The aim of this study is to learn about the safety of empagliflozin in dialysis patients as a preparation for a future large clinical trial. Empagliflozin has been approved by the Food and Drug Administration for the treatment of either type 2 diabetes, heart failure, or chronic kidney disease among patients not on dialysis. The use of empagliflozin has not been studied or approved among patients on dialysis for kidney failure because empagliflozin acts on the kidneys. However, recent experimental studies have indicated that empagliflozin may provide direct heart benefits. Some dialysis patients have substantial residual kidney function, which may be protected by empagliflozin. Participants will be given empagliflozin for three (3) months on top of the standard of care (usual medical care for participants' condition) and will be followed up until one (1) month after the last dose. The investigators will collect information about participants' general health, obtain blood, urine, and imaging studies, check home blood pressure, monitor home blood sugar levels, and ask health-related questions to assess the safety and potential benefits of empagliflozin over four (4) months, including one month before the three (3)-month empagliflozin treatment.
The incidence of end-stage kidney disease (ESKD) in the US ranks among the highest in the world. ESKD is the last phase of chronic kidney disease when the kidneys are functioning below 10-15% of normal capacity, and the patient is on dialysis. According to the US Renal Data System (USRDS), 120,834 individuals started dialysis and nearly 524,000 people were living on dialysis in 2017.1 Although advancement in technology and general medical care has led to a modest decrease in mortality among dialysis patients, their mortality rate remains extremely high at approximately 16.5 per 100 patient-years. The leading cause of death among dialysis patients is cardiovascular disease (CVD), accounting for almost 45% of deaths. Unfortunately, established therapies to prevent incident CVD in the general population, such as renin-angiotensin system inhibitors or statins, have not been shown to be effective in the dialysis population. Sodium-glucose transporter type 2 (SGLT2) inhibitors are originally approved by FDA for the treatment for type 2 diabetes. SGLT2 is localized to the brush border of the early proximal tubule, and hence, SGLT2inhibitors induce osmotic diuresis and natriuresis but do not activate the systemic renin-angiotensin-aldosterone system.2 Recent clinical trials have consistently shown their potent renal and cardiovascular benefits in both diabetic and non-diabetic patients, which cannot be explained only by their glucose-lowering and diuretic properties. In fact, diuretics have not been shown to reduce cardiovascular mortality and such benefits of SGLT2 inhibitors are clear even among non-diabetic populations.3-5 Their renoprotective effect potentially extends to the dialysis population where residual kidney function (RKF) still plays a major role in solute clearance and volume control and has a strong association with patient outcomes.6 Patients who retain greater RKF can consume a more liberal diet and have better nutritional status, less pill burden, better blood pressure, and less interdialytic fluid gain with less frequent intradialytic hypotension, as well as greater quality of life and better survival.6 The pathophysiology underlying the cardiovascular benefits of SGLT2 inhibitors are yet to be fully elucidated, but a recent in-vitro studies indicate its direct effects on cardiomyocytes. Therefore, the investigators hypothesize that dialysis patients also benefit from SGLT2 inhibitors even if they do not have any RKF. Efficacy and safety studies with SGLT2 inhibitors did not enroll end-stage kidney disease (ESKD) patients on dialysis. Empagliflozin, canagliflozin, and dapagliflozin can be started if the glomerular filtration rate is more than 20-25 mL/min per 1.73 m2 and can be continued until dialysis initiation or kidney transplant. From a pharmacokinetics standpoint, those SGLT2 inhibitors are extensively metabolized by glucuronidation into inactive metabolites, and are not likely to cause dose-dependent toxicity even in ESKD. Nevertheless, extra caution is necessary for their use in the setting of ESKD because SGLT2 inhibitors are not well dialyzable due to large distribution volumes and high protein binding rates. Our overall goal is to conduct a non-randomized feasibility clinical trial of empagliflozin in the dialysis population to obtain data that will help plan future larger, sufficiently powered efficacy clinical trials. The investigators plan to enroll a total of 24 dialysis patients (18 patients on hemodialysis and 6 patients on peritoneal dialysis). After one month of the run-in period, participants will take oral empagliflozin for 3 months. \*Hemodialysis is a form of renal replacement therapy that utilizes an external filter (dialyzer) to remove wastes from the bloodstream. Peritoneal dialysis utilizes the peritoneum as a filter to remove wastes.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
24
Participants in Group I will be asked to take empagliflozin 25 mg after each hemodialysis session at home.
Participants assigned to Group II will be asked to take empagliflozin 10 mg each morning between 8:30 and 9:30 a.m. at home.
University of Mississippi Medical Center
Jackson, Mississippi, United States
RECRUITINGJackson Medicall Mall Dialysis Clinic
Jackson, Mississippi, United States
RECRUITINGProportion of eligible patients out of screened patients
Time frame: During the screening process
Success rate of obtaining consent from those eligible patients
Time frame: During the enrollment process
Proportion of missing doses
The investigators will do pill count using medication bottles and calculate the proportion of missing doses from each patient.
Time frame: 3 months
Proportion of empagliflozin discontinuation
Proportion of participants who discontinue empagliflozin for any reason
Time frame: 3 months
Dropout rate
Proportion of participants who dropped out from the study for any reason
Time frame: 3 months
Length of time on continuous glucose monitoring
Continuous glucose monitoring will be done for up to 14 days.
Time frame: 3 months
Completion rate of timed urine collection
Time frame: 3 months
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 1st blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: Immediately before the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 2nd blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 30 minutes of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 3rd blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 1 hour of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 4th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 1.5 hours of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 5th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 2 hours of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 6th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 3 hours of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 7th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 4 hours of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 8th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 8 hours of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 9th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 12 hours of the first dose
Blood empagliflozin concentrations after the first dose among patients on peritoneal dialysis
The 10th blood draw for the pharmacokinetic study among patients on peritoneal dialysis
Time frame: At 24 hours of the first dose
Random blood empagliflozin level
Time since the last dose will be recorded.
Time frame: At Month 1
Random blood empagliflozin level
Time since the last dose will be recorded.
Time frame: At Month 2
Random blood empagliflozin level
Time since the last dose will be recorded.
Time frame: At Month 3
Peritoneal dialysis clearance of empagliflozin
Peritoneal dialysis fluid will be collected for 24 hours.
Time frame: At Month 3
Number of Participants with Hepatic injury
defined by an elevation of AST and/or ALT \>3-fold upper limit of normal (ULN) combined with an elevation of total bilirubin \>2-fold ULN measured, and/or marked peak aminotransferase (ALT and/or AST) elevations ≥5-fold ULN
Time frame: 3 months
Number of Participants with Ketoacidosis
defined by elevated serum beta hydroxybutyrate ≥3.0 mmol/L
Time frame: 3 months
Number of Participants with Lower limb amputation
defined by any non-trauma-related event leading to a lower limb procedure of amputation, auto-amputation or disarticulation
Time frame: 3 months
Number of Participants with Symptomatic urinary tract infection
defined by symptoms consistent with urinary tract infection plus pyuria and bacteriuria - urine culture sample has to be taken and sent to central lab for confirmation of the diagnosis
Time frame: 3 months
Number of Participants with genital infection
per patient report
Time frame: 3 months
Number of Participants with Tinea cruris
per patient report
Time frame: 3 months
Number of Participants with Nausea
per patient report
Time frame: 3 months
Number of Participants with Vomiting
per patient report
Time frame: 3 months
Number of Participants with Skin and soft tissue infection
per patient report
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Time frame: 3 months
Days on continuous glucose monitoring (CGM)
Per CGM report
Time frame: Run in (within one month prior to the study start)
Days on continuous glucose monitoring (CGM)
Per CGM report
Time frame: At Month 0
Days on continuous glucose monitoring (CGM)
Per CGM report
Time frame: At Month 2
% Time of active CGM
Per CGM report
Time frame: Run in (within one month prior to the study start)
% Time of active CGM
Per CGM report
Time frame: At Month 0
% Time of active CGM
Per CGM report
Time frame: At Month 2
Average glucose
Per CGM report
Time frame: Run in (within one month prior to the study start)
Average glucose
Per CGM report
Time frame: At Month 0
Average glucose
Per CGM report
Time frame: At Month 2
Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)
Per CGM report
Time frame: Run in (within one month prior to the study start)
Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)
Per CGM report
Time frame: At Month 0
Glucose management indicator (estimated A1C level based on the average glucose level from CGM readings for 14 or more days)
Per CGM report
Time frame: At Month 2
Glucose variability
Per CGM report
Time frame: Run in (within one month prior to the study start)
Glucose variability
Per CGM report
Time frame: At Month 0
Glucose variability
Per CGM report
Time frame: At Month 2
Time in very high range (%)
Percent time for plasma glucose \>250 mg/dL
Time frame: Run in (within one month prior to the study start)
Time in very high range (%)
Percent time for plasma glucose \>250 mg/dL
Time frame: At Month 0
Time in very high range (%)
Percent time for plasma glucose \>250 mg/dL
Time frame: At Month 2
Time in high range (%)
Percent time for plasma glucose \>180 to 250 mg/dL
Time frame: Run in (within one month prior to the study start)
Time in high range (%)
Percent time for plasma glucose \>180 to 250 mg/dL
Time frame: At Month 0
Time in high range (%)
Percent time for plasma glucose \>180 to 250 mg/dL
Time frame: At Month 2
Time in target range (%)
Percent time for plasma glucose \>70 to 180 mg/dL
Time frame: Run in (within one month prior to the study start)
Time in target range (%)
Percent time for plasma glucose \>70 to 180 mg/dL
Time frame: At Month 0
Time in target range (%)
Percent time for plasma glucose \>70 to 180 mg/dL
Time frame: At Month 2
Time in low range (%)
Percent time for plasma glucose \>54 to 70 mg/dL
Time frame: Run in (within one month prior to the study start)
Time in low range (%)
Percent time for plasma glucose \>54 to 70 mg/dL
Time frame: At Month 0
Time in low range (%)
Percent time for plasma glucose \>54 to 70 mg/dL
Time frame: At Month 2
Time in very low range (%)
Percent time for plasma glucose 54 mg/dL or lower
Time frame: Run in (within one month prior to the study start)
Time in very low range (%)
Percent time for plasma glucose 54 mg/dL or lower
Time frame: At Month 0
Time in very low range (%)
Percent time for plasma glucose 54 mg/dL or lower
Time frame: At Month 2
Number of Participants with Hypoglycemia levels 1
Plasma glucose \<70 mg/dL for ≥15 minutes
Time frame: Run in (within one month prior to the study start)
Number of Participants with Hypoglycemia levels 1
Plasma glucose \<70 mg/dL for ≥15 minutes
Time frame: At Month 0
Number of Participants with Hypoglycemia levels 1
Plasma glucose \<70 mg/dL for ≥15 minutes
Time frame: At Month 2
Number of Participants with Hypoglycemia levels 2
Plasma glucose \<54 mg/dL for ≥15 minutes
Time frame: Run in (within one month prior to the study start)
Number of Participants with Hypoglycemia levels 2
Plasma glucose \<54 mg/dL for ≥15 minutes
Time frame: At Month 0
Number of Participants with Hypoglycemia levels 2
Plasma glucose \<54 mg/dL for ≥15 minutes
Time frame: At Month 2
Number of Participants with Prolonged hypoglycemia
Plasma glucose \<54 mg/dL for ≥2.0 hours
Time frame: Run in (within one month prior to the study start)
Number of Participants with Prolonged hypoglycemia
Plasma glucose \<54 mg/dL for ≥2.0 hours
Time frame: At Month 0
Number of Participants with Prolonged hypoglycemia
Plasma glucose \<54 mg/dL for ≥2.0 hours
Time frame: At Month 2
Changes from baseline to Month 3 in left ventricular end-diastolic volume
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in left ventricular end-systolic volume
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in left ventricular mass index
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in left ventricular ejection fraction
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in left ventricular diastolic function
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in longitudinal global strain
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in radial global strain
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in circumferential global strain
To be evaluated by transthoracic echocardiogram (optional)
Time frame: 3 months
Changes from baseline to Month 3 in home systolic blood pressure
Time frame: 3 months
Changes from baseline to Month 3 in home diastolic blood pressure
Time frame: 3 months
Changes from baseline to Month 3 in Kidney Disease Quality of Life (KDQOL)-36 questionnaire
Details are available at the URL below. https://www.rand.org/content/dam/rand/www/external/health/surveys\_tools/kdqol/kdqol36.pdf
Time frame: 3 months
Changes from baseline to Month 3 in residual kidney function
Renal urea clearance
Time frame: 3 months
Changes from baseline to Month 3 in hemoglobin
Time frame: 3 months
Changes from baseline to Month 3 in erythropoiesis stimulating drug dose
Time frame: 3 months
Hospitalization/Emergency room visit rate for heart failure
Time frame: 3 months
Cardiovascular mortality
Time frame: 3 months
All-cause mortality
Time frame: 3 months
Changes Estimated glomerular filtration rate (GFR) from baseline to Month 3
Estimated by Cystatin C and beta-2 macroglobulin
Time frame: 3 months