Efficacy and Mechanisms of Dapagliflozin in Promoting Kidney Function and Cardiovascular Health in Kidney Transplant Recipients

Phase 4

Recruiting

Brief Summary: Long-term allograft function in kidney transplant recipients (KTRs) remain suboptimal, and graft failure causes significant morbidity and mortality, with cardiovascular disease being the leading cause of death in KTRs and the most common cause of death with a functioning graft. Sodium-glucose cotransporter 2 (SGLT2) inhibitors safely lower cardiovascular and kidney disease risk in the non-transplant population, yet data in KTRs are lacking. This clinical trial seeks to establish the efficacy and safety of dapagliflozin, a SGLT2 inhibitor, for improving cardiovascular and kidney graft function in adult KTRs with type 2 diabetes and post-transplant diabetes, and to leverage innovate translational methods to define the underlying mechanisms of action.

Recruitment & Eligibility

Inclusion Criteria

Age 18-80 years
Kidney transplant received 1 year prior to randomization
estimated glomerular filtration rate 30-90 ml/min/1.73m2
Urine albumin to creatinine ratio (ACR) 30-5000 mg/g
Pre-existing type 2 diabetes or post-transplant diabetes mellitus
Blood pressure <130/80 mm Hg prior to randomization
Able to provide informed consent
Stable immunosuppression for at least 3 months prior to baseline consisting of tacrolimus, mycophenolate mofetil/mycophenolic acid and prednisone
Stable anti-hypertensive regimen for at least 1month prior to baseline
Stable diabetes management for at least 3 months prior to baseline
Stable angiotensin converting enzyme inhibitor/angiotensin receptor blocker use for at least 3 months prior to baseline (if applicable)
Glucagon-like peptide-1 receptor agonist (GLP-1RA) for at least 3 months prior to baseline (if applicable)

Exclusion Criteria

Type 1 diabetes
Anticipated life expectancy <1 year
Uncontrolled hypertension
Hemoglobin A1c >9%
Body mass index >40 kg/m2
New York Heart Association Class 3 or 4 heart failure symptoms, an EF ≤30%, or hospitalization for heart failure in the past 3 months
Pregnancy, plans to become pregnant, or breastfeeding
Current use of sodium glucose cotransporter-2 (SGLT2) inhibitors
Current urinary or urogenital infection
Use of anticoagulants (contraindication to kidney biopsy)
Magnetic resonance imaging (MRI) contraindications
History of lower-limb amputation irrespective of etiology
Known hypersensitivity to dapagliflozin

Arm && Interventions

Group	Intervention	Description
Dapagliflozin	Dapagliflozin 10mg Tab	Participants will receive dapagliflozin 10mg daily
Placebo	Placebo	Participants will receive one placebo tablet daily

Primary Outcome Measures

Name	Time	Method
Albuminuria	Change from baseline to 12 months	Measured by urine albumin to creatinine ratio

Secondary Outcome Measures

Name	Time	Method
Kidney morphometry, metabolomics from paired kidney biopsies	Change from baseline to 12 months	measured by single cell RNA sequencing from paired kidney biopsies
Left ventricular mass	Change from baseline to 12 months	measured by cardiac MRI
estimated glomerular filtration rate	Change from baseline to 12 months	estimated by CKD epi equation
safety and tolerability	baseline, 6 and 12 months	assessed on basis of adverse events
Kidney fibrosis	Change from baseline to 12 months	Measured by Magnetic Resonance Imaging (MRI) and kidney biopsy tissue
Kidney oxygenation	Change from baseline to 12 months	Measured by MRI
Arterial stiffness	Change from baseline to 12 months	Measured by aortic pulse wave velocity

Locations (1): University of Colorado Anschutz Medical Campus
🇺🇸
Aurora, Colorado, United States

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