Kidney Transplant Recipients, Post-transplant Diabetes Mellitus, Type 2 Diabetes
Conditions
Brief summary
This study will be a randomized, double-blind, placebo-controlled clinical trial comparing the SGLT2 inhibitor dapagliflozin to placebo in 52 kidney transplant recipients (KTR) with or without pre-existing type 2 diabetes (T2D) or post-transplant diabetes mellitus (PTDM). The primary outcome of the trial is to determine if dapagliflozin is superior to placebo in reduction of blood pressure in KTR.
Detailed description
Kidney transplantation is the renal replacement therapy of choice for patients with end stage renal disease (ESRD). It has been well established that kidney transplantation improves patient survival and quality of life, and results in significant savings to the health care system. Despite the survival benefit conferred by transplantation, KTR still face a number of challenges, especially in patients with diabetes. First, KTR still have a higher risk of mortality than their age-matched counterparts without kidney disease. This mortality risk is even greater amongst KTR with diabetes. Furthermore, mortality from cardiovascular disease (CVD) continues to be an important problem after transplantation. Another major challenge faced by KTR is the continuing risk of developing graft failure over time. Unfortunately, in the subgroup of KTR with diabetes, the incidence of graft failure is 50% higher than the general kidney transplant recipient population, and recurrent diabetic kidney disease (DKD) occurs in almost half of allografts after transplantation. Current strategies in the management of graft dysfunction and chronic kidney disease (CKD) are focused on optimizing immunosuppression and control of hypertension and dyslipidemia. Accordingly, there is an important unmet need for cardio- and renoprotective strategies to address premature death and graft loss in the KTR population. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are glucose lowering agents that are effective in the treatment of T2D, resulting not only in improved glycemic control, but also weight loss, blood pressure and albuminuria reduction. Several clinical trials have shown significant benefits of SGLT2i on cardiovascular and renal outcomes. Given the glucose-dependent and independent effects of SGLT2i, as well as the accumulating evidence demonstrating cardiorenal protection in non-KTR, the use of these agents in KTR is attractive - especially since traditional renin-angiotensin-aldosterone system inhibitors are not effective. Moreover, the use of SGLT2i as a cardiorenal protective therapy may be of particular value in KTR given the high burden of comorbidities such as diabetes, CVD and hypertension, as well as the ongoing challenges of premature death and graft loss in this population. This study will be a randomized, double-blind, placebo-controlled clinical trial comparing the SGLT2 inhibitor dapagliflozin to placebo in 52 KTR with or without pre-existing T2D or PTDM. The primary outcome of the trial is to determine if dapagliflozin is superior to placebo in reduction of blood pressure in KTR. The secondary outcomes of this study include metabolic, vascular, renal and transplant-specific measures. These outcomes have been included to elucidate the potential mechanisms responsible for blood pressure lowering, and putative cardio- and renoprotective effects in KTR. Safety outcomes will also be assessed.
Interventions
Dapagliflozin will be administered in a dose of 10 mg/day for 12 weeks.
DRUGPlacebo Matching Dapagliflozin Oral Tablet
Placebo will be administered for 12 weeks.
Sponsors
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
Each bottle of drug will be identified with a unique Composite ID in order to maintain the blind. By way of an Unblinding List, Pharmacy will provide treatment allocations of each Composite ID. The Unblinding List will be maintained within a secure location in the Pharmacy. Blinded personnel will not have access to this list.
Intervention model description
Study participants will be allocated to receive either 10 mg daily of dapagliflozin or a matching placebo for 12 weeks in a 1:1 ratio while continuing on existing medical therapy for glycemic control as recommended by Diabetes Canada.
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or females \>18 years old ≥ 6months after kidney transplantation; 2. In patients with T2D or PTDM, HbA1c \<12.0%; 3. eGFR ≥30 ml/min/1.73m\^2 (as per the CKD-EPI equation); 4. BMI ≤45kg/m\^2; 5. Blood pressure ≤160/90 and ≥90/60 at screening.
Exclusion criteria
1. Diagnosis of type 1 diabetes; 2. Presence of severe peripheral vascular disease (i.e. prior amputation, gangrene, non-healing ulcer or ischemic rest pain); 3. Presence of acute coronary syndrome, stroke or transient ischemic attack in the 3 months prior to screening; 4. Prior episode of graft pyelonephritis in the 1 month prior to screening; 5. Episode of acute graft rejection in the 3 months prior to screening; 6. Initiation of a new immunosuppressive agent or discontinuation of an immunosuppressive agent in the 1 month prior to screening; 7. Untreated urinary or genital tract infection; 8. Severe hypoglycemia within 3 months of screening, or hypoglycemia unawareness; 9. Pre-menopausal women who are nursing, pregnant, or of child-bearing potential and not practicing an acceptable method of birth control; 10. Participation in another trial with an investigational drug within 30 days of informed consent; 11. Alcohol or drug abuse within 3 months prior to informed consent that would interfere with trial participation; 12. Any ongoing clinical condition that would jeopardize subject safety or study compliance based on investigator judgement. 13. Patients currently using antipsychotic medications. 14. Use of SGLT2 inhibitors within 1 month of starting the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Systolic Blood Pressure (SBP) | Change from baseline SBP at 12 weeks of treatment | SBP |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Plasma Glucose | Change from baseline fasting plasma glucose at 12 weeks of treatment | Fasting plasma glucose |
| Glycated Hemoglobin (HbA1c) | Change from baseline HbA1c at 12 weeks of treatment | HbA1c |
| Carotid-femoral Pulse Wave Velocity | Change from baseline arterial stiffness at 12 weeks of treatment | Measured using a Sphygmocor device |
| Systemic Vascular Resistance | Change from baseline systemic vascular resistance at 12 weeks of treatment | Measured using non-invasive cardiac output monitor (NICOM) |
| Measured GFR | Change from baseline GFR (based on plasma iohexol clearance) at 12 weeks of treatment | GFR |
| Proximal Tubular Natriuresis | Change from baseline proximal tubular natriuresis at 12 weeks of treatment | Measured by fractional excretion of exogenous lithium (FELi) |
| UACR | Change from baseline albuminuria at 12 weeks of treatment | Albuminuria |
| Weight | Change from baseline weight at 12 weeks of treatment | Weight |
Countries
Canada
Contacts
PRINCIPAL_INVESTIGATORSunita KS Singh, MD MSc FRCPC
University Health Network, Toronto General Hospital
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 56 years |
| Estimated glomerular filtration rate (eGFR) | 62.4 mL/min/1.73 m^2 |
| Race/Ethnicity, Customized Asian | 8 Participants |
| Race/Ethnicity, Customized Black | 5 Participants |
| Race/Ethnicity, Customized Caucasian | 24 Participants |
| Race/Ethnicity, Customized Latinx | 1 Participants |
| Race/Ethnicity, Customized Other | 3 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 19 Participants |
| Time since transplant | 7.9 years STANDARD_DEVIATION 9 |
| Urine albumin-to-creatinine ratio (UACR) | 2.3 mg/mmol |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 26 |
| other Total, other adverse events | 2 / 26 | 2 / 26 |
| serious Total, serious adverse events | 0 / 26 | 1 / 26 |
Outcome results
None listed