Metformin in Kidney Disease

Sponsor
VA Office of Research and Development (U.S. Fed)
Overall Status
Completed
CT.gov ID
NCT02252081
Collaborator
(none)
125
1
2
63
2

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

Study Type:
Interventional
Actual Enrollment :
125 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
Dysmetabolism of Chronic Kidney Disease and Vascular Health
Actual Study Start Date :
Oct 1, 2014
Actual Primary Completion Date :
Dec 31, 2019
Actual Study Completion Date :
Dec 31, 2019

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

  1. 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

  1. 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.

  2. 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

  1. 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

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.
Responsible Party:
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT02252081
Other Study ID Numbers:
  • ENDA-014-13F
  • 1I01CX000982-01A1
First Posted:
Sep 29, 2014
Last Update Posted:
Nov 4, 2021
Last Verified:
Oct 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by VA Office of Research and Development
Additional relevant MeSH terms:

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

1. Primary Outcome
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
2. Secondary Outcome
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
3. Secondary Outcome
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
4. Other Pre-specified Outcome
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

[Not Specified]

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
Email adriana.hung@va.goc
Responsible Party:
VA Office of Research and Development
ClinicalTrials.gov Identifier:
NCT02252081
Other Study ID Numbers:
  • ENDA-014-13F
  • 1I01CX000982-01A1
First Posted:
Sep 29, 2014
Last Update Posted:
Nov 4, 2021
Last Verified:
Oct 1, 2021