Pushing the limits of LDL cholesterol: Emerging paradigms in cardiovascular risk reduction.

LDL cholesterol (LDL-C) has long been recognized as a primary contributor to cardiovascular disease. Over time, guideline-recommended LDL-C targets have varied considerably, trending toward progressively more aggressive therapeutic goals. The focus on residual risk reduction and development of novel therapies-including PCSK9 inhibitors, siRNA-based treatments, and ANGPTL3 inhibitors-have significantly expanded the options for achieving unprecedentedly low LDL-C levels. Given the fundamental role of cholesterol in cellular function, it has been long been postulated that very low cholesterol could be associated with adverse events. In this review, we dissect the benefits and potential risks of very low LDL-C levels. We begin by providing an overview of the evolution of LDL-C targets in previous guidelines and highlighting therapies-including newer agents-used for aggressive LDL-C lowering. Drawing on clinical and genetic evidence, we then examine the benefits and risks associated with achieving very low LDL-C levels. Finally, we present a practical framework for balancing the potential risks and benefits of intensive LDL-C reduction in patient care.