DeBoer MD, et al. - Using data from the Diabetes Prevention Program (DPP), researchers assessed if changes in the severity of metabolic syndrome (MetS) during prediabetes treatment are related to decreased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). For this investigation, data from 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 was analyzed. Findings revealed that 1-year changes in MetS severity z score (MetS-Z) and waist circumference most strongly correlated with risk of T2DM within 1-5 years. On the other hand, a 1-year change in MetS-Z, glucose, and systolic blood pressure was linked to the risk of CVD. In mediation analyses, 1-year changes in MetS-Z, waist circumference, glucose, and triglycerides mediated the impact of lifestyle modification on T2DM risk; MetS-Z and glucose mediated the effect of metformin. Study findings suggested that altered disease risk is reflected by these changes in risk indicators of MetS severity during intervention in the DPP, and might help in tracking earlier responses to treatment and in motivating patients.