Comparison of LDL-C Reduction Using Different Evolocumab Doses and Intervals: Biological Insights and Treatment...

The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduces low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular events.

To compare LDL-C reduction using evolocumab 140 mg once every 2 weeks (Q2W) or 420 mg monthly (QM) versus lower doses (70 mg Q2W or 280 mg QM) or placebo.

Patients received evolocumab 70 or 140 mg Q2W, 280 or 420 mg QM, or placebo Q2W or QM in two 12-week phase 2 studies: one with and one without statins. Changes from baseline in LDL-C were compared across Q2W doses and across QM doses.

The analysis included 741 patients. Mean (95% confidence interval [CI]) reduction in LDL-C across Q2W visits through week 12 was 63.0% (60.3% to 65.7%) for evolocumab 140 mg Q2W, compared to 41.3% (38.6% to 44.0%) for 70 mg Q2W and 1.9% (4.6% reduction to 0.8% increase) for placebo Q2W (each P < .001 vs 140 mg Q2W), and 62.7% (60.1% to 65.3%) for 420 mg QM, compared to 55.5% (52.9% to 58.0%) for 280 mg QM and 2.5% (5.1% reduction to 0.1% increase) for placebo QM (each P < .001 vs 420 mg QM). Similar results were observed at the mean of weeks 10 and 12. In a subgroup (n = 151) with weekly assessments from weeks 8 to 12, mean (95% CI) peak effect on LDL-C reduction was 72.8% (67.7% to 77.9%) for 140 mg Q2W and 69.0% (63.6% to 74.3%) for 420 mg QM. Trough effect at week 12 underestimated LDL-C reduction. Median peak-trough variability was 20.5%, 21.1%, 31.9%, and 35.1% for evolocumab 140 mg Q2W, 420 mg QM, 70 mg Q2W, and 280 mg QM, respectively.

Evolocumab 140 mg Q2W and 420 mg QM yielded similar LDL-C reduction. These doses sustained maximal LDL-C reduction, resulting in greater stability in LDL-C reduction over the dosing interval compared to lower doses. These results support evolocumab doses of either 140 mg Q2W or 420 mg QM.