CANagliflozin In DIALysis Patients

Overview

Rationale: Sodium glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of drugs originally developed for the treatment of diabetes. Cardiovascular outcome trials with these drugs showed also beneficial effects of these agents on heart failure, cardiovascular disease and kidney outcomes. Secondary analyses from these trials demonstrated that these benefits were consistent in patients with or with-out type 2 diabetes and with or without chronic kidney disease (CKD) with a lower eGFR threshold of 20 mL/min/1.73m2. However, it is not yet clear if these drugs can also be used in patients with severe kidney disease who require dialysis. This is in part explained because SGLT2 inhibitors bind to a transporter which is located in the luminal side of proximal tubes in the kidney. If kidney function is low, and these patients have no or limited filtering capacity, it is possible that the efficacy of these drugs decrease. Notwithstanding, several animal experiments and preliminary clinical data have suggested that these drugs do have kidney and cardiac protective effects in case of severely decreased kidney function. We hypothesize that SGLT2 inhibitors are distributed to several tissues in the body on top of the kidney and therefore we would like to investigate the specific tissue distribution of SGLT2 inhibitors in patients on dialysis with-and without residual diuresis.

Main objective: The main objective of this exploratory study is to investigate specific tissue distribution of SGLT2 inhibitors in patients on dialysis with-and without residual diuresis and visualize this by the use of 18F- canagliflozin. Secondary objective: To investigate 18F- canagliflozin binding in specific regions of interest: * The proximal tubule of the kidney * Cardiac tissue * Vascular tissue * Brain tissue To compare whether tissue distribution is different between dialysis patients who have and that do not have residual diuresis. Study design: This is an open-label exploratory study. The study will consist of a screening visit and 2 study days, separated by a one-week interval. Study population: The trial population will consists of 10 patients ≥18 years of age who are on dialysis for more than 3 months with or without residual diuresis and as exclusion criteria a total cumulative radiation burden above 1mSv per year (from the age of 18 years), a history of hypersensitivity to canagliflozin, any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications or peripheral/cardiovascular disease. Interventions: On both study days, a blood sample will be obtained for routine clinical care. A non-diagnostic CT scan will be performed to optimally position the individual subjects for the dynamic PET scan. In all subjects, two 60-minute dynamic PET scans will be obtained. On the first study day, following IV radiotracer administration, a baseline 60-minute PET scan will be taken to measure uptake and accumulation of 18F- canagliflozin. On the second study day (approximately 1 week after the first study day), following oral administration of 600 mg canagliflozin, a second IV radiotracer dose will be administered followed by a 60- minute dynamic PET scan (post-drug). Venous lines will be placed prior to the PET-scans to inject the dose and for venous sampling. In this study venous sampling was implemented as arterial sampling appeared to be burdensome for both personnel and participants. Main study endpoint: The main endpoint of the study is overall drug tissue disposition of SGLT2 in patients on dialysis quantified by images obtained by PET imaging. Secondary study endpoint: Receptor occupancy of SGLT2 in the regions of interest (proximal tubule of the kidney, cardiac tissue, vascular tissue, brain tissue) as quantified by images obtained by PET imaging. Study visits: Screening visit, study day 1, study day 2. Sample size: The sample size planned for this study is 10 participants, allocated n=5 to the residual diuresis group and n = 5 to the non-residual diuresis group. The sample size is based on prior experience of a variability and feasibility study with 18-F canagliflozin in a cohort of 9 patients with T2DM.