Metformin in Kidney Disease
Study Details
Study Description
Brief Summary
Chronic kidney disease (CKD) is a major global health problem associated with substantial costs and resource utilization. Currently, CKD affects more than 500 million people worldwide. Patients with CKD have unacceptably high mortality rates due to cardiovascular (CV) causes, which are not entirely explained by traditional CV risk factors. The mortality rates in advanced CKD are six times higher compared to the Medicare population, with CVD accounting for the overwhelming majority of deaths. Insulin resistance (IR) is common in CKD patients and may represent a central link between CKD and the increased CVD risk observed in this population. Insulin resistance may increase CV risk by impairing and worsening endothelial function, increasing reactive oxygen species, and exacerbating systemic inflammation-hence, insulin resistance is considered a "non-traditional CV risk factor" in CKD.
Obesity (defined by a body mass index [BMI] of at least 30 kg/m2) is a major public health problem-the upward trend in obesity prevalence across regions and continents is a worldwide concern. Obesity increases the risk for cardiovascular disease and death. In the general population, obesity hastens death by 9.4 years. Obesity is an independent risk factor for CKD. Besides its contribution to the development of diabetes and hypertension, increased fat mass may also have a direct impact on kidney function.
In spite of the increasing prevalence of both obesity and CKD, the impact of obesity in the CKD population is not known, especially in terms of the exaggerated metabolic disturbances associated with their coexistence. It is highly likely that these two conditions have profound interactions that exaggerate the severity of the metabolic derangements when they coexist, particularly in regards to adipokine dysregulation, the risk of "insulin resistance", and downstream effects on vascular health. The current proposal will attempt to characterize the relative and combined impact of both obesity and CKD on metabolic disturbances, which may aid in risk stratification and identifying specific targets for intervention.
The ultimate goal of this proposal is to understand the relative and combined impact of obesity and CKD on the generation and maintenance of insulin resistance and their impact on cardiovascular health.
Specific Aim 2: To study the effects of metformin, an AMPK activator, on metabolic disturbances associated with obesity and moderate CKD.
S.A.2.a: To test if metformin will improve LAR in obese patients with moderate CKD compared to placebo.
S.A.2.b: To test if metformin will improve markers of systemic inflammation, oxidative stress, endothelial dysfunction in obese patients with moderate CKD compared to placebo.
S.A.2.c: To test if metformin will improve atherosclerosis markers and reduce clinical CVD events in obese patients with moderate CKD compared to placebo.
Hypothesis: The investigators hypothesize that the administration of metformin in obese CKD patients will significantly improve the adipokine profiles-particularly through a reduction in LAR. Additionally, that it will improve systemic inflammation, oxidative stress and endothelial function, which may or may not be mediated by changes in adipokines. Finally, the investigators hypothesize that improvements in these markers of vascular health will translate into reduced arterial stiffness and less clinical CV events
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Active Comparator: metformin 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min |
Drug: metformin
500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min
|
Placebo Comparator: Placebo placebo pill(s) orally per day for 16 weeks |
Drug: Placebo
placebo pill(s) orally per day for 16 weeks
|
Outcome Measures
Primary Outcome Measures
- Change is Leptin to Adiponectin Ratio (LAR) [16 weeks after start of treatment]
Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD
Secondary Outcome Measures
- Change in Flow-mediated Dilation (FMD) [16 weeks after the start of treatment]
Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group.
- Aortic Pulse-wave Velocity (aPWV) [16 weeks after starting treatment]
is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease
Other Outcome Measures
- Estimated Glomerular Filtration Rate (eGFR) [baseline and 16 weeks after starting treatment]
eGFR is a measurement of kidney function, this was a descriptive measurement
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Age 18 years old;
-
Ability to give informed consent;
-
Life expectancy greater than 6 months;
-
Estimated GFR 30-59 ml/min/1.73m^2;
-
Overweight (BMI >=25 to < 30 kg/m2) or obese (BMI >=30 kg/m2); or normal (BMI >=18.5 to <25 kg/m^2) if pre-diabetic or insulin resistant.
Exclusion Criteria:
-
Pregnancy or breast feeding;
-
Presence or history of Diabetes Mellitus type I or II
-
History of metformin use or any insulin sensitizer or any drug for the treatment of metabolic syndrome over the last one year;
-
Any acute kidney injury episode in the last 4 months due to the risk of recurrent AKI;
-
Proteinuria of > 5 g in 24 hours determined by a 24 hour urine collection or PCR > 4.5;
-
Uncontrolled hypertension with systolic blood pressure 160 mmHg and diastolic blood pressure 100 mmHg;
-
Patients with new changes to their antihypertensive regimen over the last 1 month;
-
Severe, unstable, or active inflammatory disease; active infection including seropositive HIV, Hepatitis B or C; active connective tissue disorder; or moderate to severe liver disease;
-
Decompensated heart failure;
-
Recent hospitalization or surgical procedure within 1 month prior to the study for any cause;
-
Current active malignancy or cancer history in the prior 5 years (excluding squamous cell and basal cell skin cancers);
-
Known intolerance to the study drug;
-
Patient receiving oral or injected steroids
-
Use of any investigational product or device within 30 days prior to screening, or requirement for any investigational agent prior to completion of all scheduled study assessments;
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Tennessee Valley Healthcare System Nashville Campus, Nashville, TN | Nashville | Tennessee | United States | 37212-2637 |
Sponsors and Collaborators
- VA Office of Research and Development
Investigators
- Principal Investigator: Adriana M Hung, MD MPH, Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
Study Documents (Full-Text)
More Information
Publications
None provided.- ENDA-014-13F
- 1I01CX000982-01A1
Study Results
Participant Flow
Recruitment Details | 65 patients did not meet inclusion criteria (normal GFR or to low GFR, new diabetes diagnosis, uncontrolled hypertension) or decline to participate. |
---|---|
Pre-assignment Detail |
Arm/Group Title | Metformin | Placebo |
---|---|---|
Arm/Group Description | 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min metformin: 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min | placebo pill(s) orally per day for 16 weeks Placebo: placebo pill(s) orally per day for 16 weeks |
Period Title: Overall Study | ||
STARTED | 30 | 30 |
COMPLETED | 24 | 26 |
NOT COMPLETED | 6 | 4 |
Baseline Characteristics
Arm/Group Title | Metformin | Placebo | Total |
---|---|---|---|
Arm/Group Description | 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min metformin: 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min | placebo pill(s) orally per day for 16 weeks Placebo: placebo pill(s) orally per day for 16 weeks | Total of all reporting groups |
Overall Participants | 30 | 30 | 60 |
Age (years) [Median (Inter-Quartile Range) ] | |||
Median (Inter-Quartile Range) [years] |
69
|
66
|
67
|
Sex: Female, Male (Count of Participants) | |||
Female |
6
20%
|
6
20%
|
12
20%
|
Male |
24
80%
|
24
80%
|
48
80%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
Asian |
0
0%
|
0
0%
|
0
0%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
7
23.3%
|
5
16.7%
|
12
20%
|
White |
23
76.7%
|
25
83.3%
|
48
80%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
Outcome Measures
Title | Change is Leptin to Adiponectin Ratio (LAR) |
---|---|
Description | Change in leptin to adiponectin ratio (LAR) after 4 months of metformin vs. placebo will be assessed as a biomarker of insulin resistance in CKD |
Time Frame | 16 weeks after start of treatment |
Outcome Measure Data
Analysis Population Description |
---|
analyzed as log transformed using ANCOVA of change, ng/µg (log transformed value) |
Arm/Group Title | Metformin | Placebo |
---|---|---|
Arm/Group Description | metformin 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min/1.73m^2; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min/1.73m^2 Placebo: placebo pill(s) orally per day for 16 weeks | placebo pill(s) orally per day for 16 weeks Placebo: placebo pill(s) orally per day for 16 weeks |
Measure Participants | 24 | 26 |
baseline |
2.2
|
1.3
|
Week 16 |
1.3
|
1.4
|
Title | Change in Flow-mediated Dilation (FMD) |
---|---|
Description | Change in FMD after 4 months of treatment with metformin will be compared to change in the placebo group. |
Time Frame | 16 weeks after the start of treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Metformin | Placebo |
---|---|---|
Arm/Group Description | 500 to 1500 mg if eGFR > 45 ml/min; 500 to 1000 mg if eGFR =< 45 ml/min metformin: 500 to 1500 mg if eGFR > 45 ml/min; 500 to 1000 mg if eGFR =< 45 ml/min | placebo pill(s) orally per day for 16 weeks Placebo: placebo pill(s) orally per day for 16 weeks |
Measure Participants | 24 | 26 |
baseline |
5.1
|
5.0
|
week 16 |
9.5
|
6.2
|
Title | Aortic Pulse-wave Velocity (aPWV) |
---|---|
Description | is a measurement of stiffening of the large elastic arteries and atherosclerosis. It is a subclinical marker of cardiovascular disease |
Time Frame | 16 weeks after starting treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Metformin | Placebo |
---|---|---|
Arm/Group Description | 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min | 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min |
Measure Participants | 24 | 26 |
baseline aPWV (cm/s) |
9.6
|
9.8
|
Week16 aPWC (cm/s) |
9.9
|
9.9
|
Title | Estimated Glomerular Filtration Rate (eGFR) |
---|---|
Description | eGFR is a measurement of kidney function, this was a descriptive measurement |
Time Frame | baseline and 16 weeks after starting treatment |
Outcome Measure Data
Analysis Population Description |
---|
kidney function measurement |
Arm/Group Title | Metformin | Placebo |
---|---|---|
Arm/Group Description | metformin: 500 to 1500 mg orally per day if eGFR > 45 ml/min/1.73m^2; 500 to 1000 mg orally per day if eGFR =< 45 ml/min/1.73m^2 orally per day for 16 weeks | matching placebo pill(s) 500 to 1500 mg orally per day if eGFR > 45 ml/min/1.73m^2; 500 to 1000 mg orally per day if eGFR =< 45 ml/min/1.73m^2 orally per day for 16 weeks |
Measure Participants | 24 | 26 |
baseline GFR |
49.5
|
48.5
|
Week 16 GFR |
52
|
48.7
|
Adverse Events
Time Frame | 16 weeks | |||
---|---|---|---|---|
Adverse Event Reporting Description | clinicaltrials.gov definitions | |||
Arm/Group Title | Metformin | Placebo | ||
Arm/Group Description | 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min metformin: 500 to 1500 mg orally per day for 16 weeks if eGFR > 45 ml/min; 500 to 1000 mg orally per day for 16 weeks if eGFR =< 45 ml/min | placebo pill(s) orally per day for 16 weeks Placebo: placebo pill(s) orally per day for 16 weeks | ||
All Cause Mortality |
||||
Metformin | Placebo | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 18/30 (60%) | 8/30 (26.7%) | ||
Serious Adverse Events |
||||
Metformin | Placebo | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 2/30 (6.7%) | 2/30 (6.7%) | ||
Cardiac disorders | ||||
acute coronary syndrome | 1/30 (3.3%) | 1 | 0/30 (0%) | 0 |
Pericarditis & chest pain | 1/30 (3.3%) | 1 | 0/30 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||
pneumonia & pneumonia related complications | 0/30 (0%) | 0 | 2/30 (6.7%) | 2 |
Other (Not Including Serious) Adverse Events |
||||
Metformin | Placebo | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 16/30 (53.3%) | 6/30 (20%) | ||
Blood and lymphatic system disorders | ||||
Hyperlactetemia without acidosis >3.5 mmol/L | 1/30 (3.3%) | 1 | 1/30 (3.3%) | 1 |
Gastrointestinal disorders | ||||
diarrhea/loose stools/flatulence | 8/30 (26.7%) | 8 | 1/30 (3.3%) | 1 |
left lower quadrant pain | 2/30 (6.7%) | 2 | 1/30 (3.3%) | 1 |
General disorders | ||||
Generalized fatigue | 1/30 (3.3%) | 1 | 1/30 (3.3%) | 1 |
Infections and infestations | ||||
Upper respiratory infection | 1/30 (3.3%) | 1 | 2/30 (6.7%) | 2 |
Respiratory, thoracic and mediastinal disorders | ||||
Asthma | 3/30 (10%) | 3 | 0/30 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Dr. Adriana Hung |
---|---|
Organization | Nashville Campus TVHS |
Phone | 6153274751 ext 6731 |
adriana.hung@va.goc |
- ENDA-014-13F
- 1I01CX000982-01A1