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Update on the Evidence for PCSK9 Inhibition to Lower LDL Cholesterol

Summary and Comment |
April 28, 2014

Update on the Evidence for PCSK9 Inhibition to Lower LDL Cholesterol

  1. JoAnne M. Foody, MD

Findings from three 12-week trials and a 1-year trial show promise for evolocumab, but we don't yet have outcomes data.

  1. JoAnne M. Foody, MD

For patients who are eligible for statin therapy but are considered to be statin intolerant, inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been proposed as an alternative mechanism of action for lowering LDL cholesterol. Evolocumab, a monoclonal antibody that inhibits PCSK9 and is administered subcutaneously, was recently tested in several manufacturer-funded phase 3 trials. Bottom-line findings are presented here.

In the DESCARTES trial, about 900 patients with hyperlipidemia were started on 4 to 12 weeks of background lipid-lowering therapy according to risk categories from the Adult Treatment Panel III of the National Cholesterol Education Program. Patients with an LDL level ≥75 mg/dL were then randomly assigned in a 2:1 ratio to receive evolocumab (420 mg) or placebo every 4 weeks. At 52 weeks, mean LDL reduction was 57% lower with evolocumab than with placebo, with significant advantages (ranging from 49% to 62%) across the various background-therapy subgroups. Side effects were generally minimal.

Several shorter-term (12-week) studies also showed significant benefits of evolocumab. In the GAUSS-2 trial, comparing evolocumab with ezetimibe in 307 statin-intolerant patients, evolocumab reduced LDL levels by 53% to 56% (a 37% to 39% advantage over ezetimibe), depending on the dosing intensity and schedule. In the MENDEL-2 trial, involving 614 statin-naive patients, evolocumab reduced LDL levels by 55% to 57% compared with placebo (a 38% to 40% advantage over ezetimibe), depending on the dosing intensity and schedule. In the LAPLACE-2 trial (unpublished results were presented at ACC 2014), involving about 1900 patients with hyperlipidemia on statin therapy, the percentage of evolocumab recipients who achieved an LDL level <70 mg/dL ranged from 86% to 95%, depending on the dosing intensity and schedule (differences with ezetimibe and placebo were significant).

Comment

In the short-term studies and the 1-year trial, evolocumab significantly lowered LDL cholesterol and had a generally favorable side-effect profile in several different patient populations with varying background therapies. However, PCSK9 inhibitors cannot be recommended as primary therapy until longer-term studies show that these LDL reductions are associated with improvements in cardiovascular outcomes. For now, clinicians should continue to define statin intolerance in a rigorous way and to provide guideline-based statin therapy to patients who tolerate it.

  • Disclosures for JoAnne M. Foody, MD at time of publication Consultant / Advisory board Aegerion; Amarin; Bristol-Myers Squibb; Janssen; Merck; Pfizer; Sanofi-Aventis; Boehringer Ingelheim Leadership positions in professional societies ACC Cardiosmart (Co-Chair)

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