Objectives: Polypharmacy and frailty are two common geriatric conditions. In community-dwelling healthy older adults, we examined whether polypharmacy is associated with frailty and affects disability-free survival (DFS), assessed as a composite of death, dementia, or persistent physical disability.

Methods: We included 19,114 participants (median age 74.0 years, IQR: 6.1 years) from ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. Frailty was assessed by a modified Fried phenotype and a deficit accumulation Frailty Index (FI). Polypharmacy was defined as concomitant use of five or more prescription medications. Multinomial logistic regression was used to examine the cross-sectional association between polypharmacy and frailty at base line, and Cox regression to determine the effect of polypharmacy and frailty on DFS over five years.

Results: Individuals with polypharmacy (vs. <5 medications) were 55% more likely to be pre-frail (relative risk ratio or rrr: 1.55; 95%confidence interval ci:1.44, 1.68) and three times frail (rrr: 3.34; 95%ci:2.64, 4.22) according fried phenotype. frailty alone was associated with double of the composite outcome (hazard hr: 2.16; 95%ci: 1.56, 2.99), but individuals using polypharmacy had a four-fold (hr: 4.24; 3.28, 5.47). effect sizes larger when assessed fi.

Conclusion: Polypharmacy was significantly associated with pre-frailty and frailty at baseline. Polypharmacy-exposed frailty increased the risk of reducing disability-free survival among older adults. Addressing polypharmacy in older people could ameliorate the impact of frailty on individuals' functional status, cognition and survival.