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EMERALD: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes (EMERALD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01808690
Recruitment Status : Completed
First Posted : March 11, 2013
Results First Posted : February 5, 2020
Last Update Posted : April 13, 2020
Sponsor:
Collaborators:
American Diabetes Association
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
University of Colorado, Denver

Brief 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.


Condition or disease Intervention/treatment Phase
Type 1 Diabetes Drug: Metformin Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 52 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Metformin on Cardiovascular Function in Adolescents With Type 1 Diabetes
Study Start Date : March 2013
Actual Primary Completion Date : December 2, 2016
Actual Study Completion Date : December 2, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Diabetes Type 1

Arm Intervention/treatment
Experimental: Metformin
Metformin will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to placebo.
Drug: Metformin
Placebo Comparator: Placebo
Placebo will be given at a dose of 1000 mg twice a day orally for three months to assess changes in insulin resistance compared to metformin.
Drug: Placebo



Primary Outcome Measures :
  1. Change in Insulin Sensitivity [ Time Frame: Baseline, Month 3 ]
    Hypothesis 1: Metformin will improve insulin function in Type 1 Diabetes. Insulin function will be measured using a euglycemic-hyperinsulinemic clamp procedure at both baseline and after 3 months of treatment. A clamp measures insulin sensitivity. A higher number indicates a better outcome; a lower number indicates a worse outcome.


Secondary Outcome Measures :
  1. Change in ADP Time Constant [ Time Frame: Baseline, Month 3 ]

    Hypothesis 1b: Metformin will improve mitochondrial function in Type 1 Diabetes. 31Phosphorus magnetic resonance spectroscopy (MRS) was used before, during, and after 90 seconds of near-maximal isometric exercise of the calf muscle for post-exercise muscle mitochondrial function. ADP time constant is the time for conversion of ADP → ATP and is a measure of muscle mitochondrial health (energy metabolism).

    A faster recovery is a better outcome; a slower recovery is a worse outcome.


  2. Change in Pulse Wave Velocity (PWV) [ Time Frame: Baseline, Month 3 ]

    Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via pulse wave velocity (PWV) by MRI. PWV is a measure of central arterial stiffness.

    A lower value indicates a better outcome.


  3. Change in Central Arterial Intimal Medial Thickness (cIMT) [ Time Frame: Baseline, Month 3 ]

    Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via central arterial intimal medial (cIMT) thickness by carotid ultrasound. cIMT is a measure used to diagnose the extent of carotid atherosclerotic vascular disease. The test measures the thickness of the inner two layers of the carotid artery-the intima and media.

    A lower result is a better outcome.


  4. Change in Cardiac Function by Echocardiogram [ Time Frame: Baseline, Month 3 ]
    Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram.

  5. Change in Aortic Wall Sheer Stress (WSS) [ Time Frame: Baseline, Month 3 ]

    Hypothesis 2a: Metformin will improve central vascular function in Type 1 Diabetes via Aortic Wall Sheer Stress (WSS) by MRI. WSS is a measure of central arterial stiffness.

    A lower value indicates a better outcome.



Other Outcome Measures:
  1. Change in Brachial Artery Distensibility [ Time Frame: Baseline, Month 3 ]

    Hypothesis 2a: Metformin will improve peripheral arterial stiffness in Type 1 Diabetes via Dynapulse.

    Peripheral arterial stiffness is measured by the distensibility of the arterial wall. Increased arterial stiffness results from reduced elasticity of the arterial wall.

    A higher result is a better outcome.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01808690


Locations
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United States, Colorado
Children's Hospital Colorado and University of Colorado Denver Health Sciences Center
Aurora, Colorado, United States, 80045
Sponsors and Collaborators
University of Colorado, Denver
American Diabetes Association
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Kristen Nadeau, MD, MS University of Colorado/Children's Hospital Colorado
  Study Documents (Full-Text)

Documents provided by University of Colorado, Denver:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of Colorado, Denver
ClinicalTrials.gov Identifier: NCT01808690    
Other Study ID Numbers: 12-1528
R56DK078645 ( U.S. NIH Grant/Contract )
First Posted: March 11, 2013    Key Record Dates
Results First Posted: February 5, 2020
Last Update Posted: April 13, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University of Colorado, Denver:
Adolescent
Youth
Diabetes
Insulin Resistance
Cardiovascular
Metformin
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs