RISE Adult Medication Study
Condition: Prediabetes; Type 2 Diabetes
MeSH terms: Prediabetic State
Intervention: Metformin; Liraglutide; Glargine; Placebo
Intervention description: Titrated to 1000 mg BID; Titrated to 1.8 mg/day; Titrated to target fasting glucose <90 mg/dl; Matching to metformin 1000 mg BI
Intervention MeSH terms: Metformin; Insulin Glargine; Liraglutide
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 267.0
Sex: All
Minimum age: 20 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      The RISE Adult Medication Study is a 4-arm, 3-center, clinical trial of adults with
      prediabetes and early type 2 diabetes to address the hypothesis that aggressive glucose
      lowering will lead to recovery of beta-cell function that will be sustained after withdrawal
      of treatment. Adult participants (ages 20-65) will be randomized to one of the following
      treatment regimens: (1) blinded placebo, (2) blinded metformin alone, (3) early intensive
      insulin treatment with basal insulin glargine followed by open-label metformin, (4) the
      glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide plus open-label metformin.

      The primary clinical question RISE will address is: Are improvements in ß-cell function
      following 12 months of active treatment maintained for 3 months following the withdrawal of
      therapy? Secondary outcomes will assess durability of glucose tolerance following withdrawal
      of therapy, and whether biomarkers obtained in the fasting state predict parameters of ß-cell
      function, insulin sensitivity and glucose tolerance and the response to an intervention.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Fasting plasma glucose 95-125 mg/dl plus 2-hour glucose ≥140 mg/dl on 75 gm OGTT plus
             HbA1c ≤7.0%. There is no upper limit for the 2-hour glucose on OGTT.

          2. Age 20-65 years

          3. Body mass index (BMI) ≥25 kg/m2 but ≤50 kg/m2

          4. Self-reported diabetes <1 year in duration

          5. Drug naïve (no prior to oral glucose lowering agent(s), insulin or other injectable
             glucose lowering agents)

        Exclusion Criteria:

          1. 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

          2. An underlying disease that affects glucose metabolism other than type 2 diabetes

          3. Taking medications that affect glucose metabolism, or has an underlying condition that
             is likely to require such medications

          4. Active infections

          5. Renal disease (serum creatinine >1.4 mg/dl for men; >1.3 mg/dl for women) or serum
             potassium abnormality (<3.4 or >5.5 mmol/l)

          6. Anemia (hemoglobin <11 g/dl in women, <12 g/dl in men) or known coagulopathy

          7. Cardiovascular disease, including uncontrolled hypertension. Participants must be able
             to safely tolerate administration of intravenous fluids required during clamp studies.

          8. History of conditions that may be precipitated or exacerbated by a study drug:

               1. Pancreatitis

               2. Serum alanine transaminase (ALT) more than 3 times the upper limit of normal

               3. Excessive alcohol intake

               4. Suboptimally treated thyroid disease

               5. Medullary carcinoma of the thyroid or MEN-2 (in participant or a family history)

               6. Hypertriglyceridemia (>400 mg/dl despite treatment)

          9. Conditions or behaviors likely to affect the conduct of the RISE Study

               1. Unable or unwilling to give informed consent

               2. Unable to adequately communicate with clinic staff

               3. Another household member is a participant or staff member in RISE

               4. Current, recent or anticipated participation in another intervention research
                  project that would interfere with any of the interventions/outcomes in RISE

               5. Weight loss of >5% in past three 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.

               6. Likely to move away from participating clinics in next two years

               7. Women of childbearing potential who are unwilling to use adequate contraception

               8. Current (or anticipated) pregnancy and lactation.

               9. Major psychiatric disorder that, in the opinion of clinic staff, would impede the
                  conduct of RISE

         10. Additional conditions may serve as criteria for exclusion at the discretion of the
             local site.