Lipoprotein(a): An Emerging Independent Risk Factor for Atherosclerotic Cardiovascular Disease

Mohammed Khaja Moinudeen; Shayna Femy; Patibandla Sathvika; Kartik Khetade; Devansh Pardhi

Lipoprotein(a): An Emerging Independent Risk Factor for Atherosclerotic Cardiovascular Disease

Author(s)	Dr Mohammed Khaja Moinudeen, Dr Shayna Femy, Ms Patibandla Sathvika, Mr Kartik Khetade, Mr Devansh Pardhi
Country	India
Abstract	Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global morbidity and mortality despite profound advancements in low-density lipoprotein cholesterol (LDL-C) reduction therapies. A substantial proportion of residual cardiovascular risk is driven by Lipoprotein(a) [Lp(a)], a distinct, low-density lipoprotein-like particle. Synthesized in the liver, Lp(a) consists of an apolipoprotein B-100 (ApoB-100) molecule covalently bound to a highly polymorphic glycoprotein, apolipoprotein(a) [Apo(a)]. Large-scale epidemiological, genome-wide association, and Mendelian randomization studies have definitively established elevated plasma Lp(a) as a causal, independent risk factor for myocardial infarction, ischemic stroke, calcific aortic valve stenosis, and peripheral arterial disease. Unlike traditional lipid markers, circulating Lp(a) concentrations are up to 90% genetically predetermined by variations in the LPA gene locus, making them highly refractory to diet, exercise, and conventional lipid-lowering regimens such as statins. In fact, statin therapy can modestly elevate baseline Lp(a) expression, emphasizing its role as a persistent driver of vascular damage. The pathogenic mechanisms of Lp(a) are multifaceted, encompassing accelerated atherogenesis through intimal cholesterol deposition, enhanced vascular inflammation driven by oxidized phospholipids (OxPL), and pro-thrombotic or anti-fibrinolytic activities mediated by structural homologies between Apo(a) and plasminogen. Major international guidelines, including those from the European Society of Cardiology (ESC) and the American Heart Association (AHA), now advocate for at least once in lifetime screening for Lp(a) in adults to optimize risk stratification. However, clinical implementation remains globally suboptimal due to measurement standardization challenges and a lack of approved targeted therapeutics. This comprehensive review examines the structural biology, dual pathogenic pathways, and changing diagnostic paradigms surrounding Lp(a). It concludes with a deep-dive analysis of emerging RNA-targeted therapies—such as Pelacarsen, Olpasiran, and Lepodisiran—that hold the promise of mitigating residual cardiovascular risk by selectively silencing Lp(a) expression.
Field	Medical / Pharmacy
Published In	Volume 8, Issue 4, July-August 2026
Published On	2026-07-24

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Lipoprotein(a): An Emerging Independent Risk Factor for Atherosclerotic Cardiovascular Disease

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