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

Type 1 Diabetes Clinical Trial

— EMERALD  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01808690
• Other study ID #: 12-1528
• Secondary ID: R56DK078645
• Status: Completed
• Phase: Phase 3
• Start date: March 2013
• Est. completion date: December 2, 2016

Study information

• Verified date: September 2021
• Source: University of Colorado, Denver
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: December 2, 2016
• Est. primary completion date: December 2, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 21 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes

Intervention

Drug:
• Metformin

• Placebo

Locations

Country	Name	City	State
United States	Children's Hospital Colorado and University of Colorado Denver Health Sciences Center	Aurora	Colorado

Sponsors (3)

Lead Sponsor	Collaborator
University of Colorado, Denver	American Diabetes Association, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in Brachial Artery Distensibility	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.	Baseline, Month 3
Primary	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	Change in ADP Time Constant	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.	Baseline, Month 3
Secondary	Change in Pulse Wave Velocity (PWV)	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.	Baseline, Month 3
Secondary	Change in Central Arterial Intimal Medial Thickness (cIMT)	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.	Baseline, Month 3
Secondary	Change in Mitral Valve E/A Ratio by Echocardiogram	Hypothesis 2b: Metformin will improve cardiac function in Type 1 Diabetes by echocardiogram.; Mitral Valve E/A ratio is the ratio of early (E) to late (A) ventricular filling velocities.; Ideal myocardial tissue relaxation is indicated by a ratio of >0.8 and <2.0.	Baseline, Month 3
Secondary	Change in Aortic Wall Sheer Stress (WSS)	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.	Baseline, Month 3