HDL has long been recognized as having a strong inverse correlation with cardiovascular events, but a new analysis of the JUPITER trial suggests that it may not predict residual risk in statin-treated patients who have reached very low LDL levels. The new report by Paul Ridker and colleagues appears in the Lancet.
Among JUPITER patients randomized to placebo, HDL levels were inversely related to vascular risk both at baseline and on-treatment. By contrast, among patients who received rosuvastatin, “no signficant relationships were noted” between HDL levels and vascular risk either at baseline or on-treatment. A similar pattern was observed with apo A1.
The JUPITER investigators write that their “data should not reduce enthusiasm for measurement of HDL-cholesterol concentration as part of an initial cardiovascular risk assessment.” But they note that “the possibility remains” that HDL will not prove a fruitful target for intervention and that the goal of raising HDL needs to be tested as a therapeutic strategy.
In an accompanying comment, Derek Hausenloy, Lionel Opie, and Derek Yellon speculate that for patients with very low LDL levels “other lipid measures (such as the apolipoprotein B to A1 ration) will provide more accurate prediction of cardiovascular risk than do HDL cholesterol concentrations.” They caution, however, that the new findings “should not detract from the fact that raising HDL cholesterol remains a major treatment strategy for the reduction of cardiovascular risk in the large majority of patients who do not have very low LDL cholesterol; the problem, in most cases, is how to achieve this strategy.”
CardioBrief asked Ridker if he thought the study suggested that drugs that target HDL are less likely to be beneficial and, if so, will this lessen the urgency in developing these drugs? And if HDL is not a good means to identify residual risk, wha will work to identify residual risk?
Here is Ridker’s response:
“It is crucial that we find out from randomized trials whether agents that substantially increase HDL benefit our patients or not, assuming they are already on a potent statin. These data do not diminish the need for such trials, but they do emphasize that the agent to be examined probably needs to increase HDL a lot.
“With regard to residual risk, we have previously found in JUPITER that both on-treatment LDL and CRP associate with residual risk, so agents that further lower LDL (or apo B) and inflammation are also targets of considerable interest.”
Here is the Lancet press release:
LEVELS OF ‘GOOD’ CHOLESTEROL LESS RELEVANT TO CARDIOVASCULAR RISK ONCE ‘BAD’ CHOLESTEROL HAS BEEN REDUCED BY TREATMENT WITH STATINS
In the general population, the more ‘good’ cholesterol* that a person has, the less likely they are to suffer a cardiovascular event. But new research shows that if a person has their levels of ‘bad’ cholesterol** substantially lowered with high-dose statin treatment, then levels of ‘good’ cholesterol in that person may no longer bear any relation to their remaining cardiovascular risk. The findings, based on the JUPITER study, are reported in an Article Online First and in an upcoming Lancet. The Article is by Professor Paul Ridker, Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston, MA, USA, and colleagues.
In the JUPITER trial, patients with average to low levels of bad cholesterol received the potent statin ‘Rosuvastatin’ at a dose of 20 mg per day, which lowered their concentrations of bad cholesterol, in many cases substantially, to those typically seen in Aboriginal populations but rarely seen in Western patients. After a median follow-up of 1·9 years in JUPITER (maximum 5 years), treatment with rosuvastatin was associated with a 54% reduction in myocardial infarction, a 48% reduction in stroke, a 46% reduction in revascularisation, a 43% reduction in venous thromboembolism, and a 20% reduction in total mortality. In this new work, the authors assessed whether residual risk after initiation of high-dose statin treatment was related to baseline or on-treatment concentrations of good cholesterol.
For the patients in the JUPITER trial who were given placebo, concentrations of good cholesterol remained predictive of cardiovascular risk, with the patients in the highest 25% of levels of good cholesterol at around half the risk of suffering a cardiovascular event as those in the lowest 25%. By contrast, among the JUPITER patients given rosuvastatin, no significant relationships were noted between concentrations of good cholesterol and residual cardiovascular risk.
The authors conclude: “Although measurement of HDL-cholesterol concentration is useful as part of initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who attain very low concentrations of LDL cholesterol.”
However, the authors add that finding out whether or not raising HDL cholesterol improves cardiac outcomes after taking statin therapy remains a very important issue that can only be addressed by randomised trials of potent, efficacious cholesterol raising agents. Such studies would assess whether substantially raising HDL cholesterol levels would provide additional cardiovascular benefit beyond statin therapy.
In an accompanying Comment, Dr Derek Hausenloy, The Hatter Cardiovascular Insititute, University College London, UK, and colleagues say: “With the advent of more potent drugs, the issue of whether raising ‘good’ cholesterol concentrations reduces cardiovascular risk in patients with very low ‘bad’ cholesterol concentrations needs to be tested in clinical studies.”
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