trial and the weighted risk ratios for clinical outcomes were calculated.

Results The meta-regression analysis included 108 randomised trials involving 299 310 participants at risk of cardiovascular events. All analyses that adjusted for changes in low density lipoprotein cholesterol showed no association between treatment induced change in high density lipoprotein cholesterol and risk ratios for coronary heart disease deaths, coronary heart disease events, or total deaths. With all trials included, change in high density lipoprotein cholesterol explained almost no variability (<1%) in any of the outcomes. The change in the quotient of low density lipoprotein cholesterol and high density lipoprotein cholesterol did not explain more of the variability in any of the outcomes than did the change in low density lipoprotein cholesterol alone. For a 10 mg/dl (0.26 mmol/l) reduction in low density lipoprotein cholesterol, the relative risk reduction was 7.2% (95% confidence interval 3.1% to 11%; P=0.001) for coronary heart disease deaths, 7.1% (4.5% to 9.8%; P<0.001) for coronary heart disease events, and 4.4% (1.6% to 7.2%; P=0.002) for total deaths, when adjusted for change in high density lipoprotein cholesterol and drug class.

Conclusions Available data suggest that simply increasing the amount of circulating high density lipoprotein cholesterol does not reduce the risk of coronary heart disease events, coronary heart disease deaths, or total deaths. The results support reduction in low density lipoprotein cholesterol as the primary goal for lipid modifying interventions.


  • We thank Christina Lacchetti, Jean Mackay, Kate Bak, and Sara Kaffashian, who helped with screening of titles and abstracts of potentially eligible publications.

  • Contributors: MB, SDW, COR, EJM, HCB, VMM, and GHG conceived, designed, and planned the study. MB, XW, AS, NV, and NB were responsible for the electronic search, data collection, full text retrieval, and data entry. MB, IFG, JJY, PJK, EAA, PW, BB, DB, AS, IW, SAdS, ZK, AJN, and EJM checked eligibility, assessed trial quality, and extracted data. QZ and SDW provided statistical expertise. COR, EJM, and GHG obtained funding. All authors discussed the results. MB and GHG drafted the manuscript; all the other authors critically revised the manuscript for important intellectual content. MB and GHG are the guarantors.

  • Funding: The study was supported by an unrestricted educational grant from Pfizer. MB is supported by a scholarship award of the Swiss National Foundation (PASMA—112951/1). JJY is supported by an Ontario Ministry of Health and Long-Term Care Career Scientist Award. The funding sources had no role in the study design; the collection, analysis, and interpretation of data; or the writing of the report.

  • Competing interests: COR is a salaried employee of Pfizer UK.

  • Ethics approval: Not needed.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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