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.