Type 1 DiabetesPhase 4MeT1NCT01813929
Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
A Phase 4 study testing Metformin in people with Type 1 Diabetes, run by University of Colorado, Denver at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 25 to 59 years
- Conditions the study is for
- Type 1 Diabetes
- What is being tested?
- Metformin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 23 participants
- Where
- 1 siteUnited States
- Study dates
- Jun 2011to 24 Mar 2017
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 25 to 59 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Age 20-59 years of age,
- 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,
- HbA1c 6.0 - 9.5, and
- Willing and able to commit to two 6 week-long periods of blinded medication followed by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.
Who cannot join
- Any comorbid condition associated with:
- inflammation,
- insulin Resistance, or
- dyslipidemia including:
- cancer,
- heart failure,
Show all 28Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of Colorado Denver
Aurora, Colorado, 80045
About this study
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.
- Conditions
- Type 1 Diabetes
- Being tested
- Metformin, Placebo
- Keywords
- Diabetes, Insulin, Metformin, Vascular, Vessels, Type 1
- Medical subject headings
- Diabetes Mellitus, Type 1, Diabetes Mellitus, Insulin Resistance
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called glucophage
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.
PlaceboDrug
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, and then the higher dose (850 mg) for the remainder of the 6 week intervention.
| Study group | Role | What they receive |
|---|---|---|
| Metformin | Experimental | Not described Receives: Drug: Metformin |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp
Determine the effect of metformin on insulin sensitivity in T1D. Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight. For this measure, insulin was infused at 40 mU/m2 surface area. Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours. The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg*min. A higher value corresponds to greater sensitivity to insulin. There is no strictly defined normal range.
Measured: End of each 6 week intervention period
Flow-mediated Brachial Artery Dilation
Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.
Measured: End of each 6 week intervention period
Secondary outcomes (22)
Arterial Stiffness by PWV
Pulse wave velocity by Sphygmacor as a measure of aortic stiffness in m/sec.
Measured: End of each 6 week intervention period
Arterial Stiffness by AI@75
Augmentation index by Sphygmacor is a measure of aortic arterial stiffness. AI@75 is the ratio of augmented pressure/pulse pressure adjusted to a heart rate of 75.
Measured: End of each 6 week intervention period
Mitochondrial Measures: Oxygen Consumption
Oxygen consumption rate with various substrates and max uncoupled O2 consumption.
Measure is performed on permeabilized muscle fibers from biopsy tissue from the vastus lateralis using the Oroboros OxygraphO2k high resolution respirometer. State 3 is full coupled oxygen flux using PMG or PMGS (pyruvate, malate, glutamate, +/- succinate) or OCMS (octanyl carnitine, malate, +/- succinate) as substrates. state 4 is after addition of oligomycin to inhibit the ATP synthase and thus corresponds to the maximum leak state where O2 consumption is limited by the buildup of the proton gradient and can only proceed as fast as the protons can leak back across the membrane. FCCP is added as an uncoupler, allowing free leakage of protons across the inner membrane, and thus measures maximum possible O2 flux. There are no defined normal ranges, but higher state 3 and uncoupled flux indicate better mitochondrial function, while state 4 is needed to correct state 3 to the fully coupled flux.
Measured: End of each 6 week intervention period
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes
Mito content by Western Blotting of electron transport chain complexes I, II, III, and V. complex 1 utilizes NADH from pyruvate/malate/glutamate while complex II utilizes FADH from succinate. complex III is the cytochrome c reductase while complex V is the ATP synthase.
Measured: End of each 6 week intervention period
Inflammatory Marker: hsCRP
hsCRP (mg/L) by Beckman Coulter assay
Measured: End of each 6 week intervention period
Heart Rate Variability
measure of autonomic function: ratio of fastest to slowest heart rate during valsalva maneuver
Measured: End of each 6 week intervention period
Continuous Glucose Monitor Measures of Mean Glucose
Mean Glucose \& Glucose Standard Deviation (Glycemic Variability) by Dexcom CGM
Measured: Last Week of each 6 Week Intervention Period (over 7 days)
Continuous Glucose Monitor Measures of Hypoglycemia
Percent of time less than 70 mg/dL during the final week of each phase by Dexcom CGM.
Measured: Last Week of each 6 Week Intervention Period (over 7 days)
Metabolic Markers: Glucagon
Glucagon (pg/ml); baseline on AM of each phase final study visit.
Measured: End of each 6 week intervention period
Metabolic Markers: Glucose, Triglycerides, Cholesterol
Glucose (mg/dL), triglycerides (mg/dL), cholesterol (mg/dL) at baseline after each phase
Measured: End of each 6 week intervention period
Metabolic Markers: Fatty Acids
fatty acids (microeq/L) at baseline after each phase in the AM of the final visit
Measured: End of each 6 week intervention period
Metabolic Markers: Glycerol
glycerol (micromol/L) at baseline after each phase in the AM of the final phase visit
Measured: End of each 6 week intervention period
Metabolic Markers: Insulin
insulin (microIU/ml) at baseline after each phase in the AM of the final phase visit
Measured: End of each 6 week intervention period
Metabolic Markers: Lactate
lactate (mmol/L) at baseline after each phase in the AM of the final phase visit
Measured: End of each 6 week intervention period
Metabolic Markers: Adiponection
adiponection (microg/ml) at baseline after each phase in the AM of the final phase visit
Measured: End of each 6 week intervention period
Vascular Markers: Endothelin-1 (pg/ml)
endothelin-1 at baseline after each phase in the AM of the final phase visit by peninsula labs radioimmunoassay
Measured: End of each 6 week intervention period
In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed
Measured by 31P-mass spec. This ratio measures mitochondrial efficiency. The higher the ratio, the more efficiently the individual converts metabolic substrates into ATP, with the ATP then available for energy-demanding cellular processes such as protein synthesis and biomass production
Measured: End of each 6 week intervention period
In Vivo Mitochondrial Function: Time Constants
Measured by 31P-mass spec. ADP time constant and phosphocreatine time constant. ADP time constant is a measure of the time required to convert 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. Similarly for phosphocreatine.
Measured: End of each 6 week intervention period
In Vivo Mitochondrial Function: QMax, VPCr
Measured by 31P-mass spec. For each measure, a higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted.
- QMax is theoretical maximum activity.
- VPCr measures the rate at which PCr is regenerated.
Measured: End of each 6 week intervention period
In Vivo Mitochondrial Function: Oxidative Phosphorylation
Measured by 31P-mass spec. A higher value indicates better mitochondrial function. All re calculated from multiple measures from the MRS spectra. These are relatively new research measures and normal values are not known or generally accepted. Oxidative Phosphorylation measures the rate at which electron transport activity generates phosphorylated energy sources (ATP and PCr)
Measured: End of each 6 week intervention period
In Vivo Mitochondrial Function:AnGly
Measured by 31P-mass spec. Anaerobic glycolysis measures the amount of anaerobic ATP generation for energy. It is generally felt that a higher value here reflects impaired mitochondrial function necessitating greater reliance on anaerobic metabolism.
Measured: End of each 6 week intervention period
Cardiac Function
Cardiac output
Measured: End of each 6 week intervention period
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Mar 2013 (estimated)
- Study startJun 2011
- Primary completion24 Mar 2017
- Study completion24 Mar 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Type 1 DiabetesStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- US Department of Veterans Affairs
- Responsible party
- Sponsor
- Investigators
- Irene Schauer, MD, PhD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01813929
- Sponsor's protocol ID
- 11-0693
- Acronym
- MeT1
- Status last verified
- Dec 2021
- First submitted
- 28 Sep 2012
- Last updated
- 21 Jan 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Jan 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Metformin on Vascular and Mitochondrial Function in Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT01813929
- Acronym / sponsor ID
- MeT1 / 11-0693
- Conditions
- Type 1 Diabetes
- Keywords
- Diabetes, Insulin, Metformin, Vascular, Vessels, Type 1
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 23 participants (actual)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- US Department of Veterans Affairs
- Study start
- Jun 2011
- Primary completion
- 24 Mar 2017 (actual)
- Study completion
- 24 Mar 2017 (actual)
- First posted
- 19 Mar 2013 (estimated)
- Results
- Posted 21 Jan 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | Experimental | Drug: Metformin |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 25 to 59 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- Age 20-59 years of age,
- 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,
- HbA1c 6.0 - 9.5, and
- Willing and able to commit to two 6 week-long periods of blinded medication followed by hyperinsulinemic euglycemic clamp, vascular testing, and muscle biopsies.
Key exclusion criteria (28 listed)
- Any comorbid condition associated with:
- Tobacco use;
- Pregnancy or women who are breastfeeding;
- Steroid use;
- Scheduled strenuous physical activity >3 days a week;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetforminAlso: glucophageSix 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. | Drug | Metformin |
| PlaceboSix-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, and then the higher dose (850 mg) for the remainder of the 6 week intervention. | Drug | Placebo |
Primary outcome
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp
Time frame: End of each 6 week intervention period
Determine the effect of metformin on insulin sensitivity in T1D. Reported measure is glucose infusion rate during hyperinsulinemic euglycemic clamp normalized to total body weight. For this measure, insulin was infused at 40 mU/m2 surface area. Blood sugar wass checked every 5 minutes and glucose infusion adjusted to maintain glucose level at 90 mg/dL for 2 hours. The glucose infusion rate for the final 30 minutes is reported as GIR (aka M-value or glucose disposal rate) in mg glucose/kg*min. A higher value corresponds to greater sensitivity to insulin. There is no strictly defined normal range.
Flow-mediated Brachial Artery Dilation
Time frame: End of each 6 week intervention period
Measure of endothelial function by brachial ultrasound of the percent dilation after 5 minutes of occlusion.
22 secondary outcomes
Arterial Stiffness by PWV
Time frame: End of each 6 week intervention period
Arterial Stiffness by AI@75
Time frame: End of each 6 week intervention period
Mitochondrial Measures: Oxygen Consumption
Time frame: End of each 6 week intervention period
Mitochondrial Measures: Protein Expression Levels of Electron Transport Chain Complexes
Time frame: End of each 6 week intervention period
Inflammatory Marker: hsCRP
Time frame: End of each 6 week intervention period
Heart Rate Variability
Time frame: End of each 6 week intervention period
Continuous Glucose Monitor Measures of Mean Glucose
Time frame: Last Week of each 6 Week Intervention Period (over 7 days)
Continuous Glucose Monitor Measures of Hypoglycemia
Time frame: Last Week of each 6 Week Intervention Period (over 7 days)
Metabolic Markers: Glucagon
Time frame: End of each 6 week intervention period
Metabolic Markers: Glucose, Triglycerides, Cholesterol
Time frame: End of each 6 week intervention period
Metabolic Markers: Fatty Acids
Time frame: End of each 6 week intervention period
Metabolic Markers: Glycerol
Time frame: End of each 6 week intervention period
Metabolic Markers: Insulin
Time frame: End of each 6 week intervention period
Metabolic Markers: Lactate
Time frame: End of each 6 week intervention period
Metabolic Markers: Adiponection
Time frame: End of each 6 week intervention period
Vascular Markers: Endothelin-1 (pg/ml)
Time frame: End of each 6 week intervention period
In Vivo Mitochondrial Function: Ratio of the Amount of ATP Generated Per Unit of Oxygen Consumed
Time frame: End of each 6 week intervention period
In Vivo Mitochondrial Function: Time Constants
Time frame: End of each 6 week intervention period
In Vivo Mitochondrial Function: QMax, VPCr
Time frame: End of each 6 week intervention period
In Vivo Mitochondrial Function: Oxidative Phosphorylation
Time frame: End of each 6 week intervention period
In Vivo Mitochondrial Function:AnGly
Time frame: End of each 6 week intervention period
Cardiac Function
Time frame: End of each 6 week intervention period
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Jan 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Irene Schauer, MD, PhD principal investigator
University of Colorado, Denver
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Metformin in people with Type 1 Diabetes, run by University of Colorado, Denver at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 21 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Jan 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Insulin Sensitivity by Hyperinsulinemic Euglycemic Clamp (time frame: End of each 6 week intervention period). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jan 2022.