Older Adults With Cardiovascular-Kidney-Metabolic Stage 2: Six-Year Risk Stratification Using NT-proBNP and TNFR1

Abstract Background Many older adults without cardiovascular disease meet criteria for CKM stage 2, but their near-term risk may differ substantially. We examined whether NT-proBNP and TNFR1 could distinguish six-year cardiovascular and mortality risk within CKM stage 2. Methods We used data from the 2016 Health and Retirement Study Venous Blood Study with follow-up through 2022. Participants were adults aged 50 years or older with measured CKM stage 0–2 and no cardiovascular disease at baseline. The main analysis focused on participants with measured CKM stage 2. NT-proBNP was evaluated using the commonly used clinical cutoff of 125 pg/mL. Among participants with NT-proBNP < 125 pg/mL, TNFR1 was further assessed using threshold analysis, restricted cubic splines, bootstrap validation, decision curve analysis, survey-weighted models, and competing-risk analysis. Results Among 6,488 eligible participants, 6,205 (95.6%) were classified as measured CKM stage 2. Within this group, participants with NT-proBNP < 125 pg/mL had lower six-year risk of cardiovascular disease or death than those with NT-proBNP > = 125 pg/mL (15.9% vs 44.0%). Among participants with NT-proBNP < 125 pg/mL, higher TNFR1 identified a subgroup with greater risk (27.5% vs 13.5%; adjusted HR 1.68 (1.37–2.05)). Risk increased stepwise across biomarker-defined groups, and sensitivity analyses showed similar patterns. Conclusions In older adults with CKM stage 2, NT-proBNP and TNFR1 identified marked differences in six-year cardiovascular and mortality risk. These biomarkers may help refine risk assessment within CKM stage 2.