Evolocumab Boosts LDL Reduction on Top of Statins: LAPLACE-2 Published

May 13, 2014

IOWA CITY, IA — The LAPLACE-2 study, a 12-week randomized, clinical trial that demonstrated the clinical effectiveness of adding the proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor evolocumab (Amgen, Thousand Oaks, CA) to statin therapy, is now published in the May 14, 2014 issue of the Journal of the American Medical Association[1].

Reported by heartwire when it was presented at the recent American College of Cardiology Scientific Sessions in Washington, DC, the LAPLACE-2 study, led by Dr Jennifer Robinson (University of Iowa, Iowa City), showed that adding evolocumab to moderate- or high-intensity statin therapy resulted in very large reductions in LDL-cholesterol levels when compared with statin therapy alone.

Briefly, 2067 patients with hypercholesterolemia or mixed dyslipidemia were randomized to one of 24 treatment groups. The active therapy was evolocumab 140 mg every two weeks or 420 mg once monthly. Patients were treated with a background of moderate-intensity statin therapy with atorvastatin 10 mg, simvastatin 10 mg, or rosuvastatin (Crestor, AstraZeneca) 5 mg or to high-intensity therapy with atorvastatin 80 mg or rosuvastatin 40 mg. Placebo and ezetimibe (Zetia, Merck/Schering-Plough) served as the comparator arms.

For those who received high-intensity atorvastatin, the addition of evolocumab reduced LDL-cholesterol levels to as low as 35 mg/dL after 12 weeks. Similarly, the monthly dose of evolocumab added to high-intensity rosuvastatin reduced LDL cholesterol down to 33 mg/dL (and down to 37 mg/dL when dosed every two weeks) by week 12. In these patients, the mean change from baseline ranged from a 59% to 65% reduction in LDL cholesterol.

When evolocumab was added to a moderate-intensity statin, the percent reduction in LDL cholesterol ranged from 59% to 66%. The achieved mean LDL-cholesterol levels when the PCSK9 inhibitor was added to a moderate-intensity statin ranged from 39 mg/dL to 49 mg/dL at week 12, depending on the statin used and the baseline LDL-cholesterol level.

In contrast, the mean reduction in LDL cholesterol with ezetimibe when added to a statin was a further 24%.

What next for evolocumab and the drug class?

The US Food and Drug Administration has said it is willing to review the data on PCSK9 inhibitors on the basis of LDL lowering alone.

For many experts, including the LAPLACE-2 investigators, more data will be needed to determine whether the large reductions in LDL-cholesterol levels reduce clinical events beyond those achieved with statins. The other worry, of course, is that there isn't a lot known about reducing LDL cholesterol to such low levels. As Dr Prediman Shah (Cedars Sinai Medical Center, Los Angeles, CA) told heartwire in March, more long-term studies will be needed to determine whether there is any "collateral damage" from such drastic reductions in LDL cholesterol.

The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) study is a 22 500-patient trial testing evolocumab against statin therapy for the reduction of the primary composite end point of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization. Although ongoing, full results won't be available until 2018 at the earliest.

Pfizer and Sanofi/Regeneron are also working on PCSK9 inhibitors, which are in various stages of development and in general have shown LDL-lowering prowess similar to evolocumab.

Robinson reports that her institution has received research grants from Amarin, Amgen, AstraZeneca, Daiichi-Sankyo, Esperion, Genentech/Hoffman La Roche, GlaxoSmithKline, Merck, Regeneron/Sanofi, and Zinfandel/Takeda; she reports serving as a consultant for Amgen, Hoffman LaRoche, Pfizer, and Sanofi. Disclosures for the coauthors are listed in the article.

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