Timing of Coffee Intake Modifies Mortality Risk in Cardiovascular‐Kidney‐Metabolic Syndrome: A Cohort and Experimental Study

The association between the timing of coffee consumption and mortality risk among individuals with cardiovascular-kidney-metabolic (CKM) syndrome remains unclear. This study aims to identify patterns of coffee intake timing and assess their links to all-cause and cause-specific mortality. This prospective cohort study included 21 553 adults with CKM syndrome from the 1999-2018 National Health and Nutrition Examination Survey. Two-step cluster analysis was used to identify temporal patterns of coffee consumption. Mortality risks were evaluated using weighted Cox proportional hazards regression models. Mouse models of CKM syndrome were established for different coffee consumption patterns. Over a median follow-up of 9.2 years, two coffee temporal patterns emerged: morning-type (47.7%) and late-day (5.3%). Among 3565 all-cause deaths, multivariable-adjusted models showed the morning-type pattern was associated with significantly reduced risks of all-cause (HR 0.79; 95% CI 0.65-0.97) and cardiovascular mortality (HR 0.75; 95% CI 0.50-0.97), independent of total intake and confounders. The relationship between coffee intake and all-cause mortality varied significantly by coffee temporal patterns (p-interaction = 0.035), with higher coffee consumption demonstrating inverse associations with all-cause mortality exclusively among morning-type consumers. In CKM mice, morning coffee improved metabolic and renal function, reduced cTnT and inflammatory markers (IL-6, IL-17A, CXCL1, CXCL2), while late-day coffee offered no benefits. Morning coffee consumption was more strongly associated with a lower risk of death in CKM than drinking coffee later. Our findings highlight the importance of coffee drinking timing in the association between coffee intake and health outcomes.