Key result
Lipophilic statins linked to ~7% higher dementia risk than hydrophilic statins, especially at LDL-C <50 mg/dL.
Why the study?
Very low LDL-C (<50 mg/dL) was previously linked to higher odds of cognitive impairment, but whether statin hydrophilicity or lipophilicity affects this risk remained unknown.
Does the use of lipophilic statins increase the risk of cognitive dysfunction compared to hydrophilic statins in older adults?
Cross-Sectional (n=3,000,000)
Does the use of lipophilic statins increase the risk of cognitive dysfunction compared to hydrophilic statins in older adults?
Odds Ratio: 1.07 (95% CI 1.04–1.09)
p-value: p=< 0.05
In older veterans, lipophilic statins are associated with a slightly higher risk of cognitive dysfunction compared to hydrophilic statins, particularly at very low LDL-C levels.
Should not alter statin selection in older adults; leaves open confounding or causality for lipophilicity at low LDL-C.
Introduction and Objective: Statins lower low density lipoprotein cholesterol (LDL-C) and reduce cardiovascular risk, but very low levels (<50 mg/dL) may have adverse effects. Prior analysis showed LDL-C <50 mg/dL was linked to a higher odds of cognitive impairment. This study examined if statin hydrophilicity or lipophilicity affected risk of cognitive dysfunction. Methods: We performed a retrospective cross-sectional analysis using the Veterans Affairs Corporate Data Warehouse. Inclusion criteria were age >65, statin use, and available LDL-C values. Presence of cognitive dysfunction was determined using Current Procedural Terminology and ICD-9/10 codes for dementia and use of dementia medications for LDL-C < 50, [50 - 75], [75 - 100], and ≥ 100 mg/dL. We also identified subjects with diabetes and microvascular disease. Stratified multivariable analyses were performed adjusting for age-cohort, sex, and race. Results: Three million patients met inclusion criteria. Mean age at statin initiation was 65 years. The cohort was predominantly male (96%), White (69%), and 18% of the patients had cognitive dysfunction. For all LDL groups except LDL-C 50-75 mg/dL, lipophilic statins were associated with higher odds of dementia compared to hydrophilic statins (LDL-C < 50 mg/dl: OR 1.07, 95% CI: 1.04-1.09, p < 0.05; LDL-C 50-75 mg/dL: OR 1.01, CI: 1.0-1.03, p=0.11; LDL-C 75-100 mg/dL: OR 1.03, CI: 1.01-1.04, p < 0.05; LDL-C > 100 mg/dL: OR 1.1, CI 1.1-1.12, p < 0.05). The increased risk for lipophilic statins was not seen in the diabetic microvascular disease subgroup (LDL-C < 50 mg/dL: OR 0.94, CI: 0.911-0.973, p < 0.05). Conclusion: In older veterans, lipophilic statins were associated with higher odds of cognitive dysfunction across most LDL-C strata, and very pronounced with LDL-C <50. These findings suggest statin lipophilicity influences cognitive risk, possibly related to ability to cross the blood-brain barrier (BBB). In diabetic microvascular disease, where dementia is increased and BBB is impaired, lipophilicity does not add further risk. Disclosure C.O. Usoh: None. M.E. DeWitt: None. J.J. Wenner: None. D. McClain: None. Funding VA Career Development Award
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USOH et al. (2026) conducted a cross-sectional in Cognitive dysfunction (n=3,000,000). Lipophilic statins vs. Hydrophilic statins was evaluated on Dementia (OR 1.07, 95% CI 1.04-1.09, p=< 0.05). In older veterans, lipophilic statins were associated with higher odds of dementia compared to hydrophilic statins, particularly at LDL-C <50 mg/dL (OR 1.07; 95% CI 1.04-1.09; p<0.05).
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