Frailty may confound the association between MASLD and cardiovascular mortality in people with cardiometabolic risk...

While metabolic dysfunction-associated steatotic liver disease (MASLD) has been consistently associated with increased cardiovascular risk in the general population, its association with cardiovascular disease (CVD) mortality in adults with established cardiometabolic risk factor (including obesity, hypertension, diabetes mellitus, or dyslipidemia) remains inconsistent. We aimed to determine whether frailty confounds the MASLD-CVD mortality association.

We analyzed 10,413 US NHANES III adults with ≥ 1 cardiometabolic risk factor. Frailty was quantified using a 49-item frailty index (FI, ranging from 0 [maximal robustness] to 1 [severe frailty]) and categorized into quartiles. Associations between MASLD and CVD mortality were assessed using multivariable Cox proportional hazards models with and without frailty adjustment. Interaction and mediation analyses were also performed.

Over a mean follow-up of 23.36 years, 1,375 (13.20%) CVD deaths occurred. Frailty was significantly associated with both MASLD and CVD mortality. There was no evidence of interaction between MASLD and frailty, and mediation analysis showed no indirect effect of MASLD on CVD mortality through frailty. In absence of frailty adjustment, MASLD was not associated with CVD mortality (HR = 0.92, 95% CI: 0.78-1.10). After adjustment for frailty, MASLD was independently associated with higher CVD mortality (HR = 1.19, 95% CI: 1.07-1.32). Stratified by FI quartiles, significant associations were observed only in the higher frailty quartiles (Q3: HR = 1.35, 95% CI: 1.03-1.77; Q4: HR = 1.70, 95% CI: 1.07-2.69). The population attributable fraction of MASLD for CVD mortality was 10.1-12.5% after frailty adjustment.

Frailty may confound the MASLD-CVD mortality relationship in people with cardiometabolic risk factors. The association between MASLD and CVD mortality is detected only when frailty is adjusted for.