TARGETING ELEVATED LIPOPROTEIN (A) WITH PCSK9 INHIBITORS: A NEW FRONTIER IN CARDIOVASCULAR RISK REDUCTION: AN UMBRELLA REVIEW

Therapeutic Area

ASCVD /CVD Risk Reduction

Background

Elevated Lipoprotein(a), a genetically inherited risk factor, is independently associated with increased cardiovascular risk. It remains underdiagnosed and undertreated in clinical practice, posing an unmet need in cardiovascular prevention. Unlike LDL-Cholestrol, lipoprotein(a) levels are not significantly influenced by diet or conventional lipid-lowering therapies such as statins. Recent studies suggest that Proprotein Convertase Subtilisin Kexin9 (PCSK9) inhibitors, initially developed for LDL-C reduction, may also reduce lipoprotein(a), offering dual benefits for patients with elevated lipoproteins(a) levels and high cardiovascular risk.

Methods

A comprehensive literature search was performed in PubMed, Embase, Web of Science, Scopus, and the Cochrane Library, covering 2014 to 2024. Eleven systematic reviews and meta-analyses, comprising 253,311 participants, were selected based on predefined inclusion criteria. Cardiovascular risk reduction (hazard ratios) and Lp(a) reduction percentages were synthesized into standardized mean percentage change metrics. Data extraction and synthesis were performed independently by three reviewers. Participants aged 18 to 65 were studied from international centers and exhibited diverse cardiovascular risk profiles, Population characteristics were analyzed using pooled clinical trial data from different phases.

Results

Lp(a) reduction was analyzed in 11 studies with 253,311 participants. The mean reduction was 25.08% (95% CI:21.94%-28.21%), with reductions ranging from 10.91% to 30.60%. Sensitivity analysis confirmed a stabilized reduction of 26.5%. There was significant heterogeneity (I2 = 99.9%) and potential publication bias (Egger’s test, p = 0.001). Cardiovascular risk reduction was assessed in seven studies, yielding a pooled Hazard Ratio (HR) of 0.85 (95% CI: 0.75- 0.96, P = 0.008), representing a 15% reduction in Atherosclerotic Cardiovascular Disease (ASCVD) risk. Moderate heterogeneity (I2 = 72%) and possible publication bias (p=0.042) were noted.

Conclusions

PCSK9 inhibitors demonstrate a dual role, effectively decreasing both LDL-C and lipoprotein(a), which has a significant role in the primary prevention of cardiovascular events. By focusing on Lp(a) that is genetically raised, these drugs may help reduce the residual cardiovascular risk that is unmet by conventional lipid-lowering interventions. Yet, because of the heterogeneity and probable publication bias, many large and focused trials are needed to validate the data, optimize these interventions, and define clinical recommendations for Lp(a) treatment.