Variation In Lipoprotein (a) Level Reduction With Potent Lipid Lowering: An Analysis Of The Cholesterol Reduction And Residual Risk In Diabetes Study

Introduction: Lipoprotein (a) [Lp(a)] is a recognized risk factor for ASCVD and a driver of residual risk. Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i) modestly decrease Lp(a) by ≈ 15%. However, there is significant heterogeneity in Lp(a) lowering response to PCSK9i. We hypothesize that the apolipoprotein a [apo(a)] isoform size is responsible for the variable response in Lp(a) lowering. Methods: We examined the change in Lp(a) levels from baseline in the Cholesterol Reduction and Residual Risk (CHORD) study. Participants with and without diabetes—all with LDL-C >100mg/dl—received potent lipid lowering therapy (LLT) for 30 days with (1) Evolocumab 140mg q 14 days, and (2) atorvastatin 80mg/day (or ezetimibe 10mg/day if already on a statin or statin intolerant). Lp(a) level was measured in the clinical lab. The apo(a) isoform size was measured by denaturing agarose gel electrophoresis followed by western blotting. Results: Among 87 participants (median age 53, 59% [51 of 87] female, 54% [47 of 87] diabetes), median Lp(a) was 35 mg/dl at baseline and 25 mg/dl at 30 days (P<0.01). Among 47 participants with a high Lp(a) at baseline (>30mg/dl), there was an average 14% reduction in Lp(a) from baseline to 30 days with considerable heterogeneity in response (Figure 1A). While baseline Lp(a) Level was not correlated with change in Lp(a) (Figure 1B), there was an inverse correlation between major isoform size and Lp(a) reduction (r= -0.64, P<0.001) (Figure 1C). After adjustment for age, sex, race/ethnicity, diabetes, and type of LLT, major isoform size was significantly associated with change in Lp(a) (Beta 0.96, 95% CI 0.94 to 0.98, P<0.001). An apo(a) isoform size of 18 discriminated the response of Lp(a) levels to LLT (isoform size ≥18 - 20% [14 to 26] reduction, isoform <18 - 5% [-8 to 19] increase). Conclusion: Our data indicate considerable variation in Lp(a) reduction with potent LLT, and that apo(a) isoform size is strongly associated with this variability.