Lp(a): A Toolkit for Health Care Professionals

14 ESC/EAS guidelines incorporate treatment algorithms for Lp(a) reduction. However, clinicians should be apprised of PCSK9 inhibitors’ effect on serum Lp(a). z Inclisiran, a small interfering RNA molecule that targets PCSK9 messenger RNA, has been evaluated in people with high risk for cardiovascular disease and elevated LDL-C. In the phase 2 ORION-1 study, a single dose of inclisiran 500 mg lowered LDL-C by 41.9% and Lp(a) by 18.2% at 180 days compared to baseline in this patient population. People randomized to the placebo arm had LDL-C rise by 2.1% and Lp(a) by 0.5%. A two-dose regimen of inclisiran 300 mg reduced LDL-C by 52.6% and Lp(a) by 25.6% at 180 days from baseline. LDL-C rose by 1.8% and Lp(a) was unchanged in the control group. Compared to placebo, inclisiran reduced Lp(a) by 25.6% in the ORION-10 trial evaluating inclisiran in people with ASCVD and by 18.6% in the ORION-11 trial that enrolled people with an ASCVD equivalent. z AKCEA-APO(a)-LRX (APO(a)- L RX ), a second-generation ASO targeting messenger RNA of the LPA gene, has been evaluated in a multicenter, double-blind phase 2 study of people with established CVD and Lp(a) levels >60 mg/dL (150 nmol/L). Patients (N=286) were randomized to one of five APO(a)-L RX groups or placebo. The primary endpoint was Lp(a) percentage change from baseline at six months. Researchers found a dose- dependent reduction in Lp(a). Compared to baseline, the lowest dose of APO(a)-L RX (20 mg every four weeks) reduced Lp(a) by 38.4 mg/dL at six months while the highest dose (20 mg every week) lowered Lp(a) by 75.1 mg/ dL at six months. The average Lp(a) reduction was 80% for patients taking of APO(a)-L RX 20 mg weekly. At six months, 23% of the group taking the lowest dose and 98% of the highest dose of APO(a)-L RX achieved Lp(a) concentrations ≤50 mg/dL. APO(a)-L RX was also associated with reductions in LDL-C and apolipoprotein B. The average Lp(a) reduction was 80% for patients taking APO(a)-LRX 20mg weekly.