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Cardiovasc Res. 2019 Jan 1;115(1):204-212. doi: 10.1093/cvr/cvy198.

Associations between cardiovascular disease, cancer, and very low high-density lipoprotein cholesterol in the REasons for Geographical and Racial Differences in Stroke (REGARDS) study.

Author information

School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.
Department of Biostatistics, UAB School of Public Health, Birmingham, AL, USA.
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA.
The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD, USA.
Department of Clinical Biochemistry, Royal Free Campus, University College London Medical School, University College London (UCL), London, UK.
Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy.
Euro-Mediterranean Institute of Science and Technology, Palermo, Italy.
Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
Metabolic Research Centre, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Preventive Cardiology, CGH Medical Center, Sterling, IL, USA.
Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland.
Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.



Relatively little is known about the health outcomes associated with very low plasma concentrations of high-density lipoprotein cholesterol (HDL-C) mainly because of the small numbers of individuals with such extreme values included in clinical trials. We, therefore, investigated the association between low and very low HDL-C concentration at baseline and incident all-cause-mortality, death from malignant disease (i.e. cancer), and with fatal or non-fatal incident coronary heart disease (CHD) in individuals from the Reasons for Geographical And Racial Differences in Stroke (REGARDS) study.

Methods and results:

Analysis was based on 21 751 participants from the REGARDS study who were free of CHD, other cardiovascular disease, and cancer at baseline and were categorized by baseline HDL-C into <30 mg/dL (very low), 30-<40 mg/dL (low), and ≥40 mg/dL (reference). A series of incremental Cox proportional hazards models were employed to assess the association between the HDL-C categories and outcomes. Statistical analysis was performed using both complete case methods and multiple imputations with chained equations. After adjustment for age, race, and sex, the hazard ratios (HRs) comparing the lowest and highest HDL-C categories were 1.48 [95% confidence interval (CI) 1.28-1.73] for all-cause mortality, 1.35 (95% CI 1.03-1.77) for cancer-specific mortality and 1.39 (95% CI 0.99-1.96) for incident CHD. These associations became non-significant in models adjusting for demographics, cardiovascular risk factors, and treatment for dyslipidaemia. We found evidence for an HDL paradox, whereby low HDL (30-<40 mg/dL) was associated with reduced risk of incident CHD in black participants in a fully adjusted complete case model (HR 0.63; 95% CI 0.46-0.88) and after multiple imputation analyses (HR 0.76; 95% CI 0.58-0.98). HDL-C (<30 mg/dL) was significantly associated with poorer outcomes in women for all outcomes, especially with respect to cancer mortality (HR 2.31; 95% CI 1.28-4.16) in a fully adjusted complete case model, replicated using multiple imputation (HR 1.81; 95% CI 1.03-3.20).


Low HDL-C was associated with reduced risk of incident CHD in black participants suggesting a potential HDL paradox for incident CHD. Very low HDL-C in women was significantly associated with cancer mortality in a fully adjusted complete case model.

[Available on 2020-01-01]

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