Reduction of Visit-to-Visit LDL-C Intraindividual Variability in Patients Treated with PCSK9 Inhibitors and Inclisiran Versus Standard Lipid-Lowering Therapy

Background Recent evidence suggests that visit-to-visit LDL-C variability—a measure of intraindividual lipid fluctuation over time—may independently influence cardiovascular risk. This study evaluated the impact of Proprotein Convertase Subtilisin/Kexin Type 9 inhibitors (PCSK9i) and inclisiran on LDL-C variability compared to standard Lipid-Lowering Therapy (LLT) in a real-world population of very high-risk patients. Methods We conducted a longitudinal, observational study including 618 patients at very high cardiovascular risk, treated at a single tertiary center. Patients were stratified into three groups: standard LLT (statins ± ezetimibe), PCSK9i, or inclisiran. LDL-C variability was assessed at four follow-up time points using both standard deviation (SD) and coefficient of variation (CV), excluding the first lipid measurement to minimize early response bias. High variability was defined as SD or CV above the population median. Major adverse cardiovascular events (MACE) were collected as exploratory outcomes. Results Patients receiving PCSK9i or inclisiran had significantly lower LDL-C variability compared to those on standard LLT (mean SD: 8.2 and 8.5 vs. 20.5 mg/dL; p < 0.001; mean CV: 0.17 and 0.16 vs. 0.31; p < 0.001). High variability in both SD and CV was observed in 77.3% of patients on standard LLT, but only in 17.2% and 17.1% of patients on PCSK9i and inclisiran, respectively. MACE incidence was higher in patients with high variability (12.5% vs. 6.1%, p = 0.012). Multivariate analysis confirmed that treatment with PCSK9i or inclisiran was independently associated with lower LDL-C variability. Conclusions In patients at very high cardiovascular risk, PCSK9i and inclisiran therapies are associated with significantly lower visit-to-visit LDL-C variability compared to standard statin-based regimens. These findings support the importance of not only achieving LDL-C targets but also maintaining lipid stability over time, which may contribute to improved cardiovascular outcomes.