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

NCT01808690 | Completed Phase 3 Results DMC

• 2 other identifiers: 12-1528R56DK078645
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 1 Diabetes

Keywords

Adolescent; Youth; Diabetes; Insulin Resistance; Cardiovascular; Metformin

Outcome Measures

Primary Outcomes (1)

• Change in Insulin Sensitivity

  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.

  Baseline, Month 3

Secondary Outcomes (5)

• Change in ADP Time Constant

  Baseline, Month 3

• Change in Pulse Wave Velocity (PWV)

  Baseline, Month 3

• Change in Central Arterial Intimal Medial Thickness (cIMT)

  Baseline, Month 3

• Change in Mitral Valve E/A Ratio by Echocardiogram

  Baseline, Month 3

• Change in Aortic Wall Sheer Stress (WSS)

  Baseline, Month 3

Other Outcomes (1)

• Change in Brachial Artery Distensibility

  Baseline, Month 3

Study Arms (2)

Metformin

EXPERIMENTAL

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

PLACEBO COMPARATOR

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

Interventions

Metformin DRUG

Metformin

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 12 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Adolescents 12-21 years of age with type 1 diabetes (defined as having positive antibodies as well as insulin requirement)
• Willing to consent for participation in study
• Body Mass Index (BMI) \>5% on growth charts

You may not qualify if:

• Current use of medications known to affect insulin sensitivity: oral glucocorticoids within 10 days, atypical antipsychotics, immunosuppressant agents, metformin or thiazolidinediones.
• Currently pregnant or breastfeeding women
• Use of a thiazolidinedione within 12 weeks
• Severe illness or Diabetic Ketoacidosis within 60 days
• Macroalbuminuria
• Hemoglobin A1c \> 12%
• Weight \> 136.4 kg or \< 42 kg, BMI \< 5%
• Creatinine \> 1.2
• Hemoglobin \< 9
• Major psychiatric or developmental disorder limiting informed consent
• Implanted metal devices
• Inability to tolerate ≥500mg twice a day of metformin

Sponsors & Collaborators

• University of Colorado, Denver: lead
• American Diabetes Association: collaborator
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Children's Hospital Colorado and University of Colorado Denver Health Sciences Center

Aurora, Colorado, 80045, United States

Location

Related Publications (2)

• Tommerdahl KL, Baumgartner K, Schafer M, Bjornstad P, Melena I, Hegemann S, Baumgartner AD, Pyle L, Cree-Green M, Truong U, Browne L, Regensteiner JG, Reusch JEB, Nadeau KJ. Impact of Obesity on Measures of Cardiovascular and Kidney Health in Youth With Type 1 Diabetes as Compared With Youth With Type 2 Diabetes. Diabetes Care. 2021 Mar;44(3):795-803. doi: 10.2337/dc20-1879. Epub 2021 Jan 5.

  PMID: 33402367 DERIVED

• Bjornstad P, Schafer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, Browne LP, Reusch JEB, Nadeau KJ. Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus. Circulation. 2018 Dec 18;138(25):2895-2907. doi: 10.1161/CIRCULATIONAHA.118.035525.

  PMID: 30566007 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus; Insulin Resistance

Interventions

Metformin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Hyperinsulinism

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Limitations and Caveats

Results may not apply to prepubertal youth. Treatment duration limited to 3 months. MRI unavailable during scanner replacement. Lacked measure to monitor BGs during vascular assessments. Not all females studied in traditional follicular phase.

Results Point of Contact

• Title: Dr. Kristen J Nadeau
• Organization: University of Colorado Denver/Children's Hospital Colorado

Kristen.Nadeau@childrenscolorado.org

720-777-2855

Study Officials

• Kristen Nadeau, MD, MS

  University of Colorado/Children's Hospital Colorado

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 6, 2013
• First Posted: March 11, 2013
• Study Start: March 1, 2013
• Primary Completion: December 2, 2016
• Study Completion: December 2, 2016
• Last Updated: September 30, 2021
• Results First Posted: February 5, 2020

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)