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Review

Update on Sodium Glucose Cotransporter Type 2 Inhibitors Use in Kidney Transplant Patients

by
Maurizio Salvadori
1,*,
Alberto Rosati
2 and
Giuseppina Rosso
2
1
Department of Renal Transplantation, Careggi University Hospital, Viale Pieraccini 18, 50139 Florence, Italy
2
Division of Nephrology, San Giovanni di Dio Hospital, 50143 Florence, Italy
*
Author to whom correspondence should be addressed.
Transplantology 2024, 5(3), 224-233; https://doi.org/10.3390/transplantology5030022
Submission received: 25 May 2024 / Revised: 8 August 2024 / Accepted: 5 September 2024 / Published: 18 September 2024
(This article belongs to the Collection Progress and Recent Advances in Solid Organ Transplantation)
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Abstract

:
Sodium glucose cotransporter type 2 inhibitors are a new class of drugs that act on the cardiovascular system, kidneys and metabolism in a multiple ways. Indeed, even though their principal action involves the transport of sodium and glucose in the convoluted distal tubule, they have multiple actions, such as antifibrotic and endothelial protective effects. Their principal mechanism consists of the loss of sodium and glucose. Therefore, they affect blood pressure and glucose metabolism. Their first use was in the diabetic general population; later, some studies documented their activity in the nondiabetic general population and in heart failure in chronic kidney disease patients. Only in recent years have several small studies documented the efficacy of these drugs in diabetic and nondiabetic kidney transplant patients; relatively large studies are rare, very recent, and open new routes for the development of these drugs.

1. Introduction

Since 2015, sequential randomized controlled trials (RCTs) have documented the efficacy of sodium glucose cotransporter 2 (SGLT2) inhibitors in improving both kidney and cardiovascular outcomes. This phenomenon was first reported in the general population, and was later reported in patients with diabetes [1]. By 2020, four compounds (empagliflozin, canagliflozin, dapagliflozin and ertugliflozin) had been studied in 47,000 patients with diabetes. Owing to their action, these compounds were subsequently studied in patients with chronic kidney disease with or without diabetes. More recently, SGLT2 inhibitors have been used in kidney transplant patients. Several studies have documented the heart- and reno-protective effects of empagliflozin [2], canagliflozin [3] and dapagliflozin [4].
The aim of this study was to examine a new class of agents (SGLT2i) in kidney transplant patients, comparing their known effects in patients with longer-term chronic nephropathies associated or not with diabetes mellitus.
A literature search was conducted on PubMed to identify the main studies conducted on the use of SGLT2i in patients with kidney disease and in patients with kidney transplant. Particular relevance was given to recent studies conducted by 2023. In addition, a search was conducted for RCTs that are ongoing to date.

2. Mechanism of Action

SGLT2 inhibitors’ mechanism of action is complex and involves effects on the heart, metabolism (Figure 1A) and kidneys (Figure 1B). Cardioprotective effects include direct cardiovascular effects that manifest through improvements in cardiac parameters, decreases in heart failure and the promotion of cardiac remodeling. In addition, SGLT2 inhibitors affect cardiac fibrosis by modulating macrophage phagocytosis and downregulating reactive oxygen and nitrogen-specific pathways [5]. Indirect cardiovascular effects are exerted through the renal system. Additionally, heart effects are induced by the improvement of endothelial dysfunction and its effect on the sympathetic nervous system, which leads to vasodilation and reductions in heart rate, preload and blood pressure.
The metabolic effect is induced by increases glucagon, non-esterified fatty acids (NEFAs), ketone utilization, lipolysis and gluconeogenesis, and a decrease in insulin. All these factors lead to decreases in body weight and LDL, and an increase in HDL.
In addition, the renal effects of SGLT2 inhibitors are direct and indirect. Reductions in proinflammatory and profibrotic molecules, a decrease in glomerular hyperfiltration with dilation of afferent arterioles, and an increase in renal blood perfusion mediate the direct effect. By binding to the Na+-H+ exchanger 3 enzyme, there is a reduction in Na+ reabsorption. Finally, there are reductions in glomerular mesangial expansion, macrophage infiltration and interstitial fibrosis [6]. All these factors lead to glycosuria, natriuresis and reductions in proteinuria and kidney injury molecules.
The indirect effect is induced by a reduction in insulin secretion, increases in glucagon secretion and erythropoietin, and increases in hematocrit and reticulocyte counts. Additionally, indirect renal effects have beneficial effects on the heart.
Factors such as glycosuria, natriuresis and tubule-glomerular feedback induce reductions in body weight and blood pressure and an improvement in HbA1c [7,8]. Ketone metabolism induced by glycosuria improves heart failure (HF) [9]. Additionally, SGLT2 inhibitors produce cardiovascular benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry. This occurs through the activation of the sirtuin 1/AMP activated protein kinase (SIRT1/AMPK) pathway, which has antioxidant and anti-inflammatory effects, increased autophagic flux and the activation of hypoxia-inducible factor (HIF-2α). The latter stimulates erythrocytosis. [10,11,12,13,14]. In addition, SGLT2 inhibitors improve endoplasmic reticulum stress [15,16]. Finally, canagliflozin reduces inflammation and fibrosis biomarkers, as documented in diabetic kidney disease [17].
All SGLT2 inhibitors are metabolized in less than 24 h by O-glucuronidation. In particular, they are metabolized only in part by cytochromes. SGLT2 inhibitors slightly inhibit CYP3A4 and ABCB1 [18]. A 23% increase in the concentration of cyclosporine in the blood has been reported for canagliflozin [19].
Owing to their complex mechanism of action, SGLT2 inhibitors have been used principally in patients affected by type 2 diabetes, often in association with other antidiabetic drugs. In the general population, their efficacy has been documented in patients affected by heart failure and metabolic diseases.
More recently, considering that type 2 diabetes, heart disease and metabolic diseases are often related to chronic kidney diseases and kidney transplantation and are associated with poor outcomes, several small and large studies have investigated the effects of SGLT2 inhibitors on kidney disease and kidney transplantation.
Notably, several adverse events have been reported with the use of SGLT2 inhibitors.
SGLT2i inhibit the cotransport of sodium and glucose in the proximal part of convoluted tubules, where 90% of glucose is reabsorbed [20,21]. As collateral effects, SGLT2 inhibitors may cause urinary and genital infections because of osmotic diuresis. In older people, an additional collateral effect is hypotension due to a loss in volume.
Other less frequent adverse events are euglycemic diabetic acidosis, distal limb amputation and acute kidney injury [22]. Physiologically, SGLT2 inhibitors cause vasoconstriction of the afferent artery, which may rarely cause a reduction in the GFR. Euglycemic ketoacidosis is more common in type 1 diabetes patients, principally in kidney transplant patients. An increased risk of lower extremity amputation was observed in the CREDENCE trial with the use of canagliflozin [23].

3. SGLT2i Effects on the Heart, Metabolism and Kidneys in Patients without Diabetes

Multiple RCTs have examined the therapeutic effectiveness of SGLT2 inhibitors in patients affected by type 2 diabetes mellitus. Notably, several studies have documented the effectiveness of SGLT2 inhibitors in nondiabetic patients affected by heart, metabolic and renal dysfunction.
Anker et al. [24] reported that empagliflozin decreased the risk of cardiovascular death and total hospitalization for heart failure (HF) by 25% and 30%, respectively, and decreased the rate of decline in the estimated glomerular filtration rate (eGFR) and the risk of adverse effects by 50%.
Diaz-Cruz et al. [25] reported that 3 months of dapagliflozin decreased blood pressure by lowering 24 h systolic blood pressure (SBP), nighttime SBP, mean arterial pressure and nocturnal hypertension.
Petrie et al. [26] demonstrated that dapagliflozin was effective in reducing cardiovascular mortality and morbidity in patients with HF, reducing the ejection fraction (EF).
Anker et al. [27] reported that in 5988 patients empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients with a left ventricular ejection fraction (LVEF) of 40% regardless of the presence or absence of diabetes.
Several trials are investigating the effects and efficacy of SGLT2 inhibitors on metabolic outcomes in patients without diabetes.
Bays et al. [28] reported that in overweight and obese subjects without diabetes, compared with a placebo, canagliflozin significantly reduced body weight.
Neeland et al. [29] reported that empagliflozin reduced endogenous glycerol gluconeogenesis in obese adults without diabetes. Additionally, SGLT2 inhibitors may prevent type 2 diabetes in obese individuals.
Faerch et al. [30] demonstrated that compared to a control and metformin therapy, treatment with dapagliflozin and interval-based exercise led to similar, but small, improvements in glycemic variability.
Finally, Veelen et al. [31] reported that dapagliflozin treatment of prediabetic insulin-resistant individuals for 14 days resulted in significant metabolic adaptations in skeletal muscle metabolism, and improved fat oxidation and mitochondrial oxidative capacity.
SGLT2 inhibitor trials have investigated the effects of SGLT2 inhibitors on renal outcomes.
Heerspink et al. [32], in the DAPA-CKD trial with 4304 patients, reported that the effects of dapagliflozin were similar in participants with or without diabetes. It has been shown to be the most effective class of drugs for preventing CKD progression since the discovery of renin–angiotensin system (RAS) inhibitors.
Harrington et al. [33], in the EMPA-KIDNEY trial with 6609 patients, demonstrated that empagliflozin lowered the risk of disease progression from kidney disease or death from CVD compared with a placebo.
Most patients included in the above trials were affected by IgA nephropathy. As a result, the EMPA-KIDNEY and DAPA-CKD trials reported a 51% reduction in the risk of CKD progression in IgA nephropathy patients [34].

4. SGLT2 Inhibitors in Kidney Transplant Patients

The abovementioned rationale also applies to kidney transplant patients, whose outcomes are strongly influenced by post-transplant diabetes, cardiovascular diseases and metabolic dysfunction.
Particular caution should be taken in treating kidney transplant patients because the incidence of infections (urinary tract infections and genital infections) could be increased by immunosuppression. In addition, the incidence of acute kidney injury and ketoacidosis sometimes encountered after transplantation could be increased by SGTL2 inhibitor use.
This has likely been the cause of the less frequent use of SGLT2 inhibitors in kidney transplant patients until recently. Indeed, only recently, two large studies on kidney transplant patients were published [35,36].
The potential benefits of SGLT2 inhibitors in CKD and kidney transplant patients are documented in Figure 2.
SGLT2 inhibitors have a direct effect on the tubular cotransporter, which increases natriuresis and glycosuria. Indirectly, increased natriuresis has been shown to decrease glomerular hyperfiltration by regulating macula density. This effect leads to decreases in renal hyperfiltration and albuminuria, which have been historically associated with slowing of the progression of CKD. Additionally, this increase in natriuresis results in a diuretic effect. In addition, another direct effect of SGLT2 inhibitors is a reduction in glycosuria reabsorption, which means better glycemic control and control of the metabolic profile owing to the effects also demonstrated by these drugs (weight loss and improved lipid profile). The most important demonstrated benefits of these drugs are a reduction in the risk of cardiovascular events, reduced mortality from cardiovascular and renal causes, and slowing of the progression of CKD. However, these significant benefits may in part be ascribed to a beneficial balance between oxidant and antioxidant pathways that are associated with anti-inflammatory or antifibrotic effects or even erythropoiesis stimulation.
The most important studies on kidney transplant patients are reported in Table 1. We observe that only recently have two large studies been reported [35,36]. Previous studies, consisting of only one RCT, several case series and retrospective studies, could not determine long-term efficacy and safety. In addition, as immunosuppression is more intensive in the first year after transplantation, the majority of studies on SGLT2 inhibitors in kidney transplant patients excluded patients in the early period after transplantation.
Owing to these limitations, all these studies [37,38,39,40,41,42,43,44,45,46] were less potent than studies on the general population or renal patients in terms of the number of patients enrolled and the quality of the study design. However, the benefits observed in these studies were similar to those reported in the general population [47,48,49,50]. Similarly, the incidence of side effects observed in this series of kidney transplant patients was similar to that observed in the general population [51]. Two recent studies have shed new light on the efficacy of SGLT2 inhibitors in kidney transplant patients. Lim et al. [35] enrolled 2083 kidney transplant recipients from six Korean hospitals. A total of 226 patients were treated with SGLT2 inhibitors. Patients were observed for 63 months, and multivariate analysis consistently revealed a decreased risk of death-censored graft failure and serum creatinine doubling in SGTL2 inhibitor users. A total of 15.6% of SGLT2 inhibitor users experienced an acute eGFR decrease during the first month, but the eGFR recovered thereafter. The risk for infections was low, as documented in previous studies [39,40].
Examining data reported by the studies in Table 1, we may observe as follows.
In a large observational study [36], 339 diabetic kidney transplant patients were given SGLT2 inhibitors for 6 months. The most frequent side effect in these patients was urinary tract infection (14%), and risk factors for developing UTIs were a prior episode and female sex. The drug efficacy evaluated at 6 months included reductions in body weight (−2.22 kg) and blood pressure, a decrease in fasting glycemia, a decrease in the serum acid level of 0.44 mg/dL, and a decrease in the urinary protein–creatinine ratio. The Hb level rose to 0.44g/dL. According to the authors, SGLT2 inhibitors should be prescribed in these patients, although with caution regarding UTIs.
Several studies documented an acute reduction in eGFR at the beginning of treatment with SGLT2 inhibitors in kidney transplant patients. This has been related to transitory tubule-glomerular feedback and is followed by eGFR recovery and stabilization. The study of Kwon et al. [52] evaluated dapagliflozin’s efficacy on microalbuminuria. The urinary albumin–creatinine ratio (UACR) at 6 months was reduced (from 118.9 ± 231.0 mcg/mg to 82.7 ± 152.1 mcg/mg; p = 0.009). This effect on the urinary albumin–creatinine ratio was also documented by many studies reported in Table 1.
A recent meta-analysis [50] documented that the use of SGLT2 inhibitors reduced the mean HbA1c by 0.57%, and the most relevant reductions were observed in patients with the highest levels.
Treatment with SGLT2 inhibitors reduced body weight in the majority of patients, as documented in the meta-analysis of Chewcharat et al. [50].

Side Effects Related to the Use of SGLT2

Several side effects have been described and are suspected to be the consequences of SGLT2 inhibitors use. Most have been described in patients with CKD, and caused discontinuation of treatment [53]. SGLT2i may cause hyperosmolarity and dehydration, an increase in uric acid, afferent arteriole constriction with reduced eGFR, and decreased organic intracellular osmolytes. Risk factors for side effects and acute kidney injury (AKI) are hypovolemia and hypotension, use of diuretics and non-steroid anti-inflammatory drugs (NSAIDs), amphotericin and myoglobin, and advanced age [54]. All these studies were conducted with patients affected by CKD.
In kidney transplant patients, these effects have not always been documented, probably because of the few and short duration of studies of renal transplant patients.
The most common side effect in kidney transplant patients is a urinary tract infection, with an incidence of 11.5%, similar to the incidence reported in a previous meta-analysis [55]. The incidence of side effects related to the use of SGLT2is has been studied in detail by a retrospective study conducted by two transplant centers [56]. The authors concluded that SGLT-2i is not associated with an increased risk of genital infection and UTI in diabetic KTRs, even in the early post-transplant period. The use of SGLT-2i reduces proteinuria in KTRs and has no adverse effects on allograft function at the 12-month follow-up.
Also, the study conducted by Sweiss et al. [57] on 49 transplant patients who received different organs demonstrated that SGLT2i can be used safely in solid organ transplant recipients.
A recent 2024 study [58] documented the synergistic effect, with added nephroprotection, of a combination of SGLT2 inhibitors and glucagon-like peptide 1 receptor agonists (GLP-1) in the post-transplant diabetes mellitus (PTDM) treatment of kidney transplant recipients.
Anyway, considering data offered from all mentioned studies, the following recommendations should be followed:
(a)
Start treatment with SGLT2 inhibitors at least 6 months after transplantation;
(b)
Start treatment if no previous rejection occurred;
(c)
Start treatment in patients with no history of UTI 6 months before starting therapy;
(d)
Start treatment only in patients without a history of vascular disease.

5. Conclusions

Overall, considering the studies on kidney transplant patients, kidney outcomes were not adequately assessed in available studies. Adverse effects were reported to occur at a similar rate compared to the general population. Anyway, data assessing SGLT2 inhibitors use in solid organ transplantation for longer durations are needed. Currently, three RCTs on SGLT2i in kidney transplant patients are enrolling (ClinicalTrials.gov ID: NCT05788276, NCT04743453 and NCT04965935) [59,60,61].

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. (A) SGLT2 action on the heart and metabolism. (B) Action of SGLT2 on the kidney. Legend for (A,B): NF-kB, nuclear factor kappa B; MCP-1, monocyte chemoattractant protein 1; TFG-β, transforming growth factor β; NEFA, non-esterified fatty acids; NO, nitric oxide; O2, oxygen; N2, nitrogen; LDL, low-density lipoprotein; HDL, high-density lipoprotein. The arrows up or down mean that the substance or the phenomenon that follow increase or decrease.
Figure 1. (A) SGLT2 action on the heart and metabolism. (B) Action of SGLT2 on the kidney. Legend for (A,B): NF-kB, nuclear factor kappa B; MCP-1, monocyte chemoattractant protein 1; TFG-β, transforming growth factor β; NEFA, non-esterified fatty acids; NO, nitric oxide; O2, oxygen; N2, nitrogen; LDL, low-density lipoprotein; HDL, high-density lipoprotein. The arrows up or down mean that the substance or the phenomenon that follow increase or decrease.
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Figure 2. Potential benefits of SGLT2 inhibitors in chronic kidney disease and renal transplant patients. The arrows up or down mean that the substance or the phenomenon that follow increase or decrease.
Figure 2. Potential benefits of SGLT2 inhibitors in chronic kidney disease and renal transplant patients. The arrows up or down mean that the substance or the phenomenon that follow increase or decrease.
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Table 1. Principal studies on SGLT2 inhibitors in kidney transplant recipients.
Table 1. Principal studies on SGLT2 inhibitors in kidney transplant recipients.
Author, Year, Study Type, Follow-UpBasal eGFR
(mL/min)		Effect on Renal Function (eGFR mL/min/1.73)Proteinuria (uPCR) g/d/(uACR) mg/gAdverse Events
Rajasekeran et al., 2017 [37], CS, n = 6, 8 mo78.6 ± 18.2No differencesNACellulitis
Shah et al., 2019 [38], PS, n = 25, 8 mo86 ± 20No differencesNANone
Schwaiger et al., 2019 [39], PS, n = 14, 12 mo55.6 ± 20.3Decrease and then stabilizeΔuACR: −25
ΔuACR: −73		UTI 5
Halden et al., 2019 [40], RCT, n = 44, 6 mo66 ± 10.5No differencesNAUTI 3
Mahling et al., 2019 [41], PS, n = 10, 6 mo57 ± 19.3No differencesNAUTI 2
Attallah et al., 2019 [42], CS, n = 25, 12 moNADecrease and then stabilizeΔuPCR −0.6 g/dUTI 2
Kong et al., 2019 [43], PS, n = 42, 12 mo60.36 ± 17No differencesΔuACR No significant changeAcute cystitis 3
Alkindi et al., 2020 [44], CS, n = 8, 12 mo75.8 ± 13.4No differencesNAUTI 1
Song et al., 2021 [45], RS, n = 50, 6 mo66.7No differencesNAUTI 7
Lemke et al., 2021 [46], RS, n = 39, 12 moNANo differencesNAUTI 6, Ketoacidosis 1
Sánchez Fructuoso et al., 2022 [36], MCO, n = 339, 12 mo58.4 (56.2–60.6)No differencesΔuPCR: −230 at 6 moUTI 14%, AKI 1.8%
Lim et al., 2022 [35], OR, PSM, n = 2083, 63 moS: 66.9 ± 17.7
C: 68.4 ± 20.1		Decrease, stabilization and ameliorationΔuPCR: urine PCR significantly decreased after SGTLi, p = 0.005NA
CS = case series; PS = prospective study; RCT = randomized controlled trial; RS = retrospective study; MCO = multi-center observational; PSM = propensity score matched; eGFR = estimated glomerular filtration rate; uPCR = urinary protein creatinine ratio; NA = not available; UTI = urinary tract infection; AKI = acute kidney injury; uACR = urinary albumin to creatinine ratio.
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Salvadori, M.; Rosati, A.; Rosso, G. Update on Sodium Glucose Cotransporter Type 2 Inhibitors Use in Kidney Transplant Patients. Transplantology 2024, 5, 224-233. https://doi.org/10.3390/transplantology5030022

AMA Style

Salvadori M, Rosati A, Rosso G. Update on Sodium Glucose Cotransporter Type 2 Inhibitors Use in Kidney Transplant Patients. Transplantology. 2024; 5(3):224-233. https://doi.org/10.3390/transplantology5030022

Chicago/Turabian Style

Salvadori, Maurizio, Alberto Rosati, and Giuseppina Rosso. 2024. "Update on Sodium Glucose Cotransporter Type 2 Inhibitors Use in Kidney Transplant Patients" Transplantology 5, no. 3: 224-233. https://doi.org/10.3390/transplantology5030022

APA Style

Salvadori, M., Rosati, A., & Rosso, G. (2024). Update on Sodium Glucose Cotransporter Type 2 Inhibitors Use in Kidney Transplant Patients. Transplantology, 5(3), 224-233. https://doi.org/10.3390/transplantology5030022

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