12/22 Limited Competition for the Continuation of the Diabetes Prevention Program Outcomes Study (DPPOS) - Clinical Center

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Project Summary Abnormal regulation of glycemia (“dysglycemia”) has a very long time course, from the earliest stage of pre- diabetes, to the onset of Type 2 diabetes (T2D), to the development of clinically detectable microvascular changes and measurable atherosclerosis, to clinically manifest complications with attendant morbidity and mortality. The Diabetes Prevention Program (DPP) focused on the pre-diabetes stage of dysglycemia and demonstrated powerful beneficial effects of lifestyle intervention (ILS) and metformin (MET), compared with placebo (PLBO), in preventing or delaying the onset of T2D over a 3-year period in a high-risk population (n=3234). The DPP also investigated and described the interventions, phenotypic and genotypic risk factors associated with T2D development, the effects of the interventions in the setting of these risk factors, the health economic implications of T2D prevention, and other outcomes of interest. Based on these results, the DPP lifestyle program has been widely implemented. The DPP Outcomes Study (DPPOS) has explored the longer- term effects of T2D prevention in the DPP cohort, bridging the period between pre-diabetes and T2D, and has examined outcomes that required more time to develop than the 3-years of DPP. DPPOS showed longer-term salutary effects of the original interventions on T2D prevention and on cardiovascular disease (CVD) risk factors. The risk for microvascular disease was significantly greater in subjects who developed T2D and increased with longer duration and higher hemoglobin A1c (HbA1c). There were no significant differences by treatment group in the prevalence of the aggregate microvascular outcome; however, compared with PLBO and MET, ILS significantly reduced the risk of microvascular disease among women and those with HbA1c ≥6.5%. During the one-year extension of DPPOS Phase 3, we will maintain and continue to follow the well- characterized and valuable DPPOS cohort, and collect measurements of outcomes as described in the protocol. We will 1) perform new analyses to characterize the heterogeneous course of dysglycemia and its long-term complications and factors that define susceptibility or resistance to diabetes, its complications, and common chronic conditions of aging, and 2) explore the factors associated with participant retention, adherence to the protocol and completion of measurements, and determine if alternative methods can be implemented to improve retention and adherence and to expand data collection. These aims will provide important insights into prediabetes and diabetes and their long-term outcomes and could serve the potential further study of the DPPOS cohort.