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Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy
  1. Kausik Ray1,
  2. Nick W J Wainwright2,
  3. Loes Visser3,4,
  4. Jacqueline Witteman3,
  5. Monique Breteler3,
  6. Baishali Ambegaonkar5,
  7. Albert Hofman3,
  8. Bruno Stricker3,
  9. Nick Wareham6,
  10. Kay Tee Khaw7,
  11. Manjinder Sandhu2
  1. 1Division of Clinical Sciences, St George's University of London, UK
  2. 2International Health Research Group, Department of Public Health and Primary Care, University of Cambridge, and Genetic Epidemiology Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  3. 3Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands
  4. 4Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
  5. 5Global Outcomes Research, Merck & Co., Inc., Whitehouse Station, New Jersey, USA
  6. 6MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital Cambridge, Cambridge, UK
  7. 7Department of Public Health and Primary Care and Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK
  1. Correspondence to Kausik Ray, Division of Clinical Sciences, St George's University of London, Cranmer Terrace, London SW17 0RE, UK; kray{at}


Background Lipid modification therapy (LMT) produces cardiovascular benefits principally through reductions in low density lipoprotein cholesterol. While recent evidence, using data from 454 participants in the Framingham Offspring Study, has suggested that increases in high density lipoprotein cholesterol (HDL-C) are also associated with a reduction in cardiovascular outcomes, independently of changes in low density lipoprotein cholesterol, replication of this finding is important. The authors therefore present further results using data from the EPIC-Norfolk (UK) and Rotterdam (The Netherlands) prospective cohort studies.

Methods A total of 1148 participants, 446 from the EPIC-Norfolk and 702 from the Rotterdam study, were assessed for lipids before and after starting LMT. Subsequent risk of cardiovascular events, ascertained through linkage with mortality records and hospital databases, was investigated using Cox proportional hazards regression. Random effects meta-analysis was used to combine results across studies.

Results Based on combined data from the EPIC-Norfolk and Rotterdam studies there was some evidence that change in HDL-C resulting from LMT was associated with reduced cardiovascular risk (HR per pooled SD (=0.34 mmol/l) increase=0.74, 95% CI 0.56 to 0.99, adjusted for age, sex and baseline HDL-C). However, this association was attenuated and was not (statistically) significant with further adjustments for non-HDL-C and for cigarette smoking history, prevalent diabetes, systolic blood pressure, body mass index, use of antihypertensive medication, previous myocardial infarction, prevalent angina and previous stroke (0.92, 0.701.20).

Conclusions Following adjustment for conventional non-lipid risk factors of cardiovascular disease, this study provides no evidence to support a significant benefit from increasing HDL-C independent of the effect of lowering non-HDL-C.

  • lipids
  • lipoproteins
  • HDL
  • atherosclerosis
  • myocardial infarction
  • risk factors
  • psychology/psychiatry

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  • KR and NWJW contributed equally to this manuscript.

  • Funding EPIC-Norfolk is supported by programme grants from the Medical Research Council UK and Cancer Research UK. The Rotterdam study of the Department of Epidemiology of the Erasmus University is supported by Erasmus MC and Erasmus University Rotterdam, the Netherlands Organization for Scientific Research (NWO), the Netherlands Organization for Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. Part of this work was supported through an unrestricted research grant from Merck and Co, USA (awarded to MS and KR).

  • Competing interests KR has received honoraria for advisory boards, consultancy or lectures (modest) from Pfizer, Astra Zeneca, Merck, Schering Plough and Roche.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by Norwich District Health Authority Ethics Committee and the review board of the Netherlands Ministry of Health, Welfare and Sports.

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