Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes

Overview[ - collapse ][ - ]

Purpose Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk in type 1 diabetes (T1D). The purpose of this study is to measure the effect of metformin on insulin sensitivity, vascular function and compliance, and mitochondrial function in T1D. The long term goal is to identify novel non-glycemic approaches to managing cardiovascular disease risk in T1D. The results of this study may validate a novel approach to T1D treatment that could significantly improve current management of cardiovascular disease risk in this high risk population.
ConditionType 1 Diabetes
InterventionDrug: Metformin
Drug: Placebo
PhasePhase 4
SponsorUniversity of Colorado, Denver
Responsible PartyUniversity of Colorado, Denver
ClinicalTrials.gov IdentifierNCT01813929
First ReceivedSeptember 28, 2012
Last UpdatedMarch 14, 2013
Last verifiedMarch 2013

Tracking Information[ + expand ][ + ]

First Received DateSeptember 28, 2012
Last Updated DateMarch 14, 2013
Start DateJune 2011
Estimated Primary Completion DateJune 2014
Current Primary Outcome Measures
  • Insulin Sensitivitybu hyperinsulinemic euglycemic clamp [Time Frame: end of each 6 week intervention period] [Designated as safety issue: No]Determine the effect of metformin on insulin sensitivity in T1D.
  • flow-mediated brachial artery dilation [Time Frame: End of each 6 week intervention period] [Designated as safety issue: No]Measure of endothelial function
Current Secondary Outcome Measures
  • arterial stiffness [Time Frame: End of each 6 week intervention period] [Designated as safety issue: No]PWV and AI by Sphygmacor
  • Mitochondrial measures [Time Frame: End of each 6 week intervention period] [Designated as safety issue: No]Mito content and electron transport chain complexes, oxygen consumption with various substrates and max uncoupled O2 consumption. oxidant generation
  • Metabolic, inflammatory, vascular, and oxidative stress markers [Time Frame: End of each 6 week intervention period] [Designated as safety issue: No]glucose, fatty acids, triglycerides, cholesterol, glycerol, insulin, lactate, counterregulatory hormones, IL6, TNF alpha, hsCRP, PAI-1, adiponection, TBARs, ICAM, endothelin-1, GSSG:GSH ratio
  • heart rate variability [Time Frame: End of each 6 week intervention period] [Designated as safety issue: No]measure of autonomic function

Descriptive Information[ + expand ][ + ]

Brief TitleEffect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
Official TitleEffect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
Brief Summary
Insulin resistance (IR) is an important contributor to increased cardiovascular disease risk
in type 1 diabetes (T1D). The purpose of this study is to measure the effect of metformin on
insulin sensitivity, vascular function and compliance, and mitochondrial function in T1D.
The long term goal is to identify novel non-glycemic approaches to managing cardiovascular
disease risk in T1D. The results of this study may validate a novel approach to T1D
treatment that could significantly improve current management of cardiovascular disease risk
in this high risk population.
Detailed DescriptionNot Provided
Study TypeInterventional
Study PhasePhase 4
Study DesignAllocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
ConditionType 1 Diabetes
InterventionDrug: Metformin
Six week intervention: study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily.
Other Names:
glucophageDrug: Placebo
Six-week intervention: Placebo will be given in a forced uptitration with 500 mg once daily for one week, twice daily for one week, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
Study Arm (s)
  • Experimental: Metformin
    Drug: Metformin
  • Placebo Comparator: Placebo
    Six week intervention: study drug/placebo will be given in a forced uptitration with 500 mg once daily for one week, 500 mg twice daily for one week, 500/1000 for one week, and then 1000mg twice daily for the remainder of the 6 week intervention. If uptitration is not tolerated, max dose will be max tolerated dose of at least 500 mg twice daily

Recruitment Information[ + expand ][ + ]

Recruitment StatusRecruiting
Estimated Enrollment100
Estimated Completion DateJune 2014
Estimated Primary Completion DateJune 2014
Eligibility Criteria
Inclusion Criteria:

1. age 20-59 years of age,

2. type 1 diabetes based on antibody-positivity, rapid persistent conversion to insulin
requirement after diagnosis, absent C-peptide, or DKA at diagnosis, or a clinical
course consistent with T1D,

3. HbA1c 6.0 - 9.5, and

4. willing and able to commit to two 6 week-long periods of blinded medication followed
by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.

Exclusion Criteria:

- Any comorbid condition associated with inflammation, IR, or dyslipidemia including
cancer, heart failure, active or end stage liver disease, kidney disease, or
rheumatological disease;

- Tobacco use;

- Pregnancy or women who are breastfeeding;

- Steroid use

- Scheduled strenuous physical activity >3 days a week.

- Angina, known CAD, or any other cardiovascular or pulmonary disease

- A history of COPD or asthma

- Presence of systolic blood pressure >190 at rest or >250 with exercise or diastolic
pressure >95 at rest or >105 with exercise

- Untreated thyroid disease

- Proteinuria (urine protein >200 mg/dl) or a creatinine > 1.5 mg/dl (males) or 1.4
mg/dL (females), suggestive of severe renal disease

- Severe Proliferative retinopathy.

- Niacin treatment

- Administration of experimental agent for T1D within 30 days prior to screening

- Recent (prior 6 months) or current metformin or thiazolidenedione use

- Hypoglycemia unawareness or recurrent severe hypoglycemia (no symptoms of
hypoglycemia with FSBS<40 and episodes of this severity >1 per week)

- Weight instability (weight change >5% in last 6 months)

- History of any organ transplant, including islet cell transplant

- Current or prior infection with HIV, hepatitis B or hepatitis C or hepatic
-insufficiency (AST or ALT > 2x the upper limits of normal)

- Any condition, medical or otherwise that would, in the opinion of the investigator,
prevent complete participation in the study, or that would pose a significant hazard
to the subject

- History of substance abuse within the 12 months prior to screening
GenderBoth
Ages25 Years
Accepts Healthy VolunteersNo
ContactsContact: Nicholas Birdsey, BS
303-877-3511
nicholas.birdsey@ucdenver.edu
Location CountriesUnited States

Administrative Information[ + expand ][ + ]

NCT Number NCT01813929
Other Study ID Numbers11-0693
Has Data Monitoring CommitteeNo
Information Provided ByUniversity of Colorado, Denver
Study SponsorUniversity of Colorado, Denver
CollaboratorsDepartment of Veterans Affairs
Investigators Principal Investigator: Irene Schauer, MD, PhD University of Colorado, Denver
Verification DateMarch 2013

Locations[ + expand ][ + ]

University of Colorado Denver
Aurora, Colorado, United States, 80045
Contact: Nathaniel Solis, BS | 303-724-6634 | nathaniel.solis@ucdenver.edu
Principal Investigator: Irene Schauer, MD, PhD
Recruiting