ABSTRACT Childhood cancer survivors have nearly twice the risk for developing diabetes compared to their siblings. Diabetes is an established cardiovascular risk factor potentiating the risk for major cardiac events among survivors, which is critical as cardiac death is the leading cause of non-cancer late mortality in this population. Thus, diabetes is a major modifiable risk factor for cardiac risk reduction. Further, diabetes is known to increase risk for other chronic health conditions, including chronic kidney disease, which survivors experience at higher rates than the general population. Fortunately, prediabetes is easily diagnosed by fasting laboratory measures. In the general population, pharmacologic therapy with metformin or intensive lifestyle intervention used in the Diabetes Prevention Program (DPP) prevents progression to diabetes. Without intervention, it is estimated that 4-10% of adults with prediabetes in the general population will become diabetic each year. Yet, little is known about prediabetes in survivors despite previous reports from the St. Jude Lifetime Cohort Study (SJLIFE) that suggest up to one-third of adult survivors are prediabetic. Our preliminary data suggests that the prevalence of prediabetes among childhood cancer survivors is near twice that of similarly aged controls among young adults (18-<45 years). Further, survivors have unique, treatment-related risk for abnormalities in glucose control and insulin homeostasis (including abdominal radiation, cranial radiation, hematopoietic cell transplant and corticosteroid exposure). Therefore, it is unknown if interventions that are used in the general population to prevent diabetes will be similarly efficacious and well tolerated among survivors. The SJLIFE cohort now contains comprehensive treatment information and direct medical assessments for over 5,000 adult survivors. Leveraging this resource, we aim to pilot an adaptive, open-label intervention to prevent diabetes using a combination of daily metformin and a digitally-delivered lifestyle change program among adult survivors of childhood cancer with prediabetes. All participants will initially take part in a lifestyle change program run-in period with the addition of daily metformin among participants who remain at high-risk for prediabetes based on laboratory criteria. The primary objective is to provide essential feasibility data as well as preliminary evidence for efficacy (improved glycemic control and/or insulin resistance) for a future randomized intervention trial for prevention of diabetes and associated cardiac complications in this high-risk population. Exploratory objectives are to evaluate the effect of treatment on insulin sensitivity, anthropometric measures, physical activity, dietary change, health-related quality of life and frailty.

RELEVANCE STATEMENT If successful, this single-institution pilot study will: 1) provide evidence that both a lifestyle-alone and a combined lifestyle and pharmacologic intervention using therapies that are each proven to prevent diabetes in the general population are feasible in survivors and 2) provide initial evidence for efficacy of this intervention to improve glucose control and insulin resistance in survivors, each of which are essential to support a future randomized clinical trial of efficacy for diabetes prevention. Given that treatment associated risks cannot be altered, diabetes prevention could provide a new way to reduce the high risk for early onset cardiac morbidity and mortality in survivors of childhood cancer.