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We analyzed plasma proteomic data from 53,030 UK Biobank participants with longitudinal follow-up. Mediation analysis evaluated circulating proteins linking three primary cardiometabolic diseases to 18 secondary outcomes. Mendelian randomization assessed potential causal relationships, and machine learning evaluated the predictive value of identified mediators. We identified 998 significant mediation pathways involving 337 unique plasma proteins. GDF15 consistently mediated associations between diabetes and cardiovascular diseases, and ACE2 linked poorly controlled diabetes to increased risk of nerve root and plexus disorders. Mediators were enriched in receptor-mediated signaling and molecular interaction pathways. Mendelian randomization supported potential causal roles for 44 proteins. Incorporating mediator proteins into machine learning models improved prediction of secondary disease risk beyond traditional clinical factors and other plasma proteins. 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