Clinical Response to Elevated Lipoprotein(a): Practical Approach for Risk Management in the Absence of Targeted Therapies

Lipoprotein(a) [Lp(a)] is a genetically determined, lifelong cardiovascular risk factor strongly associated with atherosclerotic cardiovascular disease (ASCVD) despite optimal low-density lipoprotein cholesterol (LDL-C) lowering. The current management is challenged by absence of outcome-proven Lp(a)-specific therapies. Statins, ezetimibe, bempedoic acid and lifestyle interventions have little or no effect on Lp(a). Statins may modestly raise levels, niacin is now contraindicated as it has not been shown to reduce cardiovascular or all-cause mortality, while PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors and inclisiran reduce Lp(a) concentrations by ~20-30%, though this effect remains secondary to their LDL-C lowering effect. The only FDA-approved therapy specifically addressing Lp(a) is lipoprotein apheresis, which reduces Lp(a) levels by 60-75%, but is restricted to specific patient populations due to invasiveness, high cost and limited availability. Future promise lies in RNA-based therapies, including antisense oligonucleotides (pelacarsen) and small-interfering RNAs (olpasiran, lepodisiran, SLN360), which achieve 80-95% sustained Lp(a) reductions. Large outcome trials will determine whether this biochemical efficacy translates into tangible clinical benefits. Current guidelines now recommend one-time lifetime Lp(a) measurement, treating ≥125 nmol/L (≥50 mg/dL) as risk-enhancing factor. High or extreme elevations, especially with ASCVD, mandate aggressive LDL-C lowering, optimization of modifiable risk factors, family cascade screening, and apheresis or referral to RNA-therapy trials in select cases. Thus, while therapeutic options remain limited, systematic measurement and risk stratification are ethically justified to prepare for imminent arrival of Lp(a) targeted therapies.