Outcomes associated with Sodium-glucose cotransporter-2 inhibitors in kidney transplant recipients: A real-world analysis using a global federated database.

doi:10.21203/rs.3.rs-4844585/v1

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Outcomes associated with Sodium-glucose cotransporter-2 inhibitors in kidney transplant recipients: A real-world analysis using a global federated database.

https://doi.org/10.21203/rs.3.rs-4844585/v1

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Rationale & Objective: Several trials have shown the nephroprotective and cardiovascular benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) among patients with native kidney disease. However, little is known about the safety and efficacy of SGLT2i in kidney transplant. The study aimed to investigate the benefits of SGLT2i in kidney transplant recipients.

Methods: Retrospective cohort study utilising data from adult kidney transplant recipients (≥ 18 years) was obtained from TriNetX, a global federated health research network. Cohorts were grouped by receipt of SGLT2i and 1:1 propensity-score matched for demographic characteristics, baseline cardiovascular comorbidities, laboratory data and immunosuppression. Cox regression produced hazard ratios with 95% CI for the outcomes.

Outcomes: Primary outcome: incident 5-year death-censored graft failure, rejection, major adverse cardiac events and mortality. Secondary outcomes: known complications of SGLT2i.

Results: 4,872 patients (mean age 59.2 years SD 12.2; 63% male). Patients in the SGLT2i cohort had statistically significantly reduced death censored graft failure (HR 0.43, 95% CI 0.37-0.51, p <0.0001), rejection (HR 0.44, 95% CI 0.39-0.50, p <0.0001, major adverse cardiovascular events (HR 0.80, 95% CI 0.70, 0.92, p 0.001) and mortality (HR 0.63 95% CI 0.55-0.72, p <0.017). The cohort identified no significant side effects associated with SGLT2i use.

Conclusion: Kidney transplant recipients treated with SGLT2i demonstrated a significant reduction in clinically relevant outcomes. The data suggests that they may have a strong beneficial role in the kidney transplant population.

Health sciences/Nephrology

Health sciences/Nephrology/Kidney

transplantation

acute rejection

cardiovascular disease

congestive heart failure

In recent years, outcomes of large multicentre randomised control trials (RCT) and meta-analysis of > 90,000 patients have demonstrated benefit of sodium-glucose co-transporter-2 inhibitors (SGLT2i) in reducing albuminuria, slowing kidney function decline and improving survival, including reducing major adverse cardiovascular events (MACE), and hospitalisation for heart failure in chronic kidney disease (CKD) patients irrespective of a diabetes diagnosis.^1–3

These findings have led to a paradigm shift in managing CKD and its associated cardiovascular disease, with SGLT2i being recommended in international guidelines.⁴ In the UK, the National Institute of Health and Care Excellence (NICE) recommends the use of SGLT2i (Dapagliflozin and Empagliflozin) to manage CKD progression and complications^5,6; however, as acknowledged by the UK Kidney Association, there is an unmet need in the evidence to support initiating this treatment in kidney transplant recipients (KTRs).⁷

In KTRs, the most common cause of allograft decline is chronic allograft nephropathy (CAN) manifested by interstitial fibrosis, tubular atrophy, fibrotic intimal thickening of arteries, and glomerulosclerosis rather than immunologically mediated damage, which may be improved through the use of SGLT2i's.⁸

Cardiovascular disease (CVD) is a significant concern for KTRs. Despite the survival benefits of kidney transplantation, CVD remains the leading cause of premature allograft loss and death, in addition to significant morbidity related healthcare costs.^9,10 Superimposed cardio-metabolic derangements amplify pre-existing risk factors for CVD in the KTRs after transplantation, such as metabolic effects of immunosuppressive regimens, obesity, post-transplant diabetes, hypertension, dyslipidaemia, and allograft dysfunction.¹¹ Hence, KTRs may greatly benefit from CVD risk modification with SGLT2i's. However, there are potential concerns of adverse pharmacological interactions including vulnerability to infections, especially urinary tract infections (UTI).

Therefore, while SGLT2is could be a promising addition to the therapeutic arsenal for KTRs, further research is needed to understand their impact in this specific patient population fully. Additional research is required to fully understand their long-term effects and safety profile in a KTR cohort. The current study, using a large prospective data set, aimed to investigate the benefits of SGLT2i in KTRs, including MACE and all-cause mortality, alongside known complications of SGLT2i.

Ethics statement

This retrospective cohort study was based on de-identified, pseudo-anonymized, or limited data from TriNetX, a global federated health research network with participating healthcare organisations (HCOs) granting the use of this data for research purposes.¹² Ethical approval for HCOs inclusion occurs via an institutional review board or independent ethics committee.¹² TriNetX includes aggregated data that is analysed and reported and given no patient level data is received, ethical approval was not require for this study

Data source, study protocol and patient selection

The TriNetX data utilised represents the Global Collaborative Network of 127 HCOs of > 110 million patients, primarily in North America (52%) and Western Europe (48%). The HCOs encompass hospitals, primary care facilities and specialist clinics with data from both insured and uninsured patients. The real-world data captured within TriNetX allows global data aggregation which has allowed the platform to develop beyond its initial aim to optimise clinical trial design and used in numerous peer-reviewed publications.^12,13

The dataset included in this study was accessed on 22nd March 2024. The datum utilised in this study, predominantly derived from electronic health records (EHR) includes demographics, diagnosis (standardised to the International Statistical Classification of Diseases and Related Health Problems 10th Revision, Clinical Modification [ICD-10CM],¹⁴ or Systematized Nomenclature of Medicine Clinical Terms [SNOMED] codes,¹⁵ laboratory results (Logical Observation Identifiers Names and Codes) [LOINC],¹⁶ and medication (as per the Anatomical Therapeutic Chemical) [ATC] classification system.¹⁷ A full list of ICD-10CM, SNOMED and LOINC codes used is shown in Supplementary Table S1.

Follow-up and clinical outcome

The primary outcome was incident death-censored graft failure, rejection rates, major adverse cardiac events (MACE) or all-cause mortality (death) by ICD-10CM (Supplementary Table S1) between 1 day after the index event (receipt of kidney transplant) and five years follow-up. MACE was defined as a composite of ischaemic heart disease (IHD), angina, acute myocardial infarction (AMI), heart failure, atrial fibrillation or flutter, ischaemic stroke, and all-cause mortality (death). Patients who experienced the primary outcome before the index outcome of kidney transplantation were excluded.

The secondary outcomes were collected on the recognised adverse events associated with SGLT2i use¹⁸: genitourinary infections, Fournier's gangrene, diabetic ketoacidosis (DKA), and lower limb amputations as identified by the ICD-10CM and (LOINC). (Supplementary Table S1)

Co-variates

To address any disparity within the cohorts we included demographic data on age, sex and ethnicity, smoking status, cardiovascular comorbidity alongside other comorbidity data collated as components of the Charlson Comorbidity Index (CCI).¹⁹ Relevant physical examination results that could be associated with the specified outcomes were retrieved: including smoking status and Body Mass Index (kg/m²) and Blood pressure readings (mm Hg).

Laboratory results were measured as a categorical variable for baseline graft function of estimated glomerular filtration rate (ml/min/1.73m² -MDRD formula) and proteinuria (mg/g). Total cholesterol levels (mmol/L), Haemoglobin A1c (%) were also extracted as cardiovascular risk factors.

Kidney transplant immunosuppression data on induction immunosuppression (alemtuzumab, basiliximab and anti-thymocyte globulin) and maintenance immunosuppression (tacrolimus, ciclosporin, mycophenolate mofetil, mycophenolic acid, azathioprine, sirolimus, everolimus, belatacept) were extracted alongside the trough tacrolimus level (ng/mL).

Study cohort

All patients who were aged > 18 years, kidney transplant recipients (KTRs) defined as a KTR by ICD-10CM or SNOMED codes and prescribed any sodium-glucose co-transporter-2 inhibitors (SGLT2i) were included. SLGT2i could be coded either as SGLT2i or as generic drug names (Empagliflozin, Dapagliflozin, Canagliflozin and Ertugliflozin).

For all participates, the index date was determined as prescription of an SGLT2i that occurred post-kidney transplant (day 1) with 5 year follow-up.. The SGLT2i naïve cohort was defined as a KTR who had not been prescribed a SGLT2i 5 years before or after kidney transplant.

Patients with dual organ transplants were excluded from the analysis.

Statistical analysis

All statistical analyses were performed on the TriNetX online platform. As a continuous variable, age was expressed as mean and standard deviation (SD) and tested for differences with an independent-sample t-test. The socio-demographic characteristics, comorbidity, transplant immunosuppression (induction and maintenance) and laboratory results were expressed as absolute frequencies and percentages and tested for differences with the chi-squared test.

Before analysis, cohorts were 1:1 propensity score matched (PSM)²⁰ for co-variates that could potentially confound the primary outcomes; these included:

Socio-demographic characteristics (age at index, gender and race),
Baseline CVD comorbidities (cardiovascular disease, diabetes mellitus, smoking status and Body Mass Index (BMI-kg/m2)
Laboratory data (Estimated Glomerular Filtration Rate (eGFR-mL/min/1.73m²) and proteinuria (mg/g))
Induction immunosuppression (basiliximab, alemtuzumab, anti-thymocyte globulin, anti-human T-lymphocyte globulin, rituximab) and maintenance immunosuppression (tacrolimus, ciclosporin, mycophenolate mofetil, mycophenolic acid, azathioprine, sirolimus, everolimus, belatacept)

PSM was performed using the online TriNetX platform. The platform uses 'greedy nearest-neighbour matching' with a caliper of 0.1 pooled standard deviations and a difference between propensity scores ≤ 0.1. Covariate balance between groups was assessed using standardised mean differences (SMDs) and included in the supplementary results; SMD between cohorts < 0.1 is considered well-matched.

Following PSM, Cox proportional hazard models were used to assess the association between SGLT2i and the primary and secondary outcomes during 5-year follow-up.

Results are reported as hazard ratio (HR) with 95% confidence intervals and Kaplan-Meier survival curves with log-rank tests. No imputations were made for missing data due to the restriction of the TriNetX analytical platform. Censoring was applied, and a patient was removed (censored) from the analysis after the last event in their electronic record. The TriNetX 'Analytics' functionality on which used the R Survival package v3.2-3 for its analysis. A p-value < 0.05 was accepted as the level of statistical significance.

Identifying cohorts

The Research Network had data available for KTRs from 76 of the 115 HCOs at the time of the search. A total of 212,603 patients were initially identified. (Supplementary Figure S1) Before propensity score matching (PSM), patients in the SGLT2i group were older, with a greater prevalence of type 2 diabetes mellitus, lower estimated glomerular filtration rates (eGFR), and more significant proteinuria. Following PSM, the cohort characteristics were well matched (Supplementary Figure S2 and Table S2).

Of those identified to receive SGLT2i in TriNetX, SGLT2i prescriptions, 2775 (56.95%) were prescribed Empagliflozin, 1711(35.12%) Dapagliflozin, 364(7.47%) Canagliflozin and 22(0.46%) Ertugliflozin, respectively.

Cohort Characteristics-Sociodemographic

Following PSM, 9,744 patients were included in the analysis (mean patient age 59.3 SD 12.2; 62.5% male). Following PSM, both cohorts (SGLT2i and SGLT2i naive) were matched for age, gender, race, and ethnicity, with no statistically significant differences between groups. (Table 1) A more extensive distribution of comorbidities in the cohorts, as included in the Charlson comorbidity index, is reported in Supplementary Table S3.

Table 1

Distribution of sociodemographic, co-morbidity profile, medications and laboratory data of SGLT2i naïve and SGLT2i cohorts post propensity score matching
	SGLT2i naïve N (%)	SGLT2i N (%)	P-value
Sample size	4,872	4,872	-
Sociodemographics
Age (Mean ± SD)	59.7 ± 11.9	59.3 ± 12.2	0.088
Male	3,072 (63.1)	3,047 (62.5)	0.600
Race
American Indian or Alaska Native	39 (0.8)	34 (0.7)	0.557
Native Hawaiian or Other Pacific Islander	15 (0.3)	20 (0.4)	0.397
Not Hispanic or Latino	3,204 (65.8)	3,236 (66.4)	0.493
Hispanic or Latino	576 (11.8)	570 (11.7)	0.850
Unknown Race (not matched)	836 (17.2)	894 (18.3)	0.124
Other Race (not matched)	256 (5.3)	196 (4.0)	0.004
Ethnicity
White	2,248 (46.1)	2,192 (45.0)	0.255
Black or African American	1,140 (23.4)	1,190 (24.4)	0.235
Asian	338 (6.9)	346 (7.1)	0.751
Unknown Ethnicity (not matched)	1,092 (22.4)	1,066 (21.9)	0.526
Co-morbidities
Cardiac co-morbidities and diabetes
Acute myocardial infarction	482 (9.9)	475 (9.7)	0.812
Subsequent STT elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction	15 (0.3)	10 (0.2)	0.317
Old myocardial infarction	523 (10.7)	528 (10.8)	0.870
Ischemic cardiomyopathy	282 (5.8)	281 (5.8)	0.965
Hypertensive heart disease	786 (16.1)	767 (15.7)	0.599
Hypertensive heart and chronic kidney disease	973 (20.0)	975 (20.0)	0.960
Cardiomyopathy	671 (13.8)	627 (12.9)	0.190
Cardiomyopathy in diseases classified elsewhere	79 (1.6)	74 (1.5)	0.684
Heart failure	1,447 (29.7)	1,389 (28.5)	0.196
Peripheral vascular disease	1339 (27.5)	1467 (30.1)	0.004
Diabetes
Type 1 diabetes mellitus^†	538 (11.0)	542 (11.1)	0.897
Type 2 Diabetes mellitus^†	3,790 (77.8)	3,730 (76.6)	0.148
Other specified diabetes mellitus^†	770 (15.8)	811 (16.6)	0.260
Diabetes mellitus due to underlying condition^†	612 (12.6)	623 (12.8)	0.738
Drug or chemical-induced diabetes mellitus^†	505 (10.4)	527 (10.8)	0.469
Smoking	1,059 (21.7)	1,073 (22.0)	0.732
Immunosuppression*
Induction Immunosuppression
Basiliximab	393 (8.1)	400 (8.2)	0.795
Alemtuzumab	42 (0.9)	43 (0.9)	0.913
Anti-thymocyte globulin	449 (9.2)	489 (10.0)	0.169
Anti-human T-lymphocyte globulin	317 (6.5)	366 (7.5)	0.052
Rituximab	90 (1.8)	96 (2.0)	0.657
Maintenance immunosuppression
Tacrolimus	3,545 (72.8)	3,592 (73.7)	0.282
Ciclosporin	403 (8.3)	354 (7.3)	0.064
Mycophenolate mofetil	2,577 (52.9)	2,595 (53.3)	0.715
Mycophenolic acid	1,710 (35.1)	1,763 (36.2)	0.262
Azathioprine	234 (4.8)	222 (4.6)	0.565
Sirolimus	299 (6.1)	270 (5.5)	0.210
Everolimus	0	0	0
Belatacept	68 (1.4)	73 (1.5)	0.671
LABORATORY DATA
CKD STAGE	SGLT2i naïve N (%)	SGLT2i N (%)	P-value
1^‡	1,347 (27.6)	1,276 (26.2)	0.105
2^‡	2,907 (59.7)	2,819 (57.9)	0.070
3^‡	3,543 (72.7)	3,484 (71.5)	0.183
4^‡	2,180 (44.7)	2,155 (44.2)	0.610
Proteinuria (Serum albumin creatinine ratio)
0–30 mg/g	331 (6.8)	315 (6.5)	0.515
30–300 mg/g	397 (8.1)	403 (8.3)	0.825
> 300mg/g	319 (6.5)	284 (5.8)	0.141
Body Mass Index (BMI) kg/m2 (Mean ± SD)	29.2 ± 5.9	30.2 ± 6.2	< 0.001
Tacrolimus level ng/mL	7.0 ± 3.8	6.6 ± 3.2	< 0.001
Other cardiovascular risk factors
Systolic Blood Pressure mm[Hg]	133.6 ± 22.2	133.8 ± 20.6	0.679
Diastolic Blood Pressure mm[Hg]	73.4 ± 12.7	75.0 ± 12.3	< 0.001
Cholesterol mg/dL	157.1 ± 52.6	159.0 ± 47.2	0.115
Haemoglobin A1c (%)	6.5 ± 1.7	7.3 ± 1.8	< 0.001
^† The reported numbers exceed the cohort size due to patients being coded using multiple interchangeable codes or duplication of coding within the database. The reported immunosuppression data is low reflecting the low reporting of this parameter within TirnetX database. ^‡ The reported numbers exceed the cohort size due to multiple eGFR values across the patient follow-up used for matching.*

Cohort Characteristics-Comorbidity and Medications

Following PSM, both cohorts were well matched for cardiovascular (CV) risk factors and immunosuppression prescription, with no statistically significant differences between groups. Heart failure was the commonest cardiac comorbidity, with 29.7% in the SGLT2i naïve and 28.5% in the SGLT2i cohort. Type 2 diabetes mellitus represented 77.8% in the SGLT2i naïve cohort and 76.6% in the SGLT2i cohort respectively. Both cohorts demonstrated that tacrolimus was the commonest maintenance immunosuppression at 66% across both cohorts. (Table 1)

Cohort Characteristics-Laboratory Data

Following PSM, both cohorts achieved good matching for kidney function and proteinuria. Peripheral vascular disease (P = 0.004), body mass index (BMI) (P = < 0.001) diastolic blood pressure (P = < 0.001), tacrolimus levels (P = < 0.001) and Haemoglobin A1c (P = < 0.001) remained significantly different between cohorts post PSM, although these results were not clinically meaningful. (Table 1)

Primary outcome

The results of Cox proportional hazard model analyses for the primary outcomes are summarised in Table 2. Kaplan - Meier survival analysis (KM) was produced for the primary outcomes (Fig. 1). This analysis highlights an increased mortality risk for SGLT2i naïve KTRs.

Table 2

Cox-regression model of Unadjusted 5-year primary outcomes for SGLT2i and SGLT2i naïve cohorts
Outcome	Cohorts	Number with outcome	HR.	95 CI	P-value
Death censored graft failure	SGLT2i naïve	742	-	-	-
Death censored graft failure	SGLT2i	192	0.43	(0.37, 0.51)	< 0.0001
Kidney Transplant Rejection	SGLT2i naïve	1,041	-	-	-
Kidney Transplant Rejection	SGLT2i	294	0.44	(0.39, 0.50)	< 0.0001
Major Adverse Cardiac Events	SGLT2i naïve	704	-	-	-
Major Adverse Cardiac Events	SGLT2i	330	0.80	(0.70, 0.92)	0.001
All-Cause Mortality	SGLT2i naïve	974	-	-	-
All-Cause Mortality	SGLT2i	343	0.63	(0.55, 0.71)	0.017

Death censored graft failure

Five-year follow-up data from the index event was reported for 7,662 (79%) patients. Of those, 934 developed death-censored graft failure and 192 (21%) of these were prescribed SGLT2i. This resulted in a HR of 0.43 (95% CI 0.37, 0.51, p < 0.0001).

Kidney rejection rates

A total of 5,162 (53%) patients had 5-year follow-up data available from the time of the index event. Of those, 1335 developed kidney rejection, and 294 (22%) of these patients were prescribed SGLT2i, with HR of 0.44 (95% CI 0.39, 0.50, p < 0.0001).

Major Adverse Cardiac Events (MACE)

There were 4,036 (41%) patients who had 5-year follow-up data available from the time of the index event. Of those, 1034 incurred MACE and 330 (32%) of these patients were prescribed SGLT2i, with HR of 0.80 (95% CI 0.70, 0.92, p 0.001).

All-cause mortality

A total of 9,627 (99%) patients had 5-year follow-up data available from the time of the index event. Of those, 1,317 died, and 343 (26%) of these patients were prescribed SGLT2i, with HR of 0.63 (95% CI 0.55, 0.72, p < 0.017).

Secondary Outcome - Complications

When considering the secondary outcome, a prescription of SGLT2i was associated with a statistically significant decreased risk of genitourinary infection (HR 0.58; 95% CI 0.50–0.67; P < 0.0001) and diabetic ketoacidosis (HR 0.82; 95% CI 0.72–0.94; P = < 0.0001). There was no statistically significant risk across the other analysed complications: Fournier's gangrene (HR 1.23; 95% CI 0.54–2.79; P 0.464), lower limb amputations (HR 0.78; 95% CI 0.58–1.05; P 0.054). (Supplementary Fig. 3). Supplementary Table S4 summarises the secondary outcomes using Cox proportional hazard model analysis results.

In this analysis, we report, for the first time, data related to the efficacy and safety of SGLT2i in a large cohort of KTRs from a large global federated healthcare network. Patients prescribed SGLT2i had statistically significantly improved five-year kidney outcomes and reduced MACE compared to a matched cohort not prescribed SGLT2i. There was also no evidence to suggest significant drug related side effects associated with SGLT2i use. No large, published studies have reported long-term outcomes on chronic allograft function, cardiovascular morbidity and mortality and graft and patient survival to compare this study's outcomes, making the study's findings novel.

CKD and proteinuria are independent predictors of mortality within the general population.²¹ Three landmark trials have evidenced the significant benefit for long-term cardiovascular and renal outcomes in initiating SGLT2i for CKD cohorts.^1,2,22 Renal outcome-specific analysis for the DAPA-CKD study² has shown the effectiveness of Dapagliflozin in reducing proteinuria and attenuation of eGFR decline.²³The outcomes of our study are comparable to the major trials and meta-analysis of SGLT2i in CKD cohorts despite the measured outcomes not being completely identical.^1–3

To date, there is limited published data to evaluate the benefit of SGLT2i in KTRs, especially regarding improvement in graft specific outcomes.²⁴ A retrospective clinical study by Demir. et al.²⁵ comparing diabetic KTRs (Post-transplant diabetes mellitus (PTDM) PTDM or pre-existing diabetes)) who were prescribed SGLT2i (n = 36) or SGLT2i naïve (n = 21) demonstrated higher acute rejection rates in the SGLT2i naïve cohort (11.1% vs 33.3%, p = 0.04) over 12month follow- up. Similarly, our study displayed increased acute rejection rates in SGLT2i naïve cohort over five-year follow-up ( 5.6% vs 20.17% p < 0.0001).

CVD remains the leading cause of death in KTRs.¹⁰ It has been established that proteinuria post-transplant is associated with MACE.^26,27 Retrospective analysis from Mathur. et al. ²⁸ on United States transplant data showed 30% of hospitalisation post-transplant was due to CVD. It must be acknowledged that KTRs do have significant 'traditional' risk factors for CVD, such as hypertension and dyslipidaemia and therefore also stand to benefit from the cardioprotective effects of SGLT2i.²⁹ Furthermore, immunosuppressive medication such as glucocorticoids and calcineurin inhibitors (CNI) also exacerbate risk of CVD.^30,31

This study has reported graft-specific outcomes and MACE events, which are important for this cohort of patients. We hypothesise the benefits of SGLT2i to KTRs observed in this study could be explained based on the following mechanisms. The well acknowledged renoprotective mechanisms of SGLT2i are through inhibiting sodium reabsorption and decreasing intraglomerular pressure through tubuloglomerular feedback.^32–34 However this retrospective study is not designed to formally test this hypothesis. Similar to the non-transplant population KTRs show a drop in eGFR following initiation of SGLT2i, which may highlight that SGLT2i are more effective than renin–angiotensin–aldosterone system blockade in inducing a haemodynamic response, given that a renal transplant is considered denervated.^35,36 These postulated pharmacodynamics may explain the observed benefit of 43% reduction in death-censored graft failure (HR 0.43, 95% CI 0.37, 0.51) and 20% (HR 0.80, 95% CI 0.70, 0.92) reduction in MACE compared to the SGLT2i naïve cohort.

Interstitial fibrosis is a cardinal feature in chronic renal allograft injury, with research identifying inflammatory macrophages and associated profibrotic cytokines such as interleukin-6 (IL-6) and Tumour necrosis factor (TNF) leading to deterioration in graft function.^37,38 An in-vitro study of canagliflozin effect on human proximal cells showed that SGLT2i reverse molecular inflammatory processes within extracellular matrix that leads to fibrosis.³⁹ A further in-vitro study has shown luseogliflozin induced neoangiogenesis via increasing vascular endothelial growth factor-A (VEGF-A) and hence halting pathways leading to interstitial fibrosis, although this was performed in a mouse model and translation of the findings to human pathology is uncertain.⁴⁰ In addition, a systematic review and meta-analysis by Theofilis. et al. ⁴¹ on mouse models exposed to SGLT2i has demonstrated the pleiotropic effect of the drug in reducing levels of inflammatory markers such as (IL-6) and TNFα. These mechanisms of SGLT2i not only would be protective in CAN and death-censored graft failure but potentially confer protection against rejection. Whilst our study is not designed to elucidate a mechanism of action of SGLT2i in KTR, it is hypothesised that these may explain, in part, the 44% (HR 0.44, 95% CI 0.39, 0.50) lower observed rejection rate in the SGLT2i cohort observed in our large retrospective study cohort of 4704 SGLT2i treated patients.

PTDM is a relatively common phenomenon and can also be attributed to a proinflammatory state that triggers renal fibrosis.⁴² PTDM has its unique pathophysiology and is associated with an 2–3 fold increase in risk of CVD, death-censored graft failure and mortality.^43,44 In our study, a significant number of participants were coded to have diabetes and, therefore, are at increased risk of MACE.⁴⁵ A RCT by Halden. et al.⁴⁶ investigated empagliflozin versus placebo for 49 KTRs with PTDM. The primary outcome was glycaemic control; there was 0.2% (p 0.025) decrease in glycated haemoglobin, which correlates with our awareness of a loss of SGLT2i-induced glucosuria at lower levels of kidney function. Importantly, as reported in our study data, there was no significant increase in UTI and no episodes of rejection in this study. Twenty-seven percent of participants reported adverse events, seven patients in the empagliflozin group and six in the placebo group, which included three episodes of UTI in both groups (P = 0.68).⁴⁶

An observational, multicentre study by Sánchez Fructuoso. et al.⁴⁷ from Spain, including 339 patients with pre-existing Type 2 diabetes or PTDM. Primary outcome was adverse effects within six months of commencing SGLT2i treatment. Fourteen percent of adverse events were due to UTI. Of those patients who had to stop taking SGLT2i, 3% definitively was due to UTI. A systematic review of 123 KTRs aimed to review the efficacy and safety of SGLT2i for diabetes management. The infection rates were low; 14 patients had UTI, and 1 had genital mycosis.⁴⁸ Data from major trials of SGLT2i alongside real world data have not showed an increased risk of UTI including in comparison to other antidiabetic medication.⁴⁹ In our study, with a significantly larger dataset, 3.5% of patients on SGLT2i developed genitourinary infections as a composite outcome compared with 10.6% of patients in the SGLT2i-naïve group.

A single-centre RCT in Norway (NCT05788276)⁵⁰ is evaluating the outcomes in Dapagliflozin prescription in KTR six weeks post transplantation with the primary outcome measure being effect on eGFR slope, and renal graft fibrosis as a secondary outcome. Furthermore, a multicentre RCT, The RENAL LIFECYCLE trial (NCT05374291)⁵¹ has commenced recruitment intending to evaluate Dapagliflozin 10 mg versus placebo in previously excluded cohorts such as KTRs and dialysis patients. The RCT aims to assess a combined endpoint of all-cause mortality, kidney failure, and hospitalisation for heart failure in the overall study population but not rejection rates nor all the components of MACE included in this study, making this study novel with x3 larger KTR population but also for the outcomes assessed.

Strengths and limitations

This study reports a large retrospective cohort of the prescription of SGLT2i in KTRs. The study is based on a large multi-million patient database from participating healthcare organisations. As such, it makes this study generalisable and reflective of clinical practice.

As acknowledged by other peer -reviewed publications which have successfully demonstrated cardio-renal outcomes utilising TriNetX.^52,53 Dependence on disease classification codes is a limitation that cannot be overcome. This was most noticeable in our study when we extracted the breakdown of comorbidities in our cohorts where evident duplication or interchangeable codes was utilised. The database also does not have the functionality to adjust for transplant type (donor after circulatory death, donation after brain death or living donor)within the included ICD-10 coding. This can limit our ability to analyse comprehensively and match the patient cohorts included in the study.

While real-world data reflects current clinical practice, the retrospective study means the cohorts are not randomised or controlled. Despite applying quasi-experimental approach with PSM replicates a randomised control trial within observational data, somewhat mitigating the risk.⁵⁴ The data are derived from electronic health records for administrative purposes; therefore, there is the potential for data errors or missing data. Patients and data may also be lost to follow-up, which could potentially skew covariate distribution and outcomes. Furthermore, the database doesn't have the functionality for us to ascertain the main indication for SGLT2i prescription, including the duration of the SGLT2i prescription; however, based on the breakdown of comorbidity we can infer that heart failure Type 2 diabetes (including possible PTDM) could have been the indications.

This novel study has shown that KTRs treated with SGLT2i have significantly reduced death-censored graft failure, rejection, major adverse cardiovascular events, and all-cause mortality. These findings suggest that SGLT2i could offer substantial benefits in the post-transplant setting. These findings underscore the need for RCTs to evaluate long-term kidney and cardiovascular outcomes with SGLT2i therapy in KTRs. RCTs would provide more definitive evidence about the safety and efficacy of SGLT2i in this unique population.

Disclosures

No funding was received to assist with the preparation of this manuscript.

PA: Employee of TriNetX, LLC

CW: Educational honorarium Astrazeneca, Boehringer, Lilly, NaPP, Pfizer, pharmacomos, vifor Fresenius and research grant from Vifor Fresenius

GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally.GYHL is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871.

LO: Consultancy fees, educational sponsorship and honorarium received from Boehringer Ingelheim, Novartis, Sandoz, Roche. No fees are personally received.

GM: Sponsorship from Roche Diagnostics and Abbott Point of Care. No fees are personally received.

AR: Received materials only grant form Roche Diagnostics for the Sarscov2 immunity Evaluation post-vaccination iN patIentS On Renal Replacement Therapy-SENIOR Study

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Yes there is potential Competing Interest. PA: Employee of TriNetX, LLC

CW: Educational honorarium Astrazeneca, Boehringer, Lilly, NaPP, Pfizer, pharmacomos, vifor Fresenius and research grant from Vifor Fresenius

GYHL: Consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. No fees are received personally. GYHL is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 899871.

LO: Consultancy fees, educational sponsorship and honorarium received from Boehringer Ingelheim, Novartis, Sandoz, Roche. No fees are personally received.

GM: Sponsorship from Roche Diagnostics and Abbott Point of Care. No fees are personally received. AR: Received materials only grant form Roche Diagnostics for the Sarscov2 immunity Evaluation post-vaccination iN patIentS On Renal Replacement Therapy-SENIOR Study

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Outcomes associated with Sodium-glucose cotransporter-2 inhibitors in kidney transplant recipients: A real-world analysis using a global federated database.

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Abstract

Figures

INTRODUCTION

METHODS

Ethics statement

Data source, study protocol and patient selection

Follow-up and clinical outcome

Co-variates

Study cohort

Statistical analysis

RESULTS

Identifying cohorts

Cohort Characteristics-Sociodemographic

Cohort Characteristics-Comorbidity and Medications

Cohort Characteristics-Laboratory Data

Primary outcome

Death censored graft failure

Kidney rejection rates

Major Adverse Cardiac Events (MACE)

All-cause mortality

Secondary Outcome - Complications

DISCUSSION

Strengths and limitations

CONCLUSION

Declarations

References

Additional Declarations

Supplementary Files

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