Effect of Evolocumab or Ezetimibe Added to Moderate- or High-Intensity Statin Therapy on LDL-C Lowering in Patients With Hypercholesterolemia: The LAPLACE-2 Randomized Clinical Trial
What is the efficacy and tolerability of evolocumab when used in combination with a moderate- versus high-intensity statin?
This was a phase 3, 12-week, randomized, multicenter, international, double-blind, placebo- and ezetimibe-controlled study. After a 4-week lipid stabilization period with moderate-intensity statin therapy, patients were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily) when added to statin therapy. The coprimary endpoints were the percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12, and at week 12.
At the mean of 10 and 12 weeks in both the moderate- and high-intensity statin-treated groups and compared to placebo, evolocumab reduced LDL-C levels by 66% (95% confidence interval [CI], 58-73%) to 75% (95% CI, 65-84%) when given every 2 weeks, and by 63% (95% CI, 54-71%) to 75% (95% CI, 67-83%) when given monthly. In those receiving high-intensity statin therapy, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89-94 mg/dl, to an on-treatment mean of 35-38 mg/dl; monthly evolocumab reduced LDL-C from a baseline mean of 89-94 mg/dl to an on-treatment mean of 33-35 mg/dl. Adverse events (most commonly musculoskeletal symptoms or headaches) occurred in 36% of evolocumab-treated patients, 40% of ezetimibe-treated patients, and 39% of placebo-treated patients.
The authors concluded that evolocumab, when added to either moderate- or high-intensity statin therapy, results in additional LDL-C lowering, independent of baseline statin type, dose, or intensity.
This is an important study that adds to the promise of inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a therapeutic target for the treatment of primary hypercholesterolemia. Previous phase 2 trials have established the tolerability of efficacy of evolocumab, a fully human monoclonal antibody against PCSK9. LAPLACE-2 extends these findings by demonstrating the incremental LDL-C lowering of evolocumab when added to background statin therapy. The results of the FOURIER trial will help establish whether the additional lowering of LDL-C with evolocumab translates to reduction in atherosclerotic cardiovascular disease events.
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