Non-diabetic Chronic Kidney Disease
Conditions
Keywords
CKD, SGLT2 inhibitor, endothelial function
Brief summary
Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), is a novel diabetic medication that reduces the risk of progression of chronic kidney disease (CKD) and heart failure and improves exercise tolerance regardless of the diabetes status. One of the important ways that empagliflozin improves health may be through its benefits on blood vessels. The effects of empagliflozin on blood vessels and physical function have not been examined in patients with chronic kidney disease, and it is less clear if empagliflozin may be beneficial in patients with chronic kidney disease without heavy urinary protein leakage. The investigators will examine if empagliflozin can improve blood vessel function and exercise tolerance in Veterans with chronic kidney disease without heavy urinary protein leakage.
Detailed description
Overall Strategy: The investigators propose a randomized, double-blind, placebo-controlled, phase-II study in 52 Veterans with non-diabetic CKD without heavy albuminuria (\<300 mg/g) and eGFR 20-59 mL/min/1.73m2 to investigate if empagliflozin, a selective SGLT2i, can improve vascular function, functional capacity, and plasma biomarkers of inflammation, oxidative stress, and nitric oxide (NO). Veterans will be recruited from the Salt Lake City VA and randomized to 10 mg of empagliflozin or placebo at 1:1 ratio and treated for 16 weeks. Overarching Hypothesis: SGLT2 inhibition improves endothelial function in both macro- and micro-vasculature, in part, by mitigating inflammation and oxidative stress and augmenting NO bioavailability in patients with CKD, even in the absence of heavy albuminuria. The improved vascular function contributes to increased functional capacity. Specific Aim 1: Comprehensively evaluate the efficacy of empagliflozin to improve vascular health, as determined by conduit artery endothelium-dependent vasodilation (flow-mediated dilation, FMD), peripheral microvasculature reactivity (passive limb movement, PLM), and arterial stiffness (carotid-femoral pulse wave velocity, PWV), in non-diabetic Veterans with CKD and albuminuria \<300 mg/g. Specific Aim 2: Evaluate the efficacy of empagliflozin to improve functional capacity using (a) handgrip exercise and (b) mobility tests (Timed Up-and-Go test, gait speeds, and 6-minute walk). Specific Aim 3 (Exploratory): Evaluate the efficacy of empagliflozin to (a) reduce plasma biomarkers of systemic inflammation (C-reactive protein, interleukin-6, tumor necrosis factor- ) and oxidative stress (free radical concentration assessed by electron paramagnetic resonance spectroscopy) and (b) increase plasma NO, as reflected by plasma nitrite and nitrosyl hemoglobin levels.
Interventions
DRUGEmpagliflozin
Empagliflozin 10 mg, encapsulated to match the placebo, will be used.
DRUGPlacebo
Matching placebo will be used.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Randomization to either the placebo or empagliflozin group will be performed using a secure web-based system and allocation of empagliflozin vs. placebo in 1:1 ratio. The allocation of the study group will remain blinded to both participants and all study staff and investigators until the completion of the study. Participants will receive encapsulated empagliflozin and matching placebo.
Intervention model description
This is a randomized, double-blind, placebo-controlled, phase-II study in 52 Veterans with non-diabetic CKD without heavy albuminuria (\<300 mg/g) and eGFR 20-59 mL/min/1.73m2.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* eGFR (estimated glomerular filtration rate) 20-59 mL/min (milliliters per minute) * albuminuria \<300 mg/g (milligrams per gram)
Exclusion criteria
* Type 1 or 2 diabetes mellitus * expected to start dialysis or receive kidney transplantation or die within 4 months * prior therapy with SGLT2i (Sodium-Glucose Co-Transporter 2 inhibitors) within the previous year * unable to participate in the physical function tests (hand grip, walk) * infections requiring intravenous antibiotic treatment * malignancy requiring systemic therapy * extremity skin ulceration requiring active therapy * history of Fournier's gangrene * severe hypoglycemia requiring external assistance within the past one year * known allergy to empagliflozin * pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in endothelium-dependent vasodilation as measured by flow mediated dilation (FMD) | baseline, 8 weeks, 16 weeks | Brachial artery FMD will be used to assess if empagliflozin can improve endothelial function of conduit arteries in the upper limb. Brachial artery FMD outcome will be quantified as the maximal change in brachial artery diameter during the two-minute period after cuff release, expressed as a percentage increase from the pre-occlusion value (%FMD). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in leg blood flow area-under-the-curve (LBF AUC) by Passive Leg Movement (PLM) | baseline, 8 weeks, 16 weeks | PLM measures the movement-induced increase of blood flow mediated mostly by nitric oxide in feed arteries and microvascular beds of the leg. The total hyperemic response to PLM, expressed as LBF AUC, will be used as the main PLM endpoint. |
| Changes in aortic stiffness as measured by carotid-femoral pulse wave velocity (PWV) | baseline, 8 weeks, 16 weeks | Carotid-femoral PWV is the gold standard for non-invasive assessment of central arterial stiffness, and our study will follow the established guidelines. |
| Changes in functional capacity as measured by handgrip exercise | baseline, 8 weeks, 16 weeks | Handgrip strength will be measured during the maximal voluntary contraction using a handgrip dynamometer. The highest value of three maximal contractions will be used. |
| Mobility | baseline, 8 weeks, and 16 weeks | Timed Up-and-Go test will be used to assess sequential mobility tasks that incorporate walking and turning. The gait speed test over a 10-meter distance will be assessed during both comfortable and fast-gait speeds. The 6-minute walk test will measure the total distance covered during a 6-minute duration. |
Countries
United States
Contacts
CONTACTMonique Cho, MD
PRINCIPAL_INVESTIGATORMonique Cho, MD
VA Salt Lake City Health Care System, Salt Lake City, UT
Outcome results
None listed