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