July 22nd, 2010
HDL and Residual Risk: A Surprising Finding in JUPITER
CardioExchange welcomes Dr. Paul Ridker to answer questions about his recent paper in the Lancet, which analyzed data from JUPITER and found that HDL may not predict residual risk in patients on high-dose statins who reach very low LDL levels such as those achieved in the treatment group in JUPITER. The findings may surprise some readers, though Ridker et al note in their report that similar findings have been observed in previous trials such as PROVE-IT. HDL was found to be inversely correlated with vascular risk in patients who were randomized to placebo in JUPITER, but there no significant relationships between HDL levels and vascular risk in the rosuvastatin-treated patients.
Is it known what effect HDL has on risk in an untreated population with LDL levels that are already at the post-treatment level in JUPITER? In other words, does the HDL effect disappear because the LDL is below a certain point or because the statin treatment brings it to that point?
There are very little prior data on what effect, if any, HDLC has on risk in populations with an average LDLC of 50 mg/dL. However, we do know from prior population and genetic studies that those lucky enough to have native LDLC levels in this range tend to have very low vascular event rates. In our analysis, we got the LDLC levels down to that range using a potent statin (rosuvastatin 20 mg). When we examine prior studies of high-dose statin therapy (atorvastatin 80 mg in both PROVE-IT and TNT) the same finding was observed, namely that residual risk on the basis of HDLC was marginal once a high-dose statin was used.
Was this same attenuation of residual risk seen across all risk strata, i.e., in the highest-risk as well as the lowest-risk participants?
JUPITER is a primary-prevention trial where the gradient of risk is relatively narrow. However, the similar findings of only marginal relation between on-treatment HDL and subsequent vascular risk in the atorvastatin 80 mg arms of the PROVE-IT and TNT trials noted above suggest that this is also true among those with recent ACS and chronic coronary disease, two very high-risk groups.
How do you think these results should inform and/or impact ongoing efforts to develop HDL-lowering therapies? What are the implications for the design of trials designed to evaluate the efficacy of HDL-raising drugs? Would you recommend that those trials only enroll patients with low HDL and no statin therapy or only those with low HDL and low LDL?
The only way to truly evaluate the role of HDL-raising agents is through carefully designed randomized trials, and I believe it very important that those studies move forward and be completed. That being said, those trials should ensure that all participants are on potent statin therapy (because these agents are already proven and will be generic very soon). More important to me than the baseline HDLC is the question of how large an HDLC increase one anticipates and whether this can be achieved safely. Agents that substantially increase HDLC would seem to hold greater promise. As with any new class of agents, the net benefit-to-risk ratio must be ascertained, so we will also need long-term follow-up in all anticipated trials.