Life’s Essential 8 and Cancer Risk: A Multistate Causal Mediation Analysis of Incident Cardiovascular Disease

Background: Life’s Essential 8 (LE8) is a comprehensive measure of cardiovascular health (CVH), with higher scores indicating better CVH. Higher LE8 has been linked to lower cancer risk, but the extent to which incident cardiovascular disease (CVD) mediates this association is unclear. Methods: In UK Biobank (2006–2010 enrollment; follow-up to May 2022), we analyzed 172,053 adults free of cancer and CVD at baseline with complete LE8 and covariates. LE8 (0–100) was categorized as High (80–100), Middle (50–79), and Low (0–49). Incident cancers were ascertained via cancer registries, and incident CVD was identified from hospital records. HRs were estimated using multivariable Cox models. Mediation by CVD was assessed using multistate causal mediation methods for time-to-event data and summarized as the proportion eliminated (PE) at 5, 10, and 15 years. Results: Mean (SD) age at baseline was 55.2 (8.1) years; 49.0% were male; 95.7% were White. Participants were 19.4% High, 73.6% Middle, and 7.1% Low LE8. Lower LE8 was associated with higher overall cancer risk (Middle vs High: HR=1.15, 95% CI: 1.10–1.20; Low vs High: HR=1.41, 95% CI: 1.32–1.50). Low vs High LE8 was associated with higher risk of breast (HR [95% CI]=1.24 [1.06–1.46]), colorectal (1.57 [1.29–1.90]), pancreatic (2.03 [1.36–3.04]), kidney (2.09 [1.45–3.03]), uterine (2.54 [1.77–3.66]), and lung cancer (6.43 [4.90–8.44]). Incident CVD mediated up to 10.61% (95% CI: 0.23–21.08) of the LE8–overall cancer association (maximum PE across 5, 10, and 15 years), and up to 8.39% (lung), 12.56% (uterine), 20.42% (colorectal), 30.52% (pancreatic), and 63.58% (kidney). Conclusions: Better CVH, assessed by LE8, was associated with lower risk of overall and several site-specific cancers. Incident CVD partially mediated these associations, modestly for overall cancer but substantially for certain sites, suggesting both CVD-mediated and CVD-independent pathways.