Expert Review: Acute Coronary Syndrome, Lipid / Metabolic

Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy

In the present study the authors aimed to replicate the earlier observation from the Framingham Offspring Study that changes in HDL-C associated with lipid modification therapy are associated with a lower risk of cardiovascular events independent of changes in LDL-C (or non-HDL-C). After adjustment for conventional non-lipid risk factors of cardiovascular disease, the authors found no evidence to support a significant benefit from increasing HDL-C independent of the effect of lowering non-HDL-C.


The clear benefits of lipid modification therapy (LMT) are thought to be related to the reductions in LDL-C. Data exists that shows a positive correlation between the level of LDL-C and the risk of cardiovascular disease (CVD). Conversely, the increase of HDL-C is associated with a reduction of CVD.

Recent evidence using data from 454 participants in the Framingham Offspring Study (FOS) recently confirmed that the increase in HDL-C is associated with a reduction in CV outcomes independently of changes in LDL-C.

Knowledge Gap

Although the data from FOS shows that HDL-C differences resulting from LMT may be relevant to CV benefit even after adjusting for changes in LDL-C, replication of such findings is important in other populations, as single studies may provide chance associations despite the use of rigorous methodology. Therefore, combining available and even controversial data in an update meta-analysis can improve the power and precision of the data.

Aim of the study

The present study sought to fill the gaps on this issue by studying the relationship between changes in HDL-C and CVD outcomes in two further prospective cohorts – the EPIC-Norfolk (UK) and the Rotterdam (The Netherlands) studies.


A total of 1148 participants (446 from the EPIC-Norfolk and 702 from the Rotterdam study) were assessed for lipids before and after the start of LMT. The association between change in HDL-C resulting from LMT (∆HDL) and incident CV endpoints verified through linkage with mortality records and hospital databases was investigated through Cox proportional hazards regression. Pooled estimates of effects from both studies – for ∆HDL-C and in ∆non-HDL-C and CVD risk – were obtained through a random effects meta-analysis.


Based on combined data from the EPIC-Norfolk and Rotterdam studies there was some evidence that changes in HDL-C resulting from LMT were associated with a 26% reduced risk of CVD with adjustment for age, sex and baseline HDL-C (HR per pooled SD (=0.34 mmol/l) increase=0.74, 95% CI 0.56 to 0.99, p=0.25).

However, with further adjustment for HDL-C and ∆non-HDL-C, this association was attenuated and was not statistically significant (HR 0.81, 95% CI 0.62 to 1.06, p=0.40). This association was further attenuated with adjustments for cigarette smoking history, prevalent diabetes, systolic blood pressure, body mass index, use of antihypertensive medication, previous myocardial infarction, prevalent angina and previous stroke (HR 0.92, 95% CI 0.70 to 1.20, p=0.43).

Additionally, there was a 34% reduced risk of CVD for 1SD decrease (=1.31 mmol/l) in ∆non-HDL-C, following adjustment for age, sex, baseline HDL-C, ∆HDL and baseline non-HDL-C (HR 0.66, 95% CI 0.50 to 0.88, p=0.50). This effect remained following adjustment for all risk factors considered (HR 0.68, 95% CI 0.50 to o.92, p=0.36).


Based on new data from a combined sample of 1148 EPIC-Norfolk and Rotterdam cohort studies, and after following adjustment for conventional non-lipid risk factors of CV disease, this study does not confirm an additional significant benefit associated with an increase in HDL-C independent of LDL-C.

Perspective-Clinical Impact

The present study provides some evidence that a change in HDL-C resulting from LMT was associated with reduced CV risk. However, this association was attenuated and was not statistically significant with further adjustment for non-HDL-C and for all risk factors considered.

According to the authors, the study has some limitations. Firstly, the present study analyses focused on HDL-C, but there is emerging evidence that HDL function rather than HDL-C may be critical to atherosclerosis. Secondly, the authors attempted, via multivariable adjustment, to control confounders. Consequently one cannot exclude the possibility of residual confounding as an explanation. Finally, while the majority of treatments were statins, the authors have combined all LMTs together and cannot exclude the possibility of differential effects within the different LMT classes.

Corresponding author from original paper

Professor Kausik Ray, Division of Clinical Sciences, St. George’s University of London, Cranmer Terrace, London SW17 ORE, UK. E-mail: 

Citation: Heart 2012 May;98(10):780-5. Epub 2012 Mar 24.

Leave a Reply

Your email address will not be published. Required fields are marked *