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Use of a Metabolic Syndrome Severity OBJECTIVE: We assessed whether changes in metabolic syndrome (MetS) severity during the treatment of prediabetes are associated with reduced risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We analyzed data from the Diabetes Prevention Program (DPP) for 2,476 adults in 1996-1999 with prediabetes randomized to receive treatment with lifestyle modification, metformin, or placebo for 2-3 years and followed through 2014 for T2DM and CVD outcomes. We calculated effect sizes from baseline in a MetS severity z score (MetS-Z) and the individual MetS components, and assessed relationships between 1-year effect size and incident T2DM and CVD using hazard ratios (HRs) and mediation analysis. RESULTS: Baseline MetS-Z and its components were associated with risk of incident T2DM and CVD. During year 1 of intervention, MetS-Z and its components decreased most with lifestyle modification, followed by treatment with metformin and placebo. Risk of T2DM within 1-5 years was most strongly associated with 1-year changes in MetS-Z and waist circumference (both HRs for a 1 SD increase = 1.80), whereas the risk of CVD was associated with a 1-year change in MetS-Z, glucose, and systolic blood pressure. In mediation analyses, the effect of lifestyle modification on T2DM risk was mediated by 1-year changes in MetS-Z, waist circumference, glucose, and triglycerides, whereas the effect of metformin was mediated by MetS-Z and glucose. CONCLUSIONS: Changes in these risk indicators of MetS severity during intervention in the DPP reflect altered disease risk and may help in tracking earlier responses to treatment and in motivating patients.