November 13, 2015

When considering ongoing treatment with lipid-lowering drugs, clinicians need to pay more attention to percent reduction in LDL cholesterol, rather than just focusing on actual LDL levels, new data suggest[1].

Presenting a new analysis from the JUPITER trial at the American Heart Association (AHA) 2015 Scientific Sessions, Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) reported that while the average reduction in LDL was 50% with intensive statin therapy, individual variability was very wide, ranging from very small reductions to reductions of 85% or greater, and the percent reduction tracked well with clinical benefit.

Ridker commented to heartwire from Medscape: "Although few clinicians recognize it, current European, Canadian, and US guidelines all incorporate percent reduction in LDL as a critical therapeutic issue. We therefore addressed the variability in percent LDL reduction in JUPITER among those taking rosuvastatin 20 mg daily.

"Our findings support broader recognition of percent reduction in LDL cholesterol as a potential target for treatment," he stated.

Implications for PCSK9 Inhibitors

He added: "Further, our data may have implications for [proprotein convertase subtilisin/kexin type 9] PCSK9 inhibitors, in that these agents may prove to be more effective for those with modest percent reductions in LDL cholesterol but less so in those where LDL levels are already down 80 percent or more. This process will be assisted if ongoing trials of PCSK9 inhibitors report results stratified by the percent reduction in LDL-C achieved by background statin therapy.

"Our data also suggest that we need to address 'residual inflammatory risk' as being separate and distinct from 'residual cholesterol risk' and use these ideas as we move forward with precision medicine," Ridker said.

In the randomized, double-blind, placebo-controlled JUPITER trial, 17,082 initially healthy men and women were randomized to rosuvastatin 20 mg or placebo and followed for up to 5 years.

For the current analysis, Ridker and colleagues assessed the intra-individual variability in LDL cholesterol in response to statin therapy and evaluated the impact of reaching 50% or greater reductions in LDL-C on the risks of developing first-ever MI, stroke, or cardiovascular death.

Results showed that the magnitude of LDL reduction directly related to the risks of cardiovascular events during the follow-up period.

Relationship Between Percent LDL Reduction and Cardiovascular Risk

Group Cardiovascular events/1000 person-years Hazard ratio (95% CI)
Placebo 11.2 1.00
No LDL reduction 9.2 0.91 (0.54-1.53)
LDL reduction <50% 6.7 0.61 (0.44-0.83)
LDL reduction >50% 4.8 0.43 (0.30-0.60)
P for trend across on-treatment LDL groups <0.00001

Similar wide individual variability in statin response and similar relationships between percent reduction and clinical outcomes were observed in comparable analyses focusing on non-HDL cholesterol and apoB.

These effects were still seen after adjustment for many characteristics associated with greater lipid response to statin therapy and were only minimally affected when tertile reductions in on-treatment lipid levels were used instead of the prespecified >50 percent threshold, Ridker reported

"These data provide general support for the concepts of introducing percent reduction in LDL cholesterol into broader clinical practice, an approach consistent with that being advocated by current European, Canadian, and US guidelines," he concluded.

Discussant of the presentation at the AHA meeting, Dr Michael Pencina, commented: "Reduction in lipid level needs to be incorporated into assessment of treatment benefit. More work is needed to better understand the interplay of cardiovascular risk, baseline lipid level, and lipid-level reduction and the most effective ways of incorporating these into patient-care recommendations."

Ridker reports receiving compensation for consultancy/advisory-board activities from Isis, Boston Heart, and Genzyme; research grants from Novartis; AstraZeneca; Amgen; Pfizer; the National Heart, Lung, and Blood Institute; the National Institutes of Health; and the National Cancer Institute. In addition he is listed as a coinventor on patents held by Brigham and Women's Hospital that relate to the use of inflammatory biomarkers to cardiovascular disease. Disclosures for the coauthors are listed in the abstract.

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