EMERALD: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Intervention: Metformin; Placebo
Intervention MeSH terms: Metformin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 52.0
Sex: All
Minimum age: 12 Years
Maximum age: 21 Years
Healthy volunteers: No
Keywords: Adolescent; Youth; Diabetes; Insulin Resistance; Cardiovascular; Metformin

Summary:

      Diabetes is increasingly common among youth, forecasting early complications. Type 1 (T1D)
      cause early heart disease, shortening lifespan despite modern improvements in control of
      blood sugars and other risk factors for heart disease. Poor insulin action, otherwise known
      as insulin resistance (IR), is the main factor causing heart disease in type 2 diabetes
      (T2D), but the cause of increased heart disease in T1D is unclear. IR may contribute to heart
      disease in T1D as in T2D, as the investigators and others have found the presence of IR in
      T1D. Much less is known about IR in T1D, but a better understanding of its role in T1D is
      critical to understanding causes of heart disease in T1D. The investigators long-term goal is
      to understand the early causes of heart disease in diabetes so that we can prevent it. The
      investigators unique initial findings suggest that even reasonably well-controlled, normal
      weight, T1D youth are IR. The IR appears directly related to the heart, blood vessel, and
      exercise defects, but in a pattern that appears very different from T2D. The goals of this
      study are to determine the unique heart, blood vessel and insulin sensitivity abnormalities
      in T1D youth, and determine whether metformin improves these abnormalities. A clear
      understanding of these factors will help determine the causes, and what treatments could help
      each abnormality.

      Hypothesis 1: Metformin will improve insulin function and mitochondrial function in T1D.

      Hypothesis 2: Metformin will improve vascular and cardiac function in T1D.

      All measures will be performed twice, before and after a 3-month randomized,
      placebo-controlled design where subjects are randomized to either metformin or placebo. The
      independent impact of insulin action as well as glucose levels, BMI, T1D duration, and gender
      on baseline outcomes and the impact of changes in insulin action, glucose levels and BMI on
      response to metformin will also be examined to help customize future strategies to prevent
      heart disease in T1D. This study will advance the field by providing new information about
      the role of poor insulin action in the heart disease of T1D, and whether improving insulin
      action in T1D is helpful. If a focus on directly improving insulin action in T1D youth is
      supported by our studies, the clinical approach to T1D management may significantly change.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Adolescents 12-21 years of age with type 1 diabetes (defined as having positive
             antibodies as well as insulin requirement)

          2. Willing to consent for participation in study

          3. Body Mass Index (BMI) >5% on growth charts

        Exclusion Criteria:

          1. Current use of medications known to affect insulin sensitivity: oral glucocorticoids
             within 10 days, atypical antipsychotics, immunosuppressant agents, metformin or
             thiazolidinediones.

          2. Currently pregnant or breastfeeding women

          3. Use of a thiazolidinedione within 12 weeks

          4. Severe illness or Diabetic Ketoacidosis within 60 days

          5. Macroalbuminuria

          6. Hemoglobin A1c > 12%

          7. Weight > 136.4 kg or < 42 kg, BMI < 5%

          8. Creatinine > 1.2

          9. Hemoglobin < 9

         10. Major psychiatric or developmental disorder limiting informed consent

         11. Implanted metal devices

         12. Inability to tolerate ≥500mg twice a day of metformin