Association of Frailty with Mortality and Incident Cardiovascular Disease: The Role of Metabolic Status

To identify whether metabolic status mediates the associations between frailty and mortality and incident cardiovascular disease (CVD), and to assess of interactive or joint relationships between frailty and metabolic status on these outcomes.

In this prospective cohort study of 456,445 UK Biobank participants, frailty was assessed using five phenotype criteria. Metabolic status was scored (0-4) based on central obesity, hypertension, hyperglycemia, and dyslipidemia. Multivariable-adjusted Cox regression models were used to assess the associations between frailty and mortality and incident CVD.

During a median follow-up of 13.8 years for mortality and 13.6 years for CVD, 30,907 deaths (7,467 CVD-related) and 37,115 incident CVD cases occurred. Frailty was associated with higher risks of all-cause mortality (hazard ratio [ HR], 2.41; 95% confidence interval [ CI], 2.31-2.51), CVD mortality ( HR, 2.64; 95% CI, 2.43-2.87), and incident CVD ( HR, 1.83; 95% CI, 1.75-1.91), compared with non-frail individuals. Metabolic status mediated 8.7%, 16.1%, and 16.4% of these associations, respectively. Frailty and metabolic status interacted multiplicatively for all-cause mortality ( P-value for interaction < 0.001) and additively for CVD mortality [relative excess risk due to interaction (RERI), 1.78; 95% CI, 0.88-2.68] and incident CVD (RERI, 0.60; 95% CI, 0.33-0.86). Joint exposure to frailty and three to four metabolic disorders conferred 3.34-, 6.32-, and 3.30-fold risks of all-cause mortality, CVD mortality, and incident CVD, respectively, compared with metabolically healthy non-frail individuals.

This study highlights the need for integrated management strategies targeting both frailty and metabolic conditions to mitigate cardiovascular and mortality risks.