In the All of Us Research Program, women had higher median LDL-C than men across most age strata, with the gap widest after age 40 and persisting regardless of statin use. Women received statins less often and appeared to respond less effectively, and Black women had the highest statin-treated median LDL-C of any race-sex group. Sex-stratified GWAS recapitulated known APOE/APOC1 effects, while LDL-C heritability and additive genetic variance did not differ by sex; residual and phenotypic variance did.
The pattern fits earlier evidence that women are undertreated for lipid control, particularly after menopause, when estrogen's LDL-lowering effect fades. The finding that genetic variance is similar while environmental variance differs points toward modifiable factors such as prescribing behavior, adherence, diet, and access, though this study cannot separate them. The apparent weaker statin response deserves caution: lower adherence, lower doses, or lower-intensity prescribing could produce the same signal, and trial meta-analyses show statins reduce relative cardiovascular risk similarly in women and men. Observational biobank data with self-selected volunteers and electronic health record gaps limit causal conclusions. This is a preprint that has not undergone peer review, so results may shift. Practically, women over 40 have good reason to ask their clinicians about LDL-C targets and statin eligibility rather than assuming lower risk. The work is confirmatory and incremental, strengthening the undertreatment case rather than overturning existing understanding.