Title: Therapeutic Targets in African-American Youth With Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      The pill metformin treats diabetes. But it does not work for all youth, especially
      African-Americans. The injectable Liraglutide treats type 2 diabetes in adults. Researchers
      want to understand how these drugs work and if they decrease excess sugar made by the liver
      in youth with type 2 diabetes.

      Objective:

      To test if using liraglutide and metformin are better than just metformin for decreasing
      excess sugar produced by the liver in African-American youth with type 2 diabetes.

      Eligibility:

      African-Americans ages 12-25 with type 2 diabetes

      Design:

      Visit 1: Participants will be screened with medical history, physical exam, and blood and
      urine tests. Participants will stop taking diabetes medicines for 1 week. They will learn how
      to check blood sugars at home twice a day.

      Visit 2: Overnight at the clinic. Participants will have:

      Vital signs taken.

      Pregnancy test.

      A thin plastic tube (IV catheter) be inserted in each forearm by needle.

      Blood drawn several times after drinking a sweet drink.

      X-ray of total body fat.

      Urine and stool collected.

      Breath tests while wearing a clear hood for up to 45 minutes.

      For several hours, participants can have only water. At 4 a.m. they will get sugar and fat
      with nonradioactive isotopes in one IV. Blood will be collected. Every 30 minutes from 9 a.m.
      to 2 p.m., they will drink small amounts of a shake and have blood drawn.

      Participants will be randomly assigned to take either both study drugs daily or just
      metformin daily.

      Visits 3-4: Participants will bring their blood sugar records and have blood tests.

      Visit 5, after 3 months: Repeat of visit 2....
    

Detailed description: 
      Type 2 Diabetes in youth is an emerging public health concern that disproportionately affects
      minority children. Among minority youth, African-Americans have the highest complication
      rates, yet the reasons underlying this health disparity are not fully understood.
      Furthermore, current treatment options are limited, and African-American youth have high
      treatment failure rates. Metformin therapy is the only oral diabetes drug approved for use in
      youth with type 2 diabetes. However, metformin works less than 50% of the time in
      African-American youth and there is marked variability among individuals. Improving outcomes
      in youth requires understanding the way that drugs such as metformin work in youth and why it
      does not work in some individuals. New evidence suggests that the ability of metformin to
      work effectively may be influenced by certain genes or differences in gut bacteria. However,
      little is known about how genes or gut bacteria may affect youth, especially
      African-Americans.

      To treat this aggressive disease, it is also necessary to simultaneously evaluate new
      therapeutic options, such as combination therapy of metformin with liraglutide in youth at
      highest risk for complications. Liraglutide is approved to treat type 2 diabetes in patient
      10 years and older as an adjunct to diet and exercise. Liraglutide may be a useful early
      treatment in youth with type 2 diabetes because it may decrease glucose produced by the liver
      (an early prominent feature of type 2 diabetes in youth). This study is designed to examine
      the mechanism of action in the liver of these 2 agents and explore how genetic and gut
      factors may influence this action.

      The primary objective of this pilot study is to compare the ability of two anti-diabetic
      regimens (metformin and liraglutide versus metformin alone) to lower gluconeogenesis (glucose
      produced by the liver) in African-American youth with type 2 diabetes. The secondary
      objectives are to evaluate the effect of these regimens on the following: (1) hepatic glucose
      production, and insulin sensitivity and (2) insulin and gut hormones concentrations (e.g.
      incretins). In addition, we will examine the relationship of known differences in genes
      associated with metformin transport and action with changes in gluconeogenesis and begin to
      explore the role of gut bacteria to metformin s glucose-lowering effect.

      The study design is a parallel-randomized intervention trial of African-American youth with
      type 2 diabetes who are not on insulin therapy and who are within 5 years of diagnosis.
      Patients aged 12- 25 years with type 2 diabetes will be enrolled. Participants will be
      randomized into two intervention arms (16 in each group): metformin and liraglutide versus
      metformin alone. The study will consist of 5 visits. At Visit 1, a medical history, physical
      examination and screening labs will be done. Then the eligible participants will undergo a
      one-week drug-free run-in. At Visit 2 there will be an overnight inpatient stay to perform
      metabolic testing prior to starting the study drug(s). Participants will start the study
      drug(s) immediately after Visit 2 and remain on the study drug(s) for 12 weeks. Follow-up
      monitoring will be performed at 4-week intervals (Visit 3 and 4). The final visit (Visit 5)
      will occur after 12 weeks.

      The ultimate goal of this multi-site project is to begin to address diabetes disparities in
      African-American youth by understanding the mechanism of action of these diabetes agents to
      inform precision medicine initiatives. This project brings together the skills and expertise
      of investigators within the National Institute of Diabetes and Digestive Disorders and Kidney
      Diseases (NIDDK), the National Human Genome Research Institute (NHGRI), and the Children s
      National Medical Center (CNMC). Patient recruitment and data collection will occur at NIH
      Clinical Center. Eligible patients may be identified through CNMC but no enrollment, informed
      consent or study visits will occur at CNMC.
    

Intervention name(s): Liraglutide; Metformin
Intervention type(s): Drug; Drug
Intervention description(s): Liraglutide (6mg/ml, 3ml ) solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6mg, 1.2mg or 1.8mg.; Metformin 500mg oral tablet
Intervention MeSH terms: Metformin; Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Diabetes; Metformin; Glucose