SGLT2i Effect on PTDM Development and Kidney Allograft Function in Non-diabetic Kidney Transplant Recipients: A Randomized, Doubleblind, Placebo Controlled, National Multicenter Trial

SGL-TX-PTDM: SGLT2i Effect on PTDM Development and Kidney Allograft Function in Kidney Transplant Recipients: A Randomized, Doubleblind, Placebo Controlled, National Multicenter Trial

The goal of this clinical trial is to find out whether 12 months of treatment with the SGLT2 inhibitor Forxiga® (dapagliflozin 10 mg once daily), compared with placebo, can reduce the risk of developing post-transplant diabetes in kidney transplant recipients who do not have diabetes at the time of transplantation.

The main questions it aims to answer are:

• Does Forxiga reduce the risk of developing post-transplant diabetes and prediabetes compared with placebo?
• Does Forxiga help preserve the function of the transplanted kidney compared with placebo?
• Is Forxiga safe for kidney transplant recipients who do not have diabetes?
• Does Forxiga affect the occurrence of urinary tract infections, the amount of protein in the urine, and other kidney- and heart-related health measures compared with placebo?

Researchers will compare Forxiga with a placebo (a look-alike tablet containing no active medicine) to see whether it can reduce the risk of post-transplant diabetes while maintaining kidney function and remaining safe to use.

Adults who have recently received a kidney transplant and do not have diabetes may take part if they meet the study requirements.

Participants will be randomly assigned to receive either Forxiga or placebo once daily for 12 months. They will attend study visits 3, 6, and 12 months after joining the study. These visits will include health checks, blood tests, and urine tests. Neither the participants nor the study doctors will know which treatment each participant is receiving.

Background Kidney transplantation is the best treatment of end-stage renal disease (ESRD), although median allograft survival is only 15 years. In non-transplant patients with chronic kidney disease (CKD) sodium-glucose co-transporter type 2 inhibitors (SGLT2i) protects kidney function and reduces decline in estimated glomerular filtration (eGFR) and in KTR with PTDM, SGLT2i improve glucose regulation.

Perspective With the current kidney transplant survival of average 15 years, app. one out of ten adult[1] kidney transplant recipients (KTR) outlive their donated kidneys. This poses a significant burden to the patients and society and increases the demand for new transplantations. WHO reported a 9% increase in the number of kidney transplant recipients from 2022 to 2023[2]. The growing population of kidney transplant recipients underscores the importance of research aimed at prolonging graft survival and preventing post-transplant diabetes mellitus (PTDM). The efficacy of SGLT2i on reducing PTDM incidence remain untested in KTR.

The SGL-TX-PTDM study aim to investigate the effect of SGLT2i on the incidence of PTDM. PTDM is associated with a 63% increased risk for graft failure and an 87% increased risk for death[8]. PTDM is therefore known to be a threat to graft and patient survival throughout many years [9]. In the long-term perspective, we hope to contribute with knowledge to preserve kidney transplant function, benefit society, and improve patients' quality of life.

Hypothesis We hypothesize that SGLT2i will reduce the incidence of PTDM in non-diabetic KTR as an add-on to standard-of-care.

Research Objective In this superior randomized controlled clinical trial we will determine the effect of oral SGLT2i compared with placebo as add-on to standard-of-care on incidence of PTDM in non-diabetic KTR.

The secondary objectives will evaluate the effect of oral SGLT2i on prediabetes status, eGFR, U-ACR, urinary tract infection, renal parameters, cardiovascular parameters and adverse events in non-diabetic KTR.

Design An investigator-initiated, placebo-controlled, double-blinded, parallel-group, randomized, national, multicenter intervention study.

Methods Adults without pre-existing diabetes who are admitted for kidney transplantation will be screened for eligibility and invited to participate. Written informed consent will be obtained prior to any study-specific procedures. When the kidney allograft achieves an estimated glomerular filtration rate (eGFR) of 25 mL/min, eligible participants will be randomized in a 1:1 allocation ratio to receive either 12 months of oral SGLT2 inhibitor therapy (Dapagliflozin 10 mg once daily) or a matching placebo. Study medication will be administered in addition to standard immunosuppressive therapy.

Participants will continue to receive routine post-transplant clinical care throughout the study period. Study assessments will be conducted at baseline and at 3, 6, and 12 months following randomization. Clinical evaluations will include blood and urine laboratory tests, with safety and efficacy monitored at each visit by the treating nephrologist.

Post-transplant diabetes mellitus (PTDM) will be assessed according to the diagnostic criteria of the American Diabetes Association (ADA). All study procedures, data collection time points, and outcome assessments follow the SPIRIT 2025 guidance for interventional trial protocols.

Primary endpoint

• PTDM incidence after 3, 6 and 12 month follow up. , defined as any of the following criteria (HbA1c ≥ 48 mmol/mol or Fasting plasma glucose ≥ 7.0 mmol/L or random plasma glucose ≥ 11.1 mmol/L)

Secondary endpoint

• Prediabetes status after 3,6 and 12 month follow up, defined as any of the following criteria (HbA1c between 39-47 mmol/mol or Impaired fasting plasma glucose between 5.6-6.9 mmol/L or Continuous glucose monitoring mean blood glucose time above range 7,8 mmol/L

  ▪ Kidney allograft function (eGFR) change after 3, 6 and 12 month follow up.

• Albumin/creatinine ratio (U-ACR) (mg/g), after 3, 6 and 12 month follow up.

• Blood samples after 3, 6 and 12 month follow up. (Creatinine (umol/L, Total-Cholesterol, Low-and high-density lipoproteins (LDL and HDL, respectively) and triglycerides, Clinical routine Tacrolimus concentration (ug/L))

• Urinary tract infection (positive culture) incidence after 3, 6 and 12 month follow up.

• Incidence of kidney transplant rejection (biopsy verified) after 3, 6 and 12 month follow up.

• Renal composite outcome after 3, 6 and 12 month follow up. (Incidence of graft failure - defined as return to dialysis or retransplantation or Incidence of ESRD (defined as eGFR<15 ml/min/1.73m2) or Incidence of > 25% increase in creatinine

• Change in Systolic blood pressure (SysBP) (mmHg) and diastolic blood pressure (DiaBP) (mmHg), after 3, 6 and 12 month follow up.

• Relative incidence of out-of-target measures of clinical routine blood Tacrolimus levels

• Urine biomarkers indicative of podocyt and tubular function from selected sites

• Incidence of: Adverse events, Serious adverse events, Serious adverse reactions, Death - all cause mortality, and Major Adverse Cardiac Events (MACE)

Tertiary endpoints

• SF-36 (Short Form Health Survey 36)

Study population A total of 184 adults without pre-existing diabetes who undergo kidney transplantation will be recruited from three Danish transplant centers: Odense University Hospital (OUH), Aarhus University Hospital (AUH), and Copenhagen University Hospital - Rigshospitalet (RH). Participants will be enrolled once the kidney allograft has achieved an estimated glomerular filtration rate (eGFR) ≥ 25 mL/min. Eligible participants will then be randomized to receive either a daily dose of SGLT2 inhibitor or matching placebo for 12 months following randomization.

Inclusion Criteria:

• Obtained written informed consent
• Male or female patients, age ≥ 18 years.
• Non-diabetic KTR
• Immunosuppressive must include Tacrolimus

Exclusion Criteria:

• Patients who is treated (diet or antidiabetics) for diabetes type 1 or 2 before randomization
• eGFR< 25 ml/min/1.73m2 (before randomization)
• Alanine aminotransferase (ALAT) > 3 x upper normal limit
• Bilirubin > 2 x upper normal limit
• Pregnancy
• Positive plasma hCG
• Breastfeeding
• Known allergy towards SGLT2i or the content substance
• Patients with chronic intestinal diseases, including inflammatory bowel diseases (e.g., Crohn's disease and ulcerative colitis) and structural conditions such as short bowel syndrome.