Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol

Laboratory methods that report low-density lipoprotein cholesterol (LDL-C) include both LDL-C and lipoprotein(a) cholesterol [Lp(a)-C] content. The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content. The authors evaluated subjects with a history of cardiovascular disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-Ccorr = laboratory-reported LDL-C − direct Lp(a)-C; and 3) LDL-CcorrDahlén = laboratory LDL-C − [Lp(a) mass × 0.30] estimated by the Dahlén formula. The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs −29% to −67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-Ccorr ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of −2% to −19%/−0.7 to −8.0 mg/dL (P = 0.95-0.05) in LDL-Ccorr, −7% to −26%/−5.4 to −9.4 mg/dL (P = 0.44-<0.0001) in laboratory-reported LDL-C, and 3.1% to 28.3%/0.1 to 9.5 mg/dL (P = 0.006-0.50) increases in LDL-CcorrDahlén. Total apoB declined by 3%-16% (P = 0.40-<0.0001), but non-Lp(a) apoB was not significantly changed. Pelacarsen significantly lowers direct Lp(a)-C and has neutral to mild lowering of LDL-Ccorr. In patients with elevated Lp(a), LDL-Ccorr provides a more accurate reflection of changes in LDL-C than either laboratory-reported LDL-C or the Dahlén formula.