# Sodium-Glucose Cotransporter-2 Inhibitor in Diabetic and Nondiabetic Renal Transplant Recipients

Lucie Maigret, Lucile Basle, Valérie Chatelet, Laure Ecotiere, Peggy Perrin, Léonard Golbin, Dominique Bertrand, Dany Anglicheau, Coralie Poulain, Cyril Garrouste, et al.

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Lucie Maigret, Lucile Basle, Valérie Chatelet, Laure Ecotiere, Peggy Perrin, et al. Sodium-Glucose Cotransporter-2 Inhibitor in Diabetic and Nondiabetic Renal Transplant Recipients. Kidney International Reports, 2025, 10 (3), pp.816-827. 10.1016/j.ekir.2024.11.033. hal-05096152

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# Sodium-Glucose Cotransporter-2 Inhibitor in Diabetic and Nondiabetic Renal Transplant Recipients

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Lucie Maigret<fnref n="1" />, Lucile Basle², Valérie Chatelet³, Laure Ecotiere⁴, Peggy Perrin⁵, Léonard Golbin⁶, Dominique Bertrand⁷, Dany Anglicheau⁸, Coralie Poulain⁹, Cyril Garrouste¹⁰, Clément Danthu¹¹, Charlotte Boud'hors¹², Yannick Le Meur¹³, Manon Dekeyser¹⁴, Fabien Duthe⁴, Bénédicte Sautenet<fnref n="1" />, Pierre-Guillaume Deliège² and Philippe Gatault<fnref n="1" />,¹⁵

**Introduction:** Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular prognosis in patients with chronic kidney disease (CKD), diabetes, and heart failure; and slow the decline of kidney dysfunction in patients with albuminuria. Although safety and efficacy of SGLT2i have not been investigated in kidney transplant recipients (KTRs), their marketing authorization leaves the possibility of their use in these patients in France.

**Methods:** This was a prospective multicenter real-life study including all consecutive KTRs treated with SGLT2i.

**Results:** We identified 347 KTRs treated with SGLT2i (97% with dapagliflozin), with an initiation of treatment most often beyond the first year after transplantation (87%). Importantly, 226 (65.1%) were diabetic and 245 (70.6%) were treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). We found a low incidence of urinary tract infections (UTIs) (6.6%) and genital mycosis (0.6%), without any serious adverse event. Overall, SGLT2i were stopped in 54 patients (15.6%). The causes of SGLT2i discontinuations were very diverse. The main causes were graft dysfunction (32%), intercurrent infections (17%), urinary infections (11%), and digestive symptoms (9%). KTRs with a low estimated glomerular filtration rate (eGFR, especially those with eGFR < 30 ml/min per 1.73 m², presented with the highest incidence of SGLT2i discontinuation (P = 0.003). SGLT2i were associated with a reduction in proteinuria, found in both diabetic and nondiabetic KTRs. In addition, they had an antihypertensive effect restricted to uncontrolled-hypertensive patients.

**Conclusion:** SGLT2i have been used in KTRs since their authorization in France. They were discontinued more frequently in patients with impaired graft function; however, the expected side effects were infrequent and not life-threatening. The short-term antiproteinuric and antihypertensive effects are promising.

Kidney Int Rep (2025) 10, 816–827; https://doi.org/10.1016/j.ekir.2024.11.033

KEYWORDS: proteinuria; renal transplantation; sodium-glucose cotransporters-2 inhibitors

© 2024 International Society of Nephrology. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

See Commentary on Page 660

SGLT2i are essential nephroprotective agents in patients with CKD. Indeed, dapagliflozin and empagliflozin slow the progression of CKD in patients with albuminuria when used as an adjunctive therapy

**Correspondence:** Philippe Gatault, Service de Néphrologie-Hypertension artérielle, Dialyses, Transplantation rénale, CHRU Bretonneau, 2 Bd Tonnellé, 37044 Tours cedex 9, France. E-mail: philippe.gatault@univ-tours.fr

Received 3 June 2024; revised 24 October 2024; accepted 18 November 2024; published online 28 November 2024

<footnote n="1">¹Service de Néphrologie-Hypertension artérielle, Dialyses, Transplantation rénale, CHRU de Tours, Tours, France; ²Service de Néphrologie, Dialyse et Transplantation, CHU de Reims, Reims, France; ³Service de Néphrologie et Transplantation Rénale, CHU de Caen, Caen, France; ⁴Service de Néphrologie et Transplantation Rénale, CHU de Poitiers, Poitiers, France; ⁵Service de Néphrologie, Dialyse et Transplantation, CHU de Strasbourg, Strasbourg, France; ⁶Service de Néphrologie et Transplantation Rénale, CHU de Rennes, Rennes, France; ⁷Service de Néphrologie et Transplantation Rénale, CHU de Rouen, Rouen, France; ⁸Département de Néphrologie et transplantation rénale, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; ⁹Service de Néphrologie et Transplantation Rénale, CHU d'Amiens, Amiens, France; ¹⁰Service de Néphrologie et Transplantation Rénale, CHU de Clermont-Ferrand, Clermont-Ferrand, France; ¹¹Service de Néphrologie et Transplantation Rénale, CHU de Limoges, Limoges, France; ¹²Service de Néphrologie et Transplantation Rénale, CHU d'Angers, Angers, France; ¹³Service de Néphrologie et Transplantation Rénale, CHU de Brest, Brest, France; ¹⁴Service de Néphrologie, CHU d'Orléans, Orléans, France; and ¹⁵Unité INSERM UMR 1327 ISCHEMIA, Tours, France</footnote>
in combination with ACE inhibitors or ARBs, regardless of diabetic status. ¹,² Moreover, cardiovascular mortality is decreased in patients with albuminuria having CKD, treated with dapagliflozin. ¹,³ Therefore, SGLT2i are recommended by Kidney Disease Improving Global Outcomes, American Diabetes Association, and the European Association for the Study of Diabetes as first-line therapy in patients with type 2 diabetes and coexisting or high-risk conditions for heart failure, CKD, or atherosclerotic cardiovascular disease. ⁴⁻⁶ They are also recommended for patients with heart failure, regardless of ejection fraction and diabetes status, as well as for patients with diabetes. ⁷,⁸ As a result, SGLT2i are widely prescribed by nephrologists, diabetologists, cardiologists, and general practitioners.

Although KTRs have been excluded from randomized clinical trials, some of their characteristics would legitimize the use of SGLT2i. First, proteinuria is frequent in KTRs and is strongly associated with an increased risk of death and graft loss. ⁹,¹⁰ Second, the increasing prevalence of pretransplant diabetes, driven by global epidemiology and the high prevalence of posttransplant diabetes mellitus are associated with poor patient and graft outcomes. ¹¹⁻¹³ Third, chronic cardiac failure is frequently observed in KTRs because of the high prevalence of coronary artery disease and hypertension. It can also be underscored that elderly recipients with numerous comorbidities, often transplanted with extended criteria donor, are particularly susceptible to developing heart failure with preserved ejection fraction. ¹⁴

Since 2019, a few case series and small comparative studies released have investigated the use of SGLT2i in diabetic KTRs with stable graft function. These studies primarily examined the use of empagliflozin that seemed not to be associated with serious adverse events. A large retrospective case-controlled cohort study from South Korea investigated the safety and efficacy of SGLT2i in diabetic KTRs, suggesting that cardiovascular and nephroprotective effects may be similar to those observed in patients with CKD, with a good safety profile. ¹⁵ These findings were corroborated by a Spanish multicenter observational study, which found reductions in blood pressure and proteinuria, and noted a slightly increased risk of UTIs, especially in female recipients and patients with a history of UTI. ¹⁶

In France, dapagliflozin was approved for use in adults with CKD and the inclusion criteria of the DAPA-CKD trial not excluding of KTRs opened the way to its use in this population. We therefore designed a prospective multicenter observational study to monitor the prescription of SGLT2i in this population, with the aim of reporting early safety and efficacy data.

# METHODS

## Study Design

GREAT-ASTRE (Gliflozin in Renal Transplantation) is an observational study that targeted to enroll all patients treated with SGLT2i in all 13 centers of the Spiesser group. Patients consented to participate in the ASTRE database that prospectively collects clinical, biological, and histological data in more than 10,000 KTRs (DR-2012-518). Visits to ASTRE were scheduled on the day of transplantation, at 3 months, 1 year, then annually. We added 3 database visits: initiation of SGLT2i, then at 3 and 6 months. We collected the following data: diabetes, weight, systolic and diastolic blood pressure, creatinine, proteinuria (g/d or protein-to-creatinine ratio), hemoglobin A1C in diabetic patients; as well as treatments related to hypertension, dyslipidemia, and diabetes.

## Selection of Patients

We aimed to include all KTRs that started SGLT2i between June 2021 and March 2023, without any exclusion criteria except those with an unknown date of initiation of treatment. This was a real-life observational study, and each center was free to decide its own clinical practice. We did nevertheless collectively agree in a scientific meeting to avoid initiation of SGLT2i in the first 3 months following the transplantation, in patients with a history of numerous UTIs and with ureteral or bladder catheter. Data on the few patients treated with SGLT2i before June 2021 were retrospectively collected.

## Objectives

Our main objective was to describe the characteristics of patients treated with SGLT2i in real-life and provide safety data. We therefore paid particular attention to collect all treatment discontinuations, including their causes and to identify UTIs and genital mycosis. In instances where the reason for treatment withdrawal was not clearly stated, individual medical files were thoroughly reviewed to determine the underlying cause.

Our secondary objectives were to describe the evolution of blood pressure, proteinuria, and eGFR on treatment. Because the 2021 race-free CKD-Epidemiology Collaboration equation was found suboptimal for the care and follow-up of transplanted patients, we used the newly developed race-free kidney recipient-specific GFR equation. ¹⁷,¹⁸ Nevertheless, we additionally estimated GFR using the race-free CKD-Epidemiology Collaboration equation, which is more largely utilized in current practice, in order to validate our primary results concerning graft function and the
use of SGLT2i, as well as to facilitate comparison with prior studies.

## Statistical Analyses

Categorical variables were provided as absolute and relative frequencies. Depending on their distribution, continuous variables are described as the mean and SD or median and interquartile range. To compare categorical variables, we used a $\chi^2$ test or Fisher exact test where appropriate. To compare continuous variables, we used a Mann Whitney test or Kruskal Wallis test.

Cumulative incidence of treatment discontinuation was assessed by using a Kaplan Meyer model. Then, we included all factors possibly associated with treatment discontinuation into a time-dependent Cox regression model. All variables associated with treatment discontinuation ($P < 0.05$) were then included in the multivariate model. We additionally built cumulative incidence by eGFR and body mass index (BMI) and compared them using Gray's test.

Next, we compared the evolution of eGFR, proteinuria, and blood pressure in patients with available data at initiation of SGLT2i and month-3, and initiation and month-6, using the Wilcoxon signed-rank test. A subgroup analysis was performed in patients with systolic and diastolic blood pressure available to determine SGLT2i's effect in normotensive and hypertensive patients. The change in proteinuria levels after initiation was specifically conducted in proteinuric patients (proteinuria > 500 mg/d or urine protein-to-creatinine ratio > 500 mg/g), as well as in diabetic and nondiabetic KTRs. All tests were 2-sided, and $P < 0.05$ was considered significant. All statistical tests were performed with R Studio software (R Studio, version 1.2.1335).

# RESULTS

## Baseline Characteristics

We included all consecutive 347 KTRs who started SGLT2i. Initiation occurred mostly (87%) after the first posttransplantation year. Baseline characteristics are shown in Table 1. Dapagliflozin was used in 335 patients (96.6%), whereas empagliflozin was given in others. At initiation of SGLT2i, eGFR ranged between 30 and 60 ml/min per 1.73 m² in 75.8% of patients and <30 ml/min per 1.73 m² in 8.4% of patients. More than two-thirds of the KTRs received ACE inhibitors ($n = 132, 38.0\%$) or ARBs ($n = 126, 36.3\%$), whereas 13 patients received a combination (3.7%). The most frequent immunosuppressive regimen consisted of a combination of calcineurin inhibitor and mycophenolate mofetil, with about half maintained on long-term corticotherapy.

<table><caption>**Table 1.** Baseline characteristics</caption><thead><tr><th>Characteristics</th><th>Great Astre Cohort, (N = 347)</th></tr></thead><tbody><tr><td>Clinical data at kidney transplantation</td><td></td></tr><tr><td>First kidney transplant (%)</td><td>334 (96.3)</td></tr><tr><td>Preemptive kidney transplant (%)</td><td>40 (11.5)</td></tr><tr><td>Deceased donor (%)</td><td>295 (85.0)</td></tr><tr><td>Multiorgan transplantation (%)</td><td>5 (1.4)<sup>a</sup></td></tr><tr><td>Induction with rATG (%)</td><td>109 (31.4)</td></tr><tr><td>Induction with basiliximab (%)</td><td>194 (55.9)</td></tr><tr><td>Coronary disease (%)</td><td>52 (15.0)</td></tr><tr><td>Heart failure (%)</td><td>23 (6.6)</td></tr><tr><td>Stroke (%)</td><td>15 (4.3)</td></tr><tr><td>Peripheral artery disease (%)</td><td>29 (8.4)</td></tr><tr><td>Hypertension (%)</td><td>291 (83.9)</td></tr><tr><td>Arrhythmia (%)</td><td>265 (76.4)</td></tr><tr><td>Clinical and biological data at initiation of SGLT2i</td><td></td></tr><tr><td>Age (yrs)</td><td>62.6 [52.1-69.5]</td></tr><tr><td>Male (%)</td><td>265 (76.4)</td></tr><tr><td>Time after transplantation (yrs)</td><td>6.7 [2.8-13.5]</td></tr><tr><td>Diabetes mellitus (%)</td><td>226 (65.1%)</td></tr><tr><td>Weight (kg)</td><td>82.0 [72.0-91.4]<sup>b</sup></td></tr><tr><td>BMI (kg/m<sup>2</sup>)</td><td>27.8 [24.5-32.0]<sup>b</sup></td></tr><tr><td>eGFR (ml/min per 1.73 m<sup>2</sup>)</td><td>44.8 [37.1-54.5]</td></tr><tr><td>Serum creatinine (µmol/l)</td><td>142 [113-173]</td></tr><tr><td>Proteinuria (mg/d)<sup>c</sup></td><td>530 [220-1546]<sup>b</sup></td></tr><tr><td>Systolic blood pressure (mm Hg)</td><td>143 [132-155]<sup>b</sup></td></tr><tr><td>Diastolic blood pressure (mm Hg)</td><td>81 [73-89]<sup>b</sup></td></tr><tr><td>Immunosuppressive regimen at initiation of SGLT2i</td><td></td></tr><tr><td>Calcineurin inhibitor (%)</td><td>261 (75.2)</td></tr><tr><td>Mycophenolate mofetil or sodium (%)</td><td>316 (91.1)</td></tr><tr><td>Steroids (%)</td><td>185 (53.3)</td></tr><tr><td>mTor inhibitors (%)</td><td>38 (11.0)</td></tr><tr><td>Belatacept (%)</td><td>14 (4.0)</td></tr><tr><td>Antihypertensive treatment at initiation of SGLT2i</td><td></td></tr><tr><td>ACE inhibitors or ARBs (%)</td><td>245 (70.6)</td></tr><tr><td>Diuretic (%)</td><td>140 (40.4)</td></tr><tr><td>Calcium channel blocker (%)</td><td>202 (58.2)</td></tr><tr><td>Beta-blockers (%)</td><td>223 (64.3)</td></tr><tr><td>Alpha-blockers (%)</td><td>59 (17.0)</td></tr><tr><td>Centrally acting antihypertensive drugs (%)</td><td>33 (9.5)</td></tr><tr><td>Hypolipemiant treatment at initiation of SGLT2i</td><td></td></tr><tr><td>Statin (%)</td><td>224 (64.6)</td></tr><tr><td>Ezefimibe (%)</td><td>48 (13.8)</td></tr></tbody></table>

ACE, angiotensin-converting enzyme; ARBs, angiotensin-receptor blockers; BMI, body mass index; eGFR, estimated glomerular filtration rate; rATG, rabbit antithymocyte globulin; SGLT2i, sodium-glucose cotransporter-2 inhibitor.

Most of the differences in the baseline characteristics between diabetic and nondiabetic patients were observed at the initiation of SGLT2i (Supplementary Table S1). The diabetic patients exhibited a higher BMI, better renal function, and lower levels of proteinuria, which may reflect the fact that diabetes was the primary indication for treatment in some cases. Of the 226 diabetic KTRs, 51.3%, 46.0%, and 2.6% had posttransplant diabetes mellitus, pretransplant type 2 diabetes, and pretransplant type 1 diabetes,

<footnote><sup>a</sup>n = 2 heart and kidney, n = 2 pancreas and kidney, n = 1 liver and kidney.</footnote>

<footnote><sup>b</sup>Missing data (20 for weight, 29 for BMI, 74 for proteinuria, 38 for blood pressure).</footnote>

<footnote><sup>c</sup>When data in mg/d was missing, it was substituted by urine protein-to-creatinine ratio in mg/g.</footnote>
respectively. Data on hemoglobin A1C was available in 130 patients at initiation of SGLT2i. Median hemoglobin A1C at initiation of SGLT2i was 7.5% (6.7–8.3). A vast majority received at least 1 antidiabetic treatment at initiation of SGLT2i (96.5%): metformin (56.2%), insulin (37.2%), dipeptidyl peptidase 4 inhibitors (26.1%). and glucagon-like peptide 1 agonists (14.6%).

Importantly, we were not able to give the indication of SGLT2i, even though baseline characteristics indirectly provide information about them (diabetes mellitus, proteinuria, cardiac disease). Thus, it is interesting to note that patient profiles were fairly homogeneous across centers (Supplementary Table S2).

Median follow-up duration was 12.0 (0.1–44.8) months. During this period, 2 patients returned to dialysis because of progression of chronic graft dysfunction. No death was reported.

## Safety Data

Ninety patients (25.9%) experienced at least 1 adverse event (Table 2). Graft dysfunction was reported in 4.9 % of patients, leading to SGLT2i withdrawal. All graft losses occurred in patients who underwent a preexisting severe and rapidly progressive graft dysfunction.

Nevertheless, we could not clearly distinguish between acute kidney disease (AKI) occurring after the introduction of SGLT2i and preexisting graft dysfunction that continued to evolve, possibly even more quickly.

The most frequent adverse event was UTI, recorded in 23 patients (6.6%). They were mostly lower UTI that hardly led to SGLT2i discontinuation. Seven patients (2% of total patients) reported pyelonephritis, whereas 3 of them had already presented at least 1 pyelonephritis after their transplantation. It was difficult to determine whether UTIs were related to treatment. However, we noticed that after SGLT2i discontinuation for UTI in 6 patients, 4 KTRs presented with other episodes. In other 17 patients who were continuing SGLT2i despite a first UTI episode, 4 experienced another symptomatic infection during the follow-up. Genital mycosis were rare (0.6 %) and were exclusively reported in diabetic patients. No Fournier's gangrene was reported. The other intercurrent infections are reported in Table 2, which primarily consisted of respiratory and digestive infections. Notably, one-third of reported digestive symptoms were attributable to gastrointestinal infections, with diarrhea being the most common manifestation. Digestive infections were due to

<table><caption>**Table 2.** Adverse events</caption><thead><tr><th>Adverse events</th><th>Great Astre cohort<br>(N = 347)</th><th>Diabetic patients<br>(n = 226)</th><th>Nondiabetic patients<br>(n = 121)</th><th>Leading to SGLT2i withdrawal<br>(n = 54)</th></tr></thead><tbody><tr><td>Graft dysfunction, n (%)</td><td>17 (4.9)</td><td>10 (4.4)</td><td>7 (5.8)</td><td>17 (100.0)</td></tr><tr><td>Infectious adverse events</td><td></td><td></td><td></td><td></td></tr><tr><td>Lower UTI, n (%)</td><td>16 (4.6)</td><td>13 (5.8)</td><td>3 (2.5)</td><td>3 (18.8)</td></tr><tr><td>Pyelonephritis, n (%)</td><td>7 (2.0)</td><td>5 (2.2)</td><td>2 (1.7)</td><td>3 (42.9)</td></tr><tr><td>Genital infection, n (%)</td><td>2 (0.6)</td><td>0 (0.0)</td><td>2 (1.7)</td><td>0 (0.0)</td></tr><tr><td>SARS-CoV-2 infection, n (%)</td><td>22 (6.3)</td><td>17 (7.5)</td><td>5 (4.1)</td><td>1 (4.6)</td></tr><tr><td>Other pulmonary infection, n (%)</td><td>6 (1.7)</td><td>6 (2.7)</td><td>0 (0.0)</td><td>1 (16.7)</td></tr><tr><td>Digestive infection, n (%)</td><td>6 (1.7)</td><td>4 (1.8)</td><td>2 (1.7)</td><td>1 (16.7)</td></tr><tr><td>CMV primary infection, n (%)</td><td>4 (1.1)</td><td>4 (1.8)</td><td>0 (0.0)</td><td>1 (25.0)</td></tr><tr><td>Other infection, n (%)</td><td>5 (1.4)</td><td>4 (1.8)</td><td>1 (0.8)</td><td>5 (100.0)</td></tr><tr><td>BKV viremia, n (%)</td><td>2 (0.6)</td><td>2 (0.9)</td><td>0 (0.0)</td><td>1 (50.0)</td></tr><tr><td>Shingles, n (%)</td><td>2 (0.6)</td><td>2 (0.9)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Digestive symptoms, n (%)</td><td>12 (3.5)</td><td>7 (3.1)</td><td>5 (4.1)</td><td>5 (41.7)</td></tr><tr><td>Other adverse events</td><td></td><td></td><td></td><td></td></tr><tr><td>Dysuria, n (%)</td><td>1 (0.3)</td><td>0 (0.0)</td><td>1 (0.8)</td><td>1 (100.0)</td></tr><tr><td>Ketoacidosis, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>1 (100.0)</td></tr><tr><td>Hypoglycemia, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Pancreatitis, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Stroke, n (%)</td><td>3 (0.9)</td><td>3 (1.3)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Myocardial infarction, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Veinous thrombosis, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Gout, n (%)</td><td>2 (0.6)</td><td>1 (0.4)</td><td>1 (0.8)</td><td>1 (50.0)</td></tr><tr><td>Amputation, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Hypotension, n (%)</td><td>2 (0.6)</td><td>2 (0.9)</td><td>0 (0.0)</td><td>1 (50.0)</td></tr><tr><td>Dizziness, n (%)</td><td>1 (0.3)</td><td>0 (0.0)</td><td>1 (0.8)</td><td>1 (100.0)</td></tr><tr><td>Oedema, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>1 (100.0)</td></tr><tr><td>Hyperkaliemia, n (%)</td><td>1 (0.3)</td><td>1 (0.4)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Basocellular tumor, n (%)</td><td>3 (0.9)</td><td>3 (1.3)</td><td>0 (0.0)</td><td>0 (0.0)</td></tr><tr><td>Spinocellular tumor, n (%)</td><td>2 (0.6)</td><td>1 (0.4)</td><td>1 (0.8)</td><td>0 (0.0)</td></tr></tbody></table>

AKI, acute kidney injury; BKV, BK virus; CMV, cytomegalovirus; SGLT2i, sodium-glucose cotransporter-2 inhibitor; UTI, urinary tract infection.
*Campylobacter*, norovirus, and *Clostridium difficile* in 3, 2, and 1 patient, respectively. Respiratory infections were mostly because of SARS-CoV-2.

Although SGLT2i are contraindicated in patients with type 1 diabetes in France, dapagliflozin was introduced in 6 KTRs with type 1 diabetes. It was also stopped for this reason in 3 of these patients in the absence of adverse event. The only case of ketoacidosis occurred in a patient with type 2 diabetes.

One patient underwent a limb amputation consid-
ered because of a preexisting infectious arthritis
(SGLT2i was continued in this KTRs), and 3 patients
experienced stroke. All strokes occurred in hyperten-
sive and insulin-requiring patients with diabetes; none
led to SGLT2i discontinuation.

Treatment Discontinuation

SGLT2i discontinuation was reported in 54 of the 347 patients over the follow-up period. Cumulative incidence of discontinuation was 7.8% (95% confidence interval: 5.4–11.2), 12.3% (95% confidence interval: 9.0–16.3] and 15.6% (95% confidence interval: 12.1–20.2) at 3, 6, and 12 months, respectively (Figure 1). The causes of discontinuation were led by graft dysfunction, reported in 4.9% of the whole cohort, which translates to 32% of all causes of discontinuation (Figure 2a). Infectious causes of treatment discontinuation other than UTIs consisted of 1 norovirus infection, 1 SARS-CoV-2 infection, 1 primary cytomegalovirus infection, 1 septic shock, and 5 nonspecified infectious causes. In total,

17% of discontinuations were caused by intercurrent
infections, which occurred significantly later than other
causes (P = 0.008). We analyzed several parameters in a
univariate model to determine if they were associated
with SGLT2i withdrawal (Table 3). We found no asso-
ciation with the baseline comedication (ACE inhibitors
or ARBs, diuretics, calcineurin inhibitors) or with the
baseline comorbidities (diabetes mellitus or high blood
pressure). Only initial eGFR and BMI were associated
with SGLT2i discontinuation in the univariate analysis
(P = 0.047 and P = 0.020, respectively). Hazard ratios
were not modified after adjustment, even though only
BMI remained significantly associated with SGLT2i
discontinuation. Regarding BMI, we did not observe a
gradual risk of SGLT2i discontinuation from KTRs with
the highest BMI (≥ 35 kg/m²) to those with the lowest
BMI (< 25 kg/m²) (Supplementary Figure S1).

To better investigate how initial eGFR predicted SGLT2i discontinuation, we categorized patients into 4 eGFR strata: < 30 ml/min per 1.73m², 30 to 44.9 ml/min per 1.73 m², 45 to 59.9 ml/min per 1.73 m², and ≥ 60 ml/min per 1.73 m². The incidence of SGLT2i discontinuation was different between groups (Figure 2b, P = 0.009). Thus, the incidence of SGLT2i discontinuation was higher in KTRs with eGFR < 45 ml/min per 1.73 m² (P = 0.03) and even more in KTRs with eGFR < 30 ml/min per 1.73 m² with about 30% of treatment withdrawal after 6 months (P = 0.003) (Supplementary Figure S2). We underscore that 40% of discontinuations were because of graft dysfunction in KTRs with eGFR < 45 ml/min per 1.73 m², compared with 10.5%

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Cumulative incidence of SGLT2 inhibitor discontinuation in the whole cohort (N = 347). SGLT2i, sodium glucose cotransporter 2 inhibitor.</figcaption></figure>
<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 2.** Causes of SGLT2 inhibitors discontinuation and incidence by graft function. (a) Pie chart of causes leading to SGLT2i discontinuation (n = 54). (b) Comparison of cumulative incidence of SGLT2i discontinuation by eGFR classes (< 30 ml/min per 1.73 m², 30 to 44 ml/min per 1.73 m², 45 to 59 ml/min per 1.73 m², and > 60 ml/min per 1.73 m²). AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; SGLT2i, sodium glucose cotransporter 2 inhibitor. eGFR is expressed in ml/min per 1.73 m².</figcaption></figure>

in the others. The race-free CKD-Epidemiology Collaboration formula was less effective in stratifying the risk of SGLT2i discontinuation according to graft function, despite the cumulative incidence curves exhibiting similar aspect (Supplementary Figure S3). Nonetheless, we identified a higher incidence of SGLT2i discontinuation in patients with an

eGFR < 30 ml/min/1.73 m² was noticed, irrespective of the GFR estimation formula (Supplementary Figure S3).

## Evolution of Renal Function, Proteinuria, and Blood Pressure Over 6 Months

We reported on creatinine levels, eGFR, proteinuria, and blood pressure in KTRs who remained on SGLT2i
<table><caption>**Table 3.** Parameters associated with SGLT2 inhibitor discontinuation</caption><thead><tr><th rowspan="2">Parameters</th><th colspan="3">Univariate analysis</th><th colspan="3">Multivariate analysis</th></tr><tr><th>HR</th><th>95% CI</th><th>P-value</th><th>HR</th><th>95% CI</th><th>P-value</th></tr></thead><tbody><tr><td>Time since Tx (per month)</td><td>1</td><td>0.999-1</td><td>0.777</td><td></td><td></td><td></td></tr><tr><td>BMI (per kg/m²)</td><td>0.934</td><td>0.882-0.990</td><td>0.020</td><td>0.934</td><td>0.881-0.990</td><td>0.022</td></tr><tr><td>SBP (per mm Hg)</td><td>1.002</td><td>0.987-1.016</td><td>0.834</td><td></td><td></td><td></td></tr><tr><td>DBP (per mm Hg)</td><td>0.998</td><td>0.974-1.022</td><td>0.853</td><td></td><td></td><td></td></tr><tr><td>Age (per yr)</td><td>1.023</td><td>0.999-1.047</td><td>0.064</td><td></td><td></td><td></td></tr><tr><td>Sexe</td><td>1.066</td><td>0.619-1.835</td><td>0.626</td><td></td><td></td><td></td></tr><tr><td>eGFR (per ml/min per 1.73 m²)</td><td>0.978</td><td>0.957-0.999</td><td>0.047</td><td>0.979</td><td>0.956-1.003</td><td>0.086</td></tr><tr><td>Diabetes mellitus</td><td>1.179</td><td>0.656-2.117</td><td>0.581</td><td></td><td></td><td></td></tr><tr><td>CNI</td><td>0.826</td><td>0.455-1.498</td><td>0.529</td><td></td><td></td><td></td></tr><tr><td>Tacrolimus</td><td>0.884</td><td>0.662-1.931</td><td>0.700</td><td></td><td></td><td></td></tr><tr><td>Tacrolimus CO</td><td>1.167</td><td>0.680-1.079</td><td>0.188</td><td></td><td></td><td></td></tr><tr><td>Ciclosporin</td><td>1.487</td><td>0.339-1.337</td><td>0.258</td><td></td><td></td><td></td></tr><tr><td>Ciclosporin CO</td><td>1.008</td><td>0.968-1.017</td><td>0.516</td><td></td><td></td><td></td></tr><tr><td>Diuretic</td><td>0.938</td><td>0.619-1.835</td><td>0.817</td><td></td><td></td><td></td></tr><tr><td>Loop diuretic</td><td>1.300</td><td>0.317-5.334</td><td>0.716</td><td></td><td></td><td></td></tr></tbody></table>

BMI, body mass index; CI, confidence interval; CNI, calcineurin inhibitor; CO, trough level; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HR, hazard ratio; SBP, systolic blood pressure; Tx, transplantation.

in Table 4, as well as in patients with and without diabetes. We found a slight reduction in eGFR at 3 and 6 months (P < 0.0001), irrespective of diabetes status. It was similarly observed using the CKD-Epidemiology Collaboration eGFR (Supplementary Table S3). In contrast, the level of proteinuria appeared to distinguish patients with a further decline of graft function because eGFR remained steady after SGLT2i initiation in patients with a proteinuria < 500 mg/d (Supplementary Table S4).

A 15% reduction in proteinuria was observed 3 months after SGLT2i initiation and remained significant over the first 6 months. In 138 patients with proteinuria > 500 mg/d, the reduction in proteinuria was observed in the first 3 months and reached 36% at 6 months (P < 0.0001) (Figure 3a). The antiproteinuric effect was similarly noticed in both proteinuric patients with diabetes (n = 70, P = 0.032) and nondiabetic patients (n = 68, P = 0.0007). (Figure 3b and c). We noted a reduction in systolic and diastolic blood pressure of about 5 and 3 mm Hg (P < 0.00001), respectively, after 3 months of SGLT2i use. The antihypertensive effect remained significant at 6 months, especially in nondiabetic patients (Table 4). We then stratified KTRs by initial blood pressure to investigate the reduction in blood pressure in hypertensive and normotensive KTRs. In patients with blood pressure ≥ 140/90 mm Hg, the systolic blood pressure decreased from 156 ± 16 mm Hg to 146 ± 168 mm Hg over the first 6 months, whereas SGLT2i had no antihypertensive effect in patients with blood pressure < 140/90 mm Hg. (Figure 4b and c).

## DISCUSSION

Our main objective was to provide reliable safety data on the use of SGLT2i in KTRs in real-life conditions. Patients' characteristics were similar to the DAPA-CKD population regarding proportion of nondiabetic patients and renal function. Notably, almost all patients received dapagliflozin, the first approved SGLT2i for patients with CKD in France. We therefore provide original data from a large cohort with distinct characteristics, differing from previous studies in KTRs that primarily enrolled diabetic recipients with good graft function and were mostly treated with empagliflozin.

First, we found that KTRs would be more prone to develop side effects leading to treatment discontinuation in comparison to nontransplanted patients. Indeed, 12.7% and 16.9% of CKD patients stopped dapagliflozin and empagliflozin over 24 months in the DAPA-CKD and EMPA-KIDNEY studies, respectively; whereas we reported 15.6% of discontinuation during a 1-year follow-up. This discontinuation rate was close to the 11.8%, 1-year withdrawal rate found in diabetic KTRs.¹⁶ In our study, treatment discontinuation occurred most often during the first 6 months following initiation. As expected, graft dysfunction and urinary infections represented 2 of the leading causes of SGLT2i discontinuation but occurred in only 23 patients (6.6% of the whole cohort). Other causes were intercurrent infections that probably led to SGLT2i suspension by clinicians as commonly done with other medications that increase the risk of AKI in infectious settings (e.g., ACE inhibitors, ARBs, and diuretics), even though we were not able to provide reliable data about resumption of treatment. Digestive
<table><caption>**Table 4.** Evolution of renal function, proteinuria and blood pressure over the first 6 months</caption><thead><tr><th>Whole cohort (N = 347)</th><th>n</th><th>At initiation (MO)</th><th>Month-3</th><th>P-value (MO-M3)</th><th>N</th><th>At initiation (MO)</th><th>Month-6</th><th>P-value (MO-M6)</th></tr></thead><tbody><tr><td>eGFR (ml/min per 1.73 m²)</td><td>265</td><td>43.8 [IQR: 37.0-53.9]</td><td>43.1 [IQR: 34.1-53.1]</td><td>&lt;0.0001</td><td>216</td><td>45.1 [IQR: 38.2-55.1]</td><td>43.5 [IQR: 35.9-53.6]</td><td>&lt;0.0001</td></tr><tr><td>Serum creatinine (µmol/l)</td><td>265</td><td>146 [IQR: 116-174]</td><td>152 [IQR: 119-186]</td><td>&lt;0.0001</td><td>216</td><td>140 [IQR: 112-172]</td><td>147 [IQR: 115-182]</td><td>&lt;0.0001</td></tr><tr><td>Proteinuria (mg/d)<sup>a</sup></td><td>168</td><td>748 [IQR: 312-1832]</td><td>637 [IQR: 276-1272]</td><td>0.0005</td><td>75</td><td>650 [IQR: 315-1448]</td><td>500 [IQR: 270-1094]</td><td>0.006</td></tr><tr><td>SBP (mm Hg)</td><td>223</td><td>143 [IQR: 132-155]</td><td>138 [IQR: 126-150]</td><td>&lt;0.0001</td><td>181</td><td>143 [IQR: 132-155]</td><td>140 [IQR: 129-152]</td><td>0.022</td></tr><tr><td>DBP (mm Hg)</td><td>219</td><td>81 [IQR: 73-99]</td><td>78 [IQR: 69-85]</td><td>&lt;0.0001</td><td>177</td><td>80 [IQR: 72-89]</td><td>78 [IQR: 70-84]</td><td>0.001</td></tr><tr><td>Diabetic patients (n = 226)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>eGFR (ml/min per 1.73 m²)</td><td>170</td><td>45.7 [IQR: 38.1-55.2]</td><td>44.7 [IQR: 34.6-54.0]</td><td>0.007</td><td>150</td><td>47.3 [IQR: 38.4-58.2]</td><td>46.4 [IQR: 38.0-55.5]</td><td>0.017</td></tr><tr><td>Serum creatinine (µmol/l)</td><td>170</td><td>141 [IQR: 112-169]</td><td>144 [IQR: 115-176]</td><td>0.004</td><td>150</td><td>137 [IQR: 108-167]</td><td>143 [IQR: 111-166]</td><td>0.020</td></tr><tr><td>Proteinuria (mg/d)<sup>a</sup></td><td>101</td><td>530 [IQR: 230-1231]</td><td>426 [IQR: 230-1003]</td><td>0.004</td><td>49</td><td>530 [IQR: 290-1210]</td><td>430 [IQR: 290-860]</td><td>0.136</td></tr><tr><td>SBP (mm Hg)</td><td>143</td><td>143 [IQR: 132-155]</td><td>138 [IQR: 127-150]</td><td>0.007</td><td>123</td><td>142 [IQR: 131-155]</td><td>140 [IQR: 128-152]</td><td>0.201</td></tr><tr><td>DBP (mm Hg)</td><td>139</td><td>80 [IQR: 71-87]</td><td>75 [IQR: 69-83]</td><td>0.002</td><td>119</td><td>79 [IQR: 70-88]</td><td>78 [IQR: 70-84]</td><td>0.023</td></tr><tr><td>Nondiabetic patients (n = 121)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>eGFR (ml/min per 1.73 m²)</td><td>95</td><td>42.3 [IQR: 35.8-51.5]</td><td>40.6 [IQR: 33.4-49.2]</td><td>0.0004</td><td>66</td><td>42.9 [IQR: 35.9-51.8]</td><td>39.0 [IQR: 33.1-46.7]</td><td>&lt;0.0001</td></tr><tr><td>Serum creatinine (µmol/l)</td><td>95</td><td>156 [IQR: 127-184]</td><td>162 [IQR: 132-205]</td><td>0.0005</td><td>66</td><td>156 [IQR: 122-179]</td><td>167 [IQR: 135-205]</td><td>&lt;0.0001</td></tr><tr><td>Proteinuria (mg/d)<sup>a</sup></td><td>67</td><td>1274 [IQR: 420-2487]</td><td>930 [IQR: 461-1784]</td><td>0.029</td><td>26</td><td>916 [IQR: 364-1865]</td><td>716 [IQR: 223-1333]</td><td>0.016</td></tr><tr><td>SBP (mm Hg)</td><td>80</td><td>145 [IQR: 134-158]</td><td>139 [IQR: 126-150]</td><td>0.0002</td><td>58</td><td>145 [IQR: 136-159]</td><td>142 [IQR: 131-151]</td><td>0.025</td></tr><tr><td>DBP (mm Hg)</td><td>80</td><td>84 [IQR: 78-91]</td><td>79 [IQR: 70-87]</td><td>0.0002</td><td>58</td><td>84 [IQR: 79-91]</td><td>79 [IQR: 70-87]</td><td>0.011</td></tr></tbody></table>

DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; IQR, interquartile range; SBP, systolic blood pressure.

symptoms responsible for SGLT2i discontinuation were diverse, with diarrhea identified as the most common side effect. It is interesting to compare our results with the Spanish cohort that enrolled 339 diabetic patients, with a lower incidence of discontinuation because of AKI.¹⁶ This difference is probably related to the lower graft function of our cohort (44 vs. 58.4 ml/min per 1.73 m²). Indeed, they reported that AKI was more frequent in patients with eGFR < 40 ml/min per 1.73 m², as we found that KTRs with eGFR < 45 ml/min per 1.73 m² had an increased risk of SGLT2i discontinuation for graft dysfunction. Whether the higher proportion of patients treated by ACE inhibitors or ARBs in our cohort could additionally contribute to increased incidence of AKI may be debated, because it has been demonstrated that SGLT2i protect patients from AKI in several meta-analysis.¹⁹⁻²¹ Interestingly, in DAPA-CKD, including nontransplanted patients treated with ACE inhibitors or ARBs, discontinuation rates were higher in patients with CKD stage 4 versus CKD stage 2 or 3; however, the rates were similar in dapagliflozin versus placebo in both CKD 4 and CKD 2 or 3 group. Finally, we consider that early introduction of SGLT2i should be encouraged; that is, for eGFR > 45 ml/min per 1.73 m². Finally, we observed that patients with the lowest BMI were more likely to discontinue treatment, which was not reported in previous studies. This finding may suggest greater fragility in these patients.

Second, we reported that UTI was the most frequent adverse event considered as related to SGLT2i. Incidence of UTI in diabetic KTRs treated by SGLT2i is known to be between 5.4% and 14%,¹⁵,¹⁶ whereas we identified that 7.9% of our diabetic KTRs developed at

least 1 UTI. Although we do not find a significantly lower incidence of UTI in nondiabetic KTRs (4.1%), the incidence of pyelonephritis (1.7%) was actually relatively close to incidence of severe UTI in non-transplanted patients that was between 1.5 and 1.7%.²,³,²² We did not report any genital infection in nondiabetic KTRs, and <1% in diabetic KTRs, like in the Korean and Spanish studies.¹⁵,¹⁶ To interpret our findings accurately, it is important to acknowledge a potential selection bias. Few SGLT2i initiations took place in the early posttransplantation period, and investigators had collectively agreed to avoid prescribing SGLT2i to patients with urologic catheters.

Our study was not designed to evaluate the risk of graft failure or cardiovascular mortality, and we did not include a control group for comparison. Nevertheless, we report an improvement in blood pressure and proteinuria over the first 6 months of treatment, which was consistent across diabetic and nondiabetic patients. These results should be considered as a preliminary promising signal that SGLT2i could have a cardiovascular protective effect in KTRs regardless of their diabetic status, given the associations between proteinuria and uncontrolled hypertension with increased graft loss and worst survival outcomes.⁹,¹⁰,²³ So far, 1 study showed an improved death-censored graft survival and patient survival in KTRs treated with SGLT2i, even though it was not confirmed after matching using a propensity score.¹⁵ A 5-year follow-up of our cohort will provide further insight into the efficacy of SGLT2i on cardiovascular and graft survival outcomes, as compared with matched patients in the ASTRE database. Although there is still no evidence

<footnote>aUrinary protein-to-creatinine ratio expressed as mg/g was used in absence of 24-hour urine collection.</footnote>
<figure><img src="image_6.png" /><figcaption>b</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>c</figcaption></figure>

<figure><img src="image_8.png" /></figure>

**Figure 3.** Evolution of proteinuria in proteinuric patients over 6 months follow-up. (a) In all proteinuric patients (at initiation: *n* = 99, at 3 months: *n* = 99, and at 6 months: *n* = 38); (b) in proteinuric diabetic patients (at initiation: *n* = 51, at 3 months: *n* = 51, and at 6 months: *n* = 22); (c) proteinuric nondiabetic patients (at initiation: *n* = 48, at 3 months: *n* = 48, and at 6 months: *n* = 16). SGLT2i, sodium glucose cotransporter 2 inhibitor.
<figure><img src="image_9.png" /><figcaption>**Figure 4.** Evolution of systolic and diastolic blood pressure over 6 months follow-up. Systolic blood pressure (left panel) and diastolic blood pressure (right panel) are presented in (a) the whole cohort (at initiation: *n* = 223, at 3 months: *n* = 223, and at 6 months: *n* = 149), (b) in patients with baseline BP > 140/90 mm Hg (at initiation: *n* = 142, at 3 months: *n* = 142, and at 6 months: *n* = 96), and (c) in patients with baseline BP < 140/90 mm Hg (at initiation: *n* = 81, at 3 months: *n* = 81, and at 6 months: *n* = 53). BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure; SGLT2i, sodium-glucose cotransporter-2 inhibitor.</figcaption></figure>

about ACE inhibitors' efficacy in graft and patient outcome in a large clinical trial of KTRs, our study highlights the potential of SGLT2i-based strategies for improving cardiovascular outcome, especially in recipients with the highest cardiovascular risk.

The first limitation of this study is the short-term follow-up that prevents us from drawing conclusions on long-term safety. However, treatment discontinuation occurred mainly in the first 6 months following initiation and was afterward mostly because of intercurrent infections unrelated to SGLT2i. The second limitation is the absence of independent committee adjudication. We therefore retrospectively interrogated investigators regarding all causes of discontinuations and infections. The extended follow-up of our ASTRE database with yearly visits will provide additional information regarding the resumption of SGLT2i and possibly recurrence of infections. The third limitation is the number of missing data, especially regarding proteinuria and blood pressure. Regarding blood

pressure, an analysis of antihypertensive medications, including possible dosage modifications during follow-up and home blood pressure monitoring should be more relevant.

In conclusion, this work supports the safety of prescribing SGLT2i to selected KTRs beyond the first transplantation year with characteristics similar to DAPA-CKD study, thus providing encouraging preliminary efficacy results on proteinuria and blood pressure.

## DISCLOSURE

All the authors declared no competing interests.

## ACKNOWLEDGMENTS

We thank all the clinical research associates who collect the data in the ASTRE database. We acknowledgment the following: Elodie Bec, Isabelle Danneville, Karine Deprez, Vanessa Goge, Carole Grand, Khier Laouamri, Jean Laporte, Mickael Martin, Annie Menguy, Fariza Mouazaoui,
Céline Nadalin, Eléonore Ourouda-Mbaya, Ludmilla Peltier, Xavier Picard, Séverine Ponsard, and Danielle Roy.

## Funding

AstraZeneca provided financial support for the ASTRE database. AstraZeneca did not participate in the collection, analysis, and interpretation of data. AstraZeneca did not influence the decision to submit the article for publication and was not involved in paper writing. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding organization.

## SUPPLEMENTARY MATERIAL

### Supplementary File (PDF)

**Figure S1.** Incidence of SGLT2 inhibitor discontinuation by initial body mass index.

**Figure S2.** SGLT2 inhibitor discontinuation according to initial estimated glomerular filtration rate.

**Figure S3.** Incidence of SGLT2 inhibitors discontinuation according to GFR estimated using race-free CKD-Epidemiology Collaboration formula.

**Table S1.** Comparison of baseline characteristics between diabetic and nondiabetic patients.

**Table S2.** Baseline characteristics of patients by centers.

**Table S3.** Evolution of GFR (ml/min/m2) estimated by 2 race-free equations over the first 6 months.

**Table S4.** Evolution of eGFR (ml/min/m2) in proteinuric and nonproteinuric patients.

## REFERENCES

1. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease. *N Engl J Med*. 2020;383:1436-1446. https://doi.org/10.1056/NEJMoa2024816

2. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in patients with chronic kidney disease. *N Engl J Med*. 2023;388:117-127. https://doi.org/10.1056/NEJMoa2204233

3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. *N Engl J Med*. 2019;380:347-357. https://doi.org/10.1056/NEJMoa1812389

4. Buse JB, Wexler DJ, Tsapas A, et al. 2019 Update to: management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). *Diabetes Care*. 2020;43:487-493. https://doi.org/10.2337/dci19-0066

5. Rossing P, Caramori ML, Chan JCN, et al. Executive summary of the KDIGO 2022 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease: an update based on rapidly emerging new evidence. *Kidney Int*. 2022;102:990-999. https://doi.org/10.1016/j.kint.2022.06.013

6. de Boer IH, Khunti K, Sadusky T, et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: improving Global Outcomes (KDIGO). *Kidney Int*. 2022;102:974-989. https://doi.org/10.1016/j.kint.2022.08.012

7. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: executive summary: A report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. *J Am Coll Cardiol*. 2022;79:1757-1780. https://doi.org/10.1016/j.jacc.2021.12.011

8. Marx N, Federici M, Schütt K, et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. *Eur Heart J*. 2023;44:4043-4140. https://doi.org/10.1093/eurheartj/ehad192

9. Weiner DE, Park M, Tighiouart H, et al. Albuminuria and allograft failure, cardiovascular disease events, and all-cause death in stable kidney transplant recipients: a cohort analysis of the FAVORIT trial. *Am J Kidney Dis*. 2019;73:51-61. https://doi.org/10.1053/j.ajkd.2018.05.015

10. Halimi JM, Matthias B, Al-Najjar A, et al. Respective predictive role of urinary albumin excretion and nonalbumin proteinuria on graft loss and death in renal transplant recipients. *Am J Transplant*. 2007;7:2775-2781. https://doi.org/10.1111/j.1600-6143.2007.02010.x

11. Sharif A, Hecking M, de Vries AP, et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions. *Am J Transplant*. 2014;14:1992-2000. https://doi.org/10.1111/ajt.12850

12. Stepanova M, Kumar A, Brandt P, et al. Impact of type 2 diabetes on the outcomes of solid organ transplantations in the U.S.: data from a national registry. *Diabetes Care*. 2023;46:2162-2170. https://doi.org/10.2337/dc23-1085

13. Lim WH, Lok CE, Kim SJ, et al. Impact of pretransplant and new-onset diabetes after transplantation on the risk of major adverse cardiovascular events in kidney transplant recipients: a population-based cohort study. *Transplantation*. 2021;105:2470-2481. https://doi.org/10.1097/TP.00000000000003639

14. Rangaswami J, Mathew RO, Parasuraman R, et al. Cardiovascular disease in the kidney transplant recipient: epidemiology, diagnosis and management strategies. *Nephrol Dial Transplant*. 2019;34:760-773. https://doi.org/10.1093/ndt/gfz053

15. Lim JH, Kwon S, Jeon Y, et al. The efficacy and safety of SGLT2 inhibitor in diabetic kidney transplant recipients. *Transplantation*. 2022;106:e404-e412. https://doi.org/10.1097/TP.00000000000004228

16. Sánchez Fructuoso AI, Bedia Raba A, Banegas Deras E, et al. Sodium-glucose cotransporter-2 inhibitor therapy in kidney transplant patients with type 2 or post-transplant diabetes: an observational multicentre study. *Clin Kidney J*. 2023;16:1022-1034. https://doi.org/10.1093/ckj/sfad007

17. Delanaye P, Masson I, Maillard N, Pottel H, Mariat C. The new 2021 CKD-EPI equation without race in a European cohort of renal transplanted patients. *Transplantation*. 2022;106:2443-2447. https://doi.org/10.1097/TP.00000000000004234

18. Raynaud M, Al-Awadhi S, Juric I, et al. Race-free estimated glomerular filtration rate equation in kidney transplant recipients: development and validation study. *BMJ*. 2023;381:e073654. https://doi.org/10.1136/bmj-2022-073654

19. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 American Diabetes Association (ADA) and Kidney Disease: improving Global Outcomes (KDIGO). *Kidney Int*. 2022;102:974-989. https://doi.org/10.1016/j.kint.2022.08.012
diabetes: a systematic review and meta-analysis. *Lancet Diabetes Endocrinol*. 2019;7:845-854. https://doi.org/10.1016/
S2213-8587(19)30256-6

20. Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis. *PLoS Med*. 2019;16:e1002983. https://doi.org/10.1371/journal.pmed.1002983

21. Donnan JR, Grandy CA, Chibrikov E, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a

systematic review and meta-analysis. *BMJ Open*. 2019;9: e022577. https://doi.org/10.1136/bmjopen-2018-022577

22. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. *N Engl J Med*. 2016;375:323-334. https://doi.org/10.1056/NEJMoa1515920

23. Opelz G, Döhler B, Collaborative Transplant Study. Collaborative transplant study. Improved long-term outcomes after renal transplantation associated with blood pressure control. *Am J Transplant*. 2005;5:2725-2731. https://doi.org/10.1111/j.1600-6143.2005.01093.x