Curriculum in cardiology
Can change in high-density lipoprotein cholesterol levels reduce cardiovascular risk?

https://doi.org/10.1016/j.ahj.2003.10.051Get rights and content

Abstract

Background

The cardiovascular risk reduction observed in many trials of lipid-lowering agents is greater than expected on the basis of observed low-density lipoprotein cholesterol (LDL-C) level reductions. Our objective was to explore the degree to which high-density lipoprotein cholesterol (HDL-C) level changes explain cardiovascular risk reduction.

Methods

A systematic review identified trials of lipid-lowering agents reporting changes in HDL-C and LDL-C levels and the incidence of coronary heart disease (CHD). The observed relative risk reduction (RRR) in CHD morbidity and mortality rates was calculated. The expected RRR, given the treatment effect on total cholesterol level, was calculated for each trial with logistic regression coefficients from observational studies. The difference between observed and expected RRR was plotted against the change in HDL-C level, and a least-squares regression line was calculated.

Results

Fifty-one trials were identified. Nineteen statin trials addressed the association of HDL-C with CHD. Limited numbers of trials of other therapies precluded additional analyses. Among statin trials, therapy reduced total cholesterol levels as much as 32% and LDL-C levels as much as 45%. HDL-C level increases were <10%. Treatment effect on HDL-C levels was not a significant linear predictor of the difference in observed and expected CHD mortality rates, although we observed a trend in this direction (P = .08). Similarly, HDL-C effect was not a significant linear predictor of the difference between observed and expected RRRs for CHD morbidity (P = .20).

Conclusions

Although a linear trend toward greater risk reduction was observed with greater effects on HDL-C, differences were not statistically significant. The narrow range of HDL-C level increases in the statin trials likely reduced our ability to detect a beneficial HDL-C effect, if present.

Section snippets

Systematic review

A systematic review of the published medical literature was conducted to identify trials of lipid-lowering agents reporting changes in HDL-C, LDL-C, or total cholesterol levels and cardiovascular outcomes. We searched the MEDLINE and HEALTHSTAR databases for English language articles published between 1965 and March 2001. The search strategy and procedure based on Medical Subject Headings was developed in collaboration with an experienced librarian. Additional articles were identified from the

Results

The search strategy identified 3779 references published between January 1965 and March 2001. The diagram in Figure 1 illustrates the inclusion and exclusion of articles at different points in the review process. We accepted 1539 titles for further screening and reviewed their abstracts. The full text of 385 articles was reviewed.

Fifty-one articles met study inclusion criteria presenting results from a randomized placebo-controlled trial with sufficient information for estimating the effects of

CHD mortality and morbidity rates

Of the 16 nonstatin trials, sufficient data were available to evaluate the relationship between HDL-C effects and CHD mortality rates in only 7 instances, including 3 trials for fibrate therapy, 1 trial of combination treatment with niacin and resin, and 4 observations for diet/oil from 3 trials, with 1 trial evaluating 2 different treatments (Table II). For evaluating the risk of CHD morbidity, 5 trials were available for fibrates, 1 for resin therapy, 1 for niacin-resin combination treatment,

Discussion

These study results evaluate the quantitative relationship between HDL-C level alternation and CHD mortality and morbidity risks in published randomized placebo-controlled trials aimed at significantly lowering LDL-C levels with statin therapy. Although a linear trend toward a greater risk reduction was observed with greater treatment effects on HDL-C levels, the association of these effects with the risk reduction not explained by LDL-C level reduction was not statistically significant.

The

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