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Effect of Pelacarsen on Lp(a) Cholesterol and Corrected LDL Cholesterol
Quick Takes
- Pelacarsen, an RNA-based antisense oligonucleotide, significantly reduces Lp(a) and has neutral to modest effects on corrected LDL-C in patients with cardiovascular disease and elevated Lp(a).
- Using a direct Lp(a) measurement to determine a corrected LDL-C provides a more accurate reflection of changes in LDL-C than laboratory-reported LDL-C in patients with elevated Lp(a) receiving pelacarsen.
Study Questions:
Does pelacarsen lower low-density lipoprotein cholesterol (LDL-C) or are effects on LDL-C a result of commercially available laboratory tests being unable to measure true LDL-C independent of lipoprotein (a) [Lp(a)]-C?
Methods:
Lp(a)-C was measured using a novel, quantitative assay in 286 subjects with a history of cardiovascular disease and elevated Lp(a). Subjects were randomized to groups of cumulative monthly doses of 20-80 mg pelacarsen versus 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 laboratory; 2) LDL-Ccorr = laboratory-reported LDL-C–direct Lp(a)-C; 3) LDL-CcorrDahlén = laboratory-reported LDL-C – [Lp(a) mass x 0.30] estimated by the Dahlén formula.
Results:
Baseline Lp(a)-C values ranged from 11.9–15.6 mg/dL. The LDLcorr was approximately 13-16 mg/dL lower than the laboratory-reported LDL-C and the LDLcorrDahlén was approximately 27-33 mg/dL lower than the laboratory-measured LDL-C. Pelacarsen significantly reduced Lp(a)-C by a mean of 29-67% in a dose-dependent manner compared with a mean decrease of 2% in pooled placebo, p = 0.001-< 0.0001. Pelacarsen was also associated with mean percent decreases in laboratory-reported LDL-C (-7% to -26%) and LDL-Ccorr (-2% to -19%) and increases in LDL-CcorrDahlén (3.1% to 28.3%), p = 0.006-0.50.
Conclusions:
Pelacarsen significantly reduces Lp(a)-C with neutral to modest effects on corrected LDL-C. Using a direct measurement of Lp(a)-C to calculate the LDL-Ccorr provides a more accurate reflection of changes in LDL-C than either laboratory-reported LDL-C or the Dahlén formula in patients with elevated Lp(a) treated with pelacarsen.
Perspective:
Lp(a) is now accepted as an independent risk factor for cardiovascular disease and is a target for new therapies such as pelacarsen. Decisions regarding choice and titration of these therapies relies on an understanding of the relative contribution of Lp(a)-C to the laboratory-reported LDL-C in patients with elevated Lp(a). This study shows that laboratory-reported LDL-C is incorrectly reported as higher than the corrected LDL-C in patients with elevated Lp(a). Measuring both LDL-C and Lp(a)-C may allow for a more personalized approach to determining cardiovascular risk using a corrected LDL-C.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Novel Agents
Keywords: Apolipoproteins, Atherosclerosis, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Dyslipidemias, Heart Disease Risk Factors, Lipoprotein(a), Oligonucleotides, Antisense, Primary Prevention, Risk Factors
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