Metformin in Kidney Disease
Condition: Chronic Kidney Disease; Cardiovascular Disease; Metabolic Syndrome
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Cardiovascular Diseases; Metabolic Syndrome
Intervention: metformin; Placebo
Intervention 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; placebo pill(s) orally per day for 16 weeks
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 125.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: metformin; cardiovascular disease; Chronic Kidney Disease; Metabolic Syndrome

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
    

Eligibility 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/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.

        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;