Very Low Cholesterol Non‐Cardiovascular Risks: A Critical Appraisal and Framework for Individualized Management

Randomized trial evidence firmly establishes that lowering LDL-C reduces atherosclerotic cardiovascular disease. However, observational studies consistently report U-shaped cholesterol-mortality associations, raising concerns about potential non-cardiovascular risks at very low levels. This narrative review (not systematic review; no PRISMA flow or formal search strategy) distinguishes observational associations from causal evidence, defines "very low cholesterol" as LDL-C < 70 mg/dL, and emphasizes patient context in personalized management for adults (not pediatrics). Epidemiologically, low cholesterol correlates with cancer, depression, hemorrhagic stroke, and infection, with biological plausibility involving membrane integrity, neurosteroid synthesis, vascular stability, and immune function. Yet these mechanisms remain speculative, and such associations are highly susceptible to reverse causation, whereby chronic illness itself lowers cholesterol. Critically, Mendelian randomization studies and meta-analyses of randomized controlled trials-including statin and PCSK9 inhibitor trials-have not demonstrated causal links between pharmacologically induced low LDL-C and these adverse outcomes. Mathematical models (quadratic, hormetic, biomechanical) are included as conceptual illustrations only and are not clinically validated. All mathematical models (quadratic, hormetic, Arrhenius, Hill, Laplace, CHI) presented herein are conceptual illustrations only, not clinically validated. They serve heuristic and hypothesis-generating purposes, not clinical prediction. For most high-risk patients, cardiovascular benefits clearly outweigh theoretical risks. However, subgroups such as the very elderly, frail individuals, or those with prior hemorrhagic stroke warrant individualized assessment guided by comorbidities, life expectancy, and treatment safety rather than cholesterol levels alone. Ultimately, observational signals do not challenge established LDL-C reduction benefits in high-risk populations; their primary value lies in reinforcing context-driven personalization at the margins of therapy.