Conference Coverage

AHA: New emphasis on percent LDL reduction on-treatment




ORLANDO – The individual variability in percent reduction in LDL cholesterol levels in response to high-intensity statin therapy is far greater than generally appreciated, and this has important implications for clinical practice, Dr. Paul M. Ridker said at the American Heart Association scientific sessions.

A new secondary analysis from the landmark JUPITER trial highlighted this substantial variability in percent reduction in LDL cholesterol on 20 mg/day of rosuvastatin (Crestor). Moreover, it showed that the size of this reduction was directly related to the magnitude of reduction in cardiovascular events.

Dr. Paul M. Ridker Bruce Jancin/Frontline Medical News

Dr. Paul M. Ridker

“These data provide general support for the concept of introducing percent reduction in LDL cholesterol into broader clinical practice,” said Dr. Ridker, director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston.

The concept of percent LDL reduction as a treatment target is already widely embedded in the ACC/AHA, European Society of Cardiology, and Canadian Cardiovascular Society cholesterol management guidelines, he noted.

For example, the 2013 ACC/AHA guidelines state that lower-risk individuals who qualify for statin therapy should receive a moderate-intensity statin regimen capable of reducing LDL by 30%-50% from baseline, while higher-risk patients should be placed on a high-intensity statin, described as an agent that gives a 50% or greater reduction in LDL. The new JUPITER analysis makes the case for featuring percent LDL reduction more prominently as an explicit personalized treatment target in the guidelines, Dr. Ridker continued.

In JUPITER, 17,802 apparently healthy subjects with an LDL cholesterol level below 130 mg/dL were randomized to rosuvastatin or placebo. The trial was halted early, after a median of 1.9 years, because the rosuvastatin group showed a compelling 44% reduction in the composite endpoint of MI, stroke, unstable angina treated by revascularization, or cardiovascular death (N Engl J Med. 2008 Nov 20;359[21]:2195-320).

In JUPITER, rosuvastatin reduced LDL cholesterol by an average of 50% in the 7,856 treated patients. But as the new analysis demonstrates, individual variability in response was huge, ranging from no LDL reduction at all to a greater than 85% reduction. And cardiovascular event rates varied accordingly: from 11.2 events per 1,000 person-years with placebo to 9.2 in rosuvastatin-treated patients with no LDL reduction, 6.7 in those with less than a 50% drop in LDL, and 4.8 events per 1,000 person-years in subjects with a greater than 50% reduction in LDL on rosuvastatin. Thus, the one-half of rosuvastatin-treated patients who had more than a 50% decrease in LDL had an adjusted 59% reduction in major cardiovascular events, compared with placebo, while those with a drop of less than 50% in LDL had a 39% risk reduction.

The same exceptionally wide individual variability was seen in on-treatment reductions in apolipoprotein B cholesterol and non–HDL cholesterol levels, and once again, the magnitude of the percent reduction in these lipids tracked with the size of the reduction in cardiovascular events.

This new analysis from JUPITER essentially confirms the findings of an earlier meta-analysis of eight randomized controlled trials with more than 38,000 patients assigned to statin therapy. The meta-analysis showed very large interindividual variations in reductions in LDL, non–HDL cholesterol, and apolipoprotein B in response to high-dose statin therapy. Moreover, patients who achieved very low LDL levels on-treatment had a lower risk of cardiovascular events than those who achieved more moderate LDL reductions (J Am Coll Cardiol. 2014 Aug 5;64[5]:485-94).

Dr. Ridker said the new findings from JUPITER and the meta-analysis, in addition to their implications for clinical practice, could also be relevant in the future with regard to treatment decisions regarding when to prescribe proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, assuming ongoing clinical trials ultimately show that this novel and expensive class of superpotent LDL-lowering agents reduces the risk of cardiovascular events.

He noted that 20% of rosuvastatin-treated JUPITER participants had a greater than 60% reduction in LDL. In theory, he explained, this might be the group where the PCSK9 inhibitors would have the least benefit because those patients already have a 70%-80% reduction in LDL on a high-intensity statin.

On the other hand, the 35% of JUPITER participants with an on-treatment LDL reduction ranging from zero to less than 40% would have the greatest theoretic benefit from a PCSK9 inhibitor, while patients who obtained a 40%-60% LDL reduction on rosuvastatin would be expected to derive an intermediate benefit from the new drugs.

Discussant Michael J. Pencina, Ph.D., said the current U.S. cholesterol management guidelines focus heavily on cardiovascular risk as determined by the risk calculator equation. This needs to be balanced by a more explicit focus on assessment of the anticipated benefit of therapy, he added. For this reason, he agreed with Dr. Ridker’s call to incorporate measurement of percent reduction in lipid levels into individualized assessment of therapeutic benefit.


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