Metformin in Kidney Disease

NCT02252081 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ENDA-014-13F1I01CX000982-01A1
• Study Type: interventional
• Target: 125
• Locations: 1 country
• Sites: 1

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

Conditions

Chronic Kidney Disease; Cardiovascular Disease; Metabolic Syndrome

Keywords

metformin; cardiovascular disease; Chronic Kidney Disease; Metabolic Syndrome

Outcome Measures

Primary Outcomes (1)

• Change is Leptin to Adiponectin Ratio (LAR)

  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

  16 weeks after start of treatment

Secondary Outcomes (2)

• Change in Flow-mediated Dilation (FMD)

  16 weeks after the start of treatment

• Aortic Pulse-wave Velocity (aPWV)

  16 weeks after starting treatment

Other Outcomes (1)

• Estimated Glomerular Filtration Rate (eGFR)

  baseline and 16 weeks after starting treatment

Study Arms (2)

metformin

ACTIVE COMPARATOR

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

Placebo

PLACEBO COMPARATOR

placebo pill(s) orally per day for 16 weeks

Drug: Placebo

Interventions

metformin DRUG

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

Placebo DRUG

placebo pill(s) orally per day for 16 weeks

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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/m\^2) or obese (BMI \>=30 kg/m\^2); or normal (BMI \>=18.5 to \<25 kg/m\^2) if pre-diabetic or insulin resistant.

You may not qualify if:

• 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;

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Nashville, Tennessee, 37212-2637, United States

Location

Related Publications (1)

• El-Damanawi R, Stanley IK, Staatz C, Pascoe EM, Craig JC, Johnson DW, Mallett AJ, Hawley CM, Milanzi E, Hiemstra TF, Viecelli AK. Metformin for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2024 Jun 4;6(6):CD013414. doi: 10.1002/14651858.CD013414.pub2.

  PMID: 38837240 DERIVED

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Cardiovascular Diseases; Metabolic Syndrome

Interventions

Metformin

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Insulin Resistance; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals

Results Point of Contact

• Title: Dr. Adriana Hung
• Organization: Nashville Campus TVHS

adriana.hung@va.goc

6153274751

Study Officials

• Adriana M Hung, MD MPH

  Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 25, 2014
• First Posted: September 29, 2014
• Study Start: October 1, 2014
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: November 4, 2021
• Results First Posted: November 4, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)