J Clin Lipidol. 2025 Nov 15:S1933-2874(25)00515-X. doi: 10.1016/j.jacl.2025.11.009. Online ahead of print.
ABSTRACT
BACKGROUND: While cholesterol-lowering trials have consistently demonstrated cardiovascular disease (CVD) benefits, some observational studies showed an elevated mortality risk from all-cause, CVD, and cancer in those with low total cholesterol (TC). This inconsistency is likely due to confounding.
OBJECTIVE: We explored potential confounders through various analytical approaches such as exclusion and adjustment.
METHODS: Using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study, we analyzed all-cause, CVD, and cancer mortality in individuals aged 35 to 69, not on cholesterol-lowering medication at baseline. We applied cohort-stratified Cox proportional hazards models to estimate the hazard ratio (HR) and 95% CI of the lowest TC group (<160 mg/dL) in reference to 160 to <200 mg/dL, after excluding self-reported CVD and cancer at baseline.
RESULTS: A total of 55,677 participants were followed over 10.1 years. Initially, the lowest TC group, compared to the reference group, had significantly elevated risks for all-cause and cancer mortality. Excluding liver diseases and adjusting for serum albumin at baseline attenuated the association to non-significant; HR (95% CI) of all-cause, cancer mortality in men: 1.37 (0.99-1.87), 1.06 (0.66-1.71), respectively. The corresponding values for women were 0.96 (0.46-2.02), 1.39 (0.58-3.34). For CVD mortality, the HR in men with low TC remained elevated, while women were nonsignificant regardless of liver diseases exclusion and albumin-adjustment.
CONCLUSION: Elevated all-cause and cancer mortality in low TC individuals was likely confounded by baseline liver diseases and serum albumin. Further research is needed to identify additional confounders.
PMID:41484028 | DOI:10.1016/j.jacl.2025.11.009