An Open-Label Pilot Intervention Trial to Prevent Diabetes in Prediabetic Adult Survivors of Childhood Cancer

Eligible subjects who meet inclusion criteria will be enrolled in a 12 week run-in period of the digital lifestyle intervention program. At the 12 week study visit, those who remain prediabetic will received metformin extended release daily, first at lower dose (500 mg/day) to minimize gastrointestinal side effects (diarrhea, nausea, flatulence, bloating), then escalated to a maximum dose of 1000 mg/day at week 14. The digitally delivered lifestyle change program will include a core curriculum focused on diet quality, food types, exercise and behavioral strategies for goal setting, and self- monitoring.

Inclusion criteria

• Investigators will recruit to enroll 55 survivors who are at least 18 but <45 years of age who participate in the St. Jude Lifetime Cohort Study (SJLIFE) and have been identified to have prediabetes defined as hemoglobin A1c (HbA1c)
• Participant in SJLIFE
• ≥18 and <45 years of age
• Prediabetic: fasting plasma glucose 105-125 mg/dL, hemoglobin A1c 5.7- 6.4% (either or both criteria may be present) According to institutional and NIH policy, the study will accession research participants regardless of sex and ethnic background. Institutional experience confirms broad representation in this regard.

Exclusion criteria

• Absence of treatment related diabetes risk. Survivors will be excluded if their cancer treatment required observation only, surgery alone not involving the abdomen or brain, radiation alone not involving the chest (pancreatic risk), abdomen or brain (e.g. retinoblastoma treated with enucleation alone, melanoma of an extremity treated with excision alone, neuroblastoma in an infant requiring observation only)
• Diabetes at baseline assessment: FPG ≥126 mg/dL, HbA1c ≥6.5% or previous diagnosis by a physician (except gestational diabetes that resolved post-partum)
• BMI <19 kg/m2
• Current metformin use (including for any period ≥30 days in the past 1yr)
• Known allergy to metformin
• Current use of other oral glucose lowering medications, non-insulin injectable diabetes medications or insulin (Appendix)
• Current participation in a lifestyle change program
• Chronic kidney disease ≥ stage IIIb (eGFR < 45 mL/min)
• Severe cardiovascular disease or recent intervention (NYHA class ≥2 or heart failure hospitalization in the past 6mo, Aortic stenosis, Heart block including LBBB or 3rd degree AV block, SBP >180 or DBP >105 mmHg, myocardial infarction or coronary revascularization in the past 1 month)
• Severe hepatic dysfunction: cirrhosis or AST/ALT >3 times upper limit of normal
• Pulmonary disease with dependence on oxygen or daily use of bronchodilators
• Weight loss >10% in the past 6 months
• Bariatric surgery in the past 2 years
• Pregnant, within 3 months post-partum, nursing, or planning to become pregnant
• Anemia: hematocrit <36% in males or <33% in females
• Ongoing alcohol or substance abuse using criteria from the AUDIT and DAST questionnaires (Appendix)
• Diagnosis of schizophrenia or other psychotic disorder
• Vision impairment limiting ability to interface with the digital program
• Unable to swallow medication
• Non-English speaking
• Cognitive impairment defined by IQ <80
• Current active cancer or undergoing treatment for active cancer