Abstract
Lipoprotein(a) [Lp(a)] represents one of cardiovascular medicine's most profound implementation gaps: a genetically determined risk factor affecting 1.5 billion people worldwide, yet historically underutilized in clinical practice despite overwhelming evidence of its importance. This review examines the transformation of Lp(a) from an untreatable genetic burden to a promising therapeutic target through four interconnected perspectives. First, we document the implementation gap, where, despite affecting 20% of the global population, screening remains below 1%. The evolution from selective screening (2018 American College of Cardiology/American Heart Association (ACC/AHA)) to universal measurement (2024 National Lipid Association (NLA) Class I recommendation) reflects growing recognition, yet persistent barriers, including reimbursement challenges, provider knowledge gaps, and laboratory standardization issues, perpetuate underutilization. Second, we synthesize evidence establishing Lp(a)'s dual nature as both a biomarker and a causal factor. Observational studies demonstrate markedly increased cardiovascular risk with elevated Lp(a), while Mendelian randomization confirms causal relationships with coronary heart disease, large-artery stroke, peripheral artery disease, and aortic stenosis, with differential effects on stroke subtypes and non-atherosclerotic outcomes. Third, we examine the transformation from genetic determinism to pharmacological tractability. Despite 70-90% heritability, novel RNA-targeted therapies achieve unprecedented 80-95% reductions, with phase 3 cardiovascular outcome trials (completing 2026-2029) poised to determine whether dramatic Lp(a) lowering translates to clinical benefit. Finally, we provide a practical management algorithm bridging current evidence-based risk stratification with emerging therapies, stratifying patients by Lp(a) levels with corresponding interventions. The Lp(a) story exemplifies how genetic insights and technological innovation can transform immutable disease aspects into treatable conditions, offering a paradigm for precision cardiovascular medicine while highlighting the urgent need to close the gap between scientific knowledge and clinical implementation.