Association of Diurnal Patterns in Salivary Cortisol with All-Cause and Cardiovascular Mortality: Findings from the Whitehall II Study

Context: Evidence for the association of cortisol with mortality or disease events is mixed, possibly due to a failure to consider diurnal cortisol patterns. Objective: Our objective was to examine the association of diurnal cortisol patterns throughout the day with cardiovascular and noncardiovascular mortality in a community-dwelling population. Design: This was a prospective cohort study among 4047 civil servants, the Whitehall II study, United Kingdom. We measured diurnal cortisol patterns in 2002-2004 from six saliva samples obtained over the course of a normal weekday: at waking, + 30 min, + 2.5 h, + 8 h, + 12 h, and bedtime. Participants were subsequently followed for all-cause and cause-specific mortality until January 2010. Participants: Participants included 4047 men and women aged 61 yr on average at baseline. Outcomes: We assessed all-cause, cardiovascular, and noncardiovascular death. Results: There were 139 deaths, 32 of which were deaths due to cardiovascular disease, during a mean follow-up period of 6.1 yr. Flatter slopes in cortisol decline across the day were associated with increased risk of all-cause mortality (hazard ratio for 1 SD reduction in slope steepness 1.30; 95% confidence interval (CI) = 1.09-1.55). This excess mortality risk was mainly driven by an increased risk of cardiovascular deaths (hazard ratio = 1.87; 95% confidence interval = 1.32-2.64). The association with cardiovascular deaths was independent of a wide range of covariates measured at the time of cortisol assessment. There was no association between morning cortisol, the cortisol awakening response, and mortality outcomes. Conclusions: These findings demonstrate, for the first time, the relationship between a flatter slope in cortisol levels across the day and an increased risk of cardiovascular disease mortality in a nonclinical population. (J Clin Endocrinol Metab 96: 1478-1485, 2011)