Intervention: Metformin
Trial phase: Phase 3
ATC code: A10BA02 | A10BD02 | A10BD03 | A10BD05 | A10BD07 | A10BD08 | A10BD10 | A10BD11 | A10BD13 | A10BD14 | A10BD15 | A10BD16 | A10BD17 | A10BD18 | A10BD20 | A10BD22 | A10BD23 | A10BD25 | A10BD26 | A10BD27
SMILES: CN(C)C(=N)NC(=N)N
Sex: All
Age groups: Child | Adult
Healthy volunteers: Accepts Healthy Volunteers
Participants at risk: 47
Group description: Metformin was titrated beginning at 500 mg/day to the maximum dose tolerated (up to 2000 mg/day).
Eligibility criteria:
Inclusion Criteria:

Fasting plasma glucose ≥90 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus laboratory-based HbA1c ≤8.0% if treatment naïve. There is no upper limit for the 2-hour glucose on OGTT. In those taking metformin laboratory-based HbA1c must be ≤7.5% if on metformin for <3 months and ≤7.0% if on metformin for 3-6 months.
Age 10-19 years
Pubertal development Tanner stage >1 as defined by breast stage >1 in girls, and testes >3 cc's in boys.
Body mass index (BMI) ≥85th percentile but ≤50 kg/m2
Self-reported diabetes <6 months in duration
Treatment with metformin for <6 months preceding screening

Exclusion Criteria:

Underlying disease likely to limit life span and/or increase risk of intervention or an underlying condition that is likely to limit ability to participate in outcomes assessment
An underlying disease that affects glucose metabolism other than type 2 diabetes mellitus
Taking medications that affect glucose metabolism, or has an underlying condition that is likely to require such medications
Treatment with insulin for >1 week preceding screening
Active infections
Renal disease (serum creatinine >1.2 mg/dl) or serum potassium abnormality (<3.4 or >5.5 mmol/l)
Anemia (hemoglobin <11 g/dl in girls, <12 g/dl in boys) or known coagulopathy
Cardiovascular disease, including uncontrolled hypertension defined as average systolic or diastolic blood pressure > 99 percentile for age or >135/90, despite adequately prescribed antihypertensive medications. Participants must be able to safely tolerate administration of intravenous fluids required during clamp studies.

History of conditions that may be precipitated or exacerbated by a study drug:

Serum alanine transaminase (ALT) more than 3 times the upper limit of normal
Excessive alcohol intake
Sub-optimally treated thyroid disease

Conditions or behaviors likely to affect the conduct of the RISE Study

Participant and/or parents unable or unwilling to give informed consent
Participant and/or parents unable to adequately communicate with clinic staff
Another household member is a participant or staff member in RISE
Current, recent or anticipated participation in another intervention research project that would interfere with any of the interventions/outcomes in RISE
Weight loss of ≥5% of body weight in the past 3 months for any reason other than post-partum weight loss. Participants taking weight loss drugs or using preparations taken for intended weight loss are excluded.
Likely to move away from participating clinics in next 2 years
Current (or anticipated) pregnancy and lactation.
A pregnancy that was completed less than 6 months prior to screening.
Breast feeding within 6 months prior to screening.
Women of childbearing potential who are unwilling to use adequate contraception
Major psychiatric disorder that, in the opinion of clinic staff, would impede the conduct of RISE
Additional conditions may serve as criteria for exclusion at the discretion of the local site.