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Statin therapy is recommended for patients who have, or are at risk for, cardiovascular disease, and this recommendation is based on strong evidence. What is not so clear is why a residual vascular risk remains in those patients who are on the treatment arms of statin trials. Low levels of high-density lipoprotein cholesterol (HDL-C) have been suggested as a potential cause of this risk, especially as they occur in many patients on statin therapy. Ridker et al (2010) therefore carried out a retrospective, post-hoc analysis of the JUPITER (Justification for the Use of statins in primary Prevention—an Intervention Trial Evaluating Rosuvastatin) trial cohort to address whether HDL-cholesterol concentrations are inversely associated with occurrence of cardiovascular events when low-density lipoprotein cholesterol (LDL-C) concentrations are reduced to very low levels through the use of statins.¹

The JUPITER trial involved 17,802 patients without diabetes or previous cardiovascular disease; individuals were randomly assigned to either the treatment arm (20 mg rosuvastatin per day) or placebo. In the analysis by Ridker et al, participants were divided into quartiles based on their HDL-C levels, and evidence of an association between these quartiles and the primary endpoint (i.e. first non-fatal myocardial infarction [MI] or stroke, hospitalisation for unstable angina, arterial revascularisation, or cardiovascular death) were sought. In the 8900 patients who received rosuvastatin, no significant relationships were noted between the quartiles of HDL-C concentration and vascular risk at baseline or on treatment. The investigators interpreted these results as evidence that HDL-C levels are not predictive of residual vascular risk among patients who attained very low concentrations of LDL-C after treatment with potent statin therapy.

Following publication of the Ridker et al article, the European Society of Cardiology (ESC) released a press statement to highlight concerns that the interpretations in the paper could deter research efforts into developing new therapeutic strategies that increase HDL-C.² Professor Dan Atar, spokesperson for the ESC, stated that: ‘If you are looking at populations with a very low incidence of cardiovascular events, and then with an intervention of any kind you reduce the risk of events even further, it is logical that you’ll washout the influence of any other effect. These patients already have achieved such low levels of LDL that no other marker will prevail as a predictor of the few remaining events.’ He also expressed concerns at how readers might not appreciate that more data is required before a qualified decision can be made about how beneficial it really is to raise HDL-C levels.²

As highlighted by Professor Atar, it is to be hoped that the HPS2-THRIVE (Treatment of High density lipoprotein to Reduce the Incidence of Vascular Events) trial, will provide some answers: this study of over 25,000 patients aims to investigate whether niacin/laropiprant combination can further reduce the risk for MI, stroke, and the need for revascularisation in patients who have already been treated to lower LDL-C levels. The trial is expected to complete in January 2013.³

Julia Morris, Editor
julia.morris@mgp.ltd.uk

References

1. Ridker P, Genest S, Boekholdt S et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. Lancet 2010; 376 (9738): 333–339.
2. European Society of Cardiology website. ESC Press Statement: No firm conclusions about HDL cholesterol can be drawn from JUPITER sub-analysis. www.escardio.org/about/press/press-releases/pr-10/Pages/No-Conclusion-JUPITER-subanalysis-PS.aspx?hit=dontmiss (accessed 4 August 2010).
3. ClinicalTrials.gov website. Treatment of HDL to Reduce the Incidence of Vascular Events HPS2-THRIVE. NCT00461630. clinicaltrials.gov/ct2/show/study/NCT00461630 (accessed 4 August 2010).G