PCSK9 inhibition
Apo(a) isoform size, not baseline Lp(a), explains why PCSK9 inhibitor combination therapy lowers Lp(a) unevenly (CHORD study, J Clin Lipidol 2025)
Original title: Variation in lipoprotein(a) response to potent lipid lowering: The role of apolipoprotein (a) isoform size
In the CHORD study, 150 participants with LDL-C above 100 mg/dL (mean age 50, 58% female, 50% non-White, 50% with diabetes) received 30 days of evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Median Lp(a) fell from 27.5 to 23 mg/dL, a 10% median reduction (P < .001), and among the 73 participants (49%) with baseline Lp(a) at or above 30 mg/dL, the median reduction was 15% (P < .001). Baseline Lp(a) level did not correlate with the magnitude of reduction (r = 0.04, P = .59), but apolipoprotein(a) isoform size did, both unadjusted (P < .001) and after adjusting for age, sex, race/ethnicity, diabetes and lipid-lowering regimen (beta 0.95, 95% CI 0.93-0.97, P < .001). The findings identify apo(a) isoform size, not baseline Lp(a) concentration, as the key driver of variable Lp(a) response to potent PCSK9-inhibitor-based lipid-lowering therapy.
Original abstract
Background: Lipoprotein(a) [Lp(a)] is a driver of residual cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) decrease Lp(a) with significant heterogeneity in response. We investigated contributors to the heterogeneous response.
Methods: Cholesterol Reduction and Residual Risk in Diabetes (CHORD) was a prospective study examining lipid lowering in participants with a low-density lipoprotein cholesterol (LDL-C) > 100 mg/dL with and without diabetes (DM) on lipid lowering therapy (LLT) for 30-days with evolocumab 140 mg every 14 days combined with either atorvastatin 80 mg or ezetimibe 10 mg daily. Lp(a) level was measured by immunoturbidometry, and the apolipoprotein(a) [apo(a)] isoform size was measured by denaturing agarose gel electrophoresis and Western blotting. We examined the change in Lp(a) levels from baseline to 30 days.
Results: Among 150 participants (mean age 50 years, 58% female, 50% non-White, 17% Hispanic, 50% DM), median (interquartile range) Lp(a) was 27.5 (8-75) mg/dL at baseline and 23 (3-68) mg/dL at 30 days, leading to a 10% (0-36) median reduction (P < .001). Among 73 (49%) participants with Lp(a) ≥ 30 mg/dL at baseline, there was a 15% (3-25) median reduction in Lp(a) (P < .001). While baseline Lp(a) level was not correlated with change in Lp(a) (r = 0.04, P = .59), apo(a) size directly correlated with Lp(a) reduction (P < .001). After adjustment for age, sex, race/ethnicity, DM, and type of LLT, apo(a) size remained positively associated with a reduction in Lp(a) (Beta 0.95, 95% confidence interval, 0.93-0.97, P < .001).
Conclusion: Our data demonstrate variation in Lp(a) reduction with potent LLT. Change in Lp(a) was strongly associated with apo(a) isoform size.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.