Elsevier

Atherosclerosis

Volume 206, Issue 2, October 2009, Pages 611-616
Atherosclerosis

HDL cholesterol protects against cardiovascular disease in both genders, at all ages and at all levels of risk

https://doi.org/10.1016/j.atherosclerosis.2009.02.041Get rights and content

Abstract

Objective

We aimed to clarify some previous inconsistencies regarding the role of high density lipoprotein cholesterol (HDL-C) as a CVD protective factor.

Methods

The SCORE dataset contained data on HDL-C for 104,961 individuals (45% women) without pre-existing coronary heart disease (CHD). These were from 7 pooled European prospective studies. The effect of HDL-C, both in quintiles and as a continuous variable, on risk of CVD and CHD mortality was examined, using Cox proportional hazards model, adjusted for age, total cholesterol, systolic blood pressure, smoking, diabetes and body mass index and stratified by gender, age group, country and category of SCORE CVD risk.

Results

A strong, graded, independent, inverse relationship between HDL-C and both CVD and CHD mortality was demonstrated. Adjusted hazard ratios per 0.5 mmol/l increase in HDL-C were 0.60 (0.51, 0.69) and 0.76 (0.70, 0.83) in women and men, respectively for the CVD mortality endpoint. The corresponding hazard ratios were 0.53 (0.42, 0.68) and 0.79 (0.64, 0.98) in elderly women and men, respectively. The relationship was significant in all SCORE CVD risk strata and age groups.

Conclusions

This multivariable analysis, the largest of its kind to date, has confirmed the inverse, independent, strong and graded relationship between HDL-C and both CVD and CHD mortality. We have clarified previous suggestions that the relationship is stronger in women and that it applies in all age groups. This is the first prospective study to demonstrate the independent relationship specifically in healthy elderly women and to show that the relationship holds at all levels of total CVD risk.

Introduction

Cardiovascular disease (CVD), including coronary heart disease (CHD), stroke and disease of the peripheral vascular system, is the most common cause of death in middle-aged and elderly people throughout the developed world. Atherosclerosis, which leads to CVD, is usually caused by a combination of interacting risk factors. High density lipoprotein cholesterol (HDL-C) is known to protect against the future development of CVD through a number of mechanisms including increasing reverse cholesterol transport, anti-inflammatory and anti-oxidant mechanisms.

Several epidemiological studies have examined the relationship between HDL-C and cardiovascular (CV) risk; most have demonstrated a strong, inverse, independent relationship between HDL-C and CVD [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. However, inconsistencies remain and these require clarification.

In the presence of an aging population there is an increased need for evidence on the effect of risk factors in the elderly, as highlighted in CVD prevention guidelines [17]. Current epidemiological studies in the elderly are generally small and those regarding HDL-C to date have yielded inconsistent results [18], [19], [20], [21], [22], [23], [24], [25], many did not include women [26], [27], [28], [29], [30], [31] or did not report on the gender-specific effect of HDL-C in this age group [8], [32]. To our knowledge, only one small prospective study of elderly women, has demonstrated a protective effect of HDL-C after adjustment for other CV risk factors [33].

While some studies demonstrated the relationship at each level of TC[1], [34]; some showed a stronger relationship at lower levels [2], [4], but one of the largest prospective studies demonstrated that HDL-C was no longer related to CVD at TC levels lower than 6.5 mmol/l [14]. Other inconsistencies include the fact that several of the studies have been undertaken in populations which oversampled those with high total risk or high cholesterol levels [5], [7], [12], [34], [35]. Others have shown that the relationship no longer holds in those without previous CHD [14]. Whether HDL-C has an effect at each level of total CV risk has not been investigated.

The SCORE function, which estimates 10 year risk of CVD mortality, was derived from 12 pooled European cohort studies [36]. In this analysis, we aimed to examine the effect of HDL-C on risk of CVD and CHD mortality in the SCORE dataset and specifically to examine interactions between effect of HDL-C and gender, the relationship in each age group including those aged >65 years, at each total cholesterol level and at each level of total CVD risk.

Section snippets

Study population

The study population used was the SCORE dataset [36]. 9 of the initial 12 studies provided data on HDL-C; 7 of these are included here. The Scottish and Russian cohorts were removed for technical reasons. Details of the included studies and references are in supplementary material. Those individuals with previously diagnosed CHD were excluded.

Methods

Endpoints were defined as follows: CHD mortality included ICD 9 codes 410–414. CVD mortality included in addition 401–409, 426–443, 798.1 and 798.2. The following definitely non-atherosclerotic causes of death were excluded: 426.7, 429.0, 430.0, 432.1, 437.3, 437.4, 437.5, as in the SCORE project [36].

Details of the methods for laboratory measurement of HDL-C and details of the individual prospective studies included are given in the online supplementary material.

The mean HDL-C in men and women

Results

2197 individuals were excluded due to previous diagnosis of CHD at baseline examination. 47,659 women and 57,302 men had data available on HDL-C and were included in the analysis. Those with missing data for any of the co-variables were excluded from the multivariable analyses; this left 43,544 women and 53,000 men. The country-specific baseline characteristics of these individuals are shown in the supplementary Tables A and B. There were 2198 fatal CVD events (70% CHD events). There was a

Discussion

The size of the SCORE dataset has allowed clarification of some of the apparent inconsistencies in the relationship between HDL-C and CV risk. The strong, inverse association between HDL-C and both CVD mortality and CHD mortality has been confirmed. The effect is robust and withstands adjustment for other CV risk factors, including factors known to be associated with HDL-C level including BMI, diabetes and smoking. The magnitude of the effect of HDL-C on CHD and CVD mortality seen in this

Conclusion

In this multivariable analysis, the largest of its kind to date, we have confirmed the inverse, strong and graded relationship between HDL-C and both CVD and CHD mortality. The relationship was robust, withstanding adjustment for other CV risk factors, including factors known to be associated with HDL-C level, including BMI, triglycerides, diabetes, smoking and family history of CHD. We have clarified previous suggestions that the relationship is stronger in women and that it applies in all age

Conflict of interest

None to declare.

Acknowledgements

*Other SCORE investigators not named as co-authors: RM Conroy, K Pyörälä, AP Fitzgerald, P Ducimetiere, I Njølstad, RG Oganov, H Tunstall-Pedoe, A Tverdal, H Wedel.

Financial disclosure: No funding received.

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