Searching in the maze: sodium–glucose cotransporter-2 inhibitors in kidney transplant recipients to improve survival

ABSTRACT

Sodium–glucose cotransporter-2 inhibitors (SGLT2is) improve cardiovascular and renal outcomes in chronic kidney disease patients with and without diabetes. Kidney transplant recipients have been excluded from landmark trials using SGLT2is and literature on safety and efficacy are scarce. Recent studies suggest that the SGLT2i use in kidney transplant recipients with diabetes is safe, paving the way to investigate whether SGLT2is could also reduce cardiovascular events and kidney function deterioration in kidney allograft recipients.

It is well documented that sodium–glucose cotransporter-2 inhibitors (SGLT2is) have cardiorenal protective effects in patients with or without diabetes. In patients with chronic kidney disease (CKD), they have shown a beneficial effect in reducing albuminuria, slowing kidney function decline and improving survival. The proposed mechanism is by an increase in sodium concentration at the macula densa, which causes vasoconstriction of the afferent arteriole and consequently reduces glomerular hyperfiltration [1]. SGTL2is have been added in international guidelines for the management of CKD patients [2].

Where do we currently stand on using SGLT2is in kidney transplant recipients (KTRs)? KTRs could benefit from SGLT2is, especially because they have a high cardiovascular burden, an increased risk of diabetes and suffer from chronic kidney allograft function deterioration. Indeed, rather than immunological-mediated damage, the most common long-term kidney allograft lesions are those usually associated with hyperfiltration, such as arteriolar hyalinosis and focal and segmental glomerulosclerosis [3]. It has to be noted that interstitial fibrosis and tubular atrophy are also common long-term injuries in grafts, which unfortunately may not be improved by the use of SGLT2is. However, all these questions remain unanswered, as the kidney transplant population has been excluded from the landmark trials using SGTL2is. There are concerns about using SGLT2is in KTRs because, with a single kidney, sometimes with a low glomerular filtration rate, and receiving immunosuppression, these patients could be more vulnerable to urinary tract infections (UTIs), pharmacological interactions and acute kidney injury [4].

Only a few observational and one small randomized clinical trial have explored the beneficial effects of SGLT2is in KTRs with type 2 diabetes (T2DM) or posttransplant diabetes mellitus (PTDM) (Table 1). They showed that these patients can also experience a reduction in plasma glucose, body weight and blood pressure with SGLT2is, with a similar rate of side effects as non-transplanted people. Moreover, there is a lack of studies exploring SGTL2is as renoprotective agents in KTRs without diabetes.

Table 1:

Main studies reporting outcomes of SGLT2is on KTRs

Study	Design	Population	Intervention	Results
Halden et al. 2019 [6]	RCT, n = 49 (22 patients on empagliflozin)	PTDM with KT >1 year, eGFR >30 ml/min/1.73 m2	Empagliflozin versus placebo	Empagliflozin:
				• Greater reduction of HbA1c: −0.2% (95% CI −0.6 to −0.1) versus 0.1% (95% CI −0.1–0.4)
				• Greater reduction in body weight: −2.5 kg (95% CI −4.0 to −0.05) versus 1.0 kg (95% CI 0.0−2.0)
				• No changes in BP or eGFR
				• No relevant pharmacokinetic interactions with immunosuppressive drugs
				• One case of urosepsis and one yeast infection
Rajasekeran et al. 2017 [10]	Case series (4 SPKT, 6 KT)	KT or SPKT on canagliflozin	Canagliflozin	• No UTI or mycotic infections
				• No episodes of AKI
				• Improvement in glycaemic control [HbA1c mean change −0.84% (SD 1.2)], weight [−2.14 kg (SD 2.8)] and BP [PAS −6.4 (SD 10.8)]
AlKindi et al. 2020 [9]	Case series (8 KT)	KT on SGLT2i (T2DM or PTDM)	Empagliflozin (6 patients) and dapagliflozin (2 patients)	At 12 months:
				• Reduction in HbA1c from 9.34% (SD 1.36) to 7.41% (SD 1.44) at 12 months
				• No significant changes in eGFR
				• No significant change in BP
				• Weight reduction from 84.8 kg (SD 12.8) to 82.8 kg (SD 11.4) at 6 months
				• One episode of UTI, no fungal infections
Attallah and Yassine 2019 [13]	Case series (8 KT)	KT on empagliflozin (T2DM or PTDM)	Empagliflozin	At 12 months:
				• HbA1c decrease of 0.85 g/dl
				• Slight decrease in eGFR, then stabilized
				• UPCR decrease of 0.6 g/day
				• Weight decrease of 2.4 kg
				• Two cases of UTI (one patient discontinued SGLT2i because of UTIs)
Schwaiger et al. 2019 [7]	Prospective interventional study (14 KT)	Stable KT with insulin	Empagliflozin	At 12 months:
				• No decrease in HbA1c. Improvement in beta-cell glucose sensitivity
				• Body weight decrease of 1.6 kg
				• At 4 weeks, a decrease in eGFR from 55.6 ml/min/1.73 m2 (SD 20.3) to 47.5  ml/min/1.73 m2 (SD 15.1). No change in UACR
				• During first 4 weeks: three UTI and one uncomplicated balanitis
Mahling et al. 2019 [14]	Prospective case series (10 KT)	Stable KT	Empagliflozin	At 12 months:
				• Stable eGFR
				• Median HbA1c 7.3–7.1%
				• Decrease in body weight −1.9 kg
				• Low rate of UTI and other side effects
Shah et al. 2019 [15]	Prospective descriptive study (24 KT)	Stable KT with T2DM or PTDM, minimum follow-up 6 months	Canagliflozin	At 6 months:
				• Weight reduction 78.6 kg (SD 12.1) to 76.1 kg (SD 11.2)
				• PAS from 142 (21) to 134 (SD 17) and PAD 81 (SD 9) to 79 (SD 8)
				• No significant change in creatinine
				• HbA1c 8.5% (SD 1.5) to 7.6% (SD 1)
				• No increase in infections
Song et al. 2020 [16]	Observational retrospective (50 KT)	KT, eGFR >30 ml/min/1.73 m2 with T2DM or PTDM	Empagliflozin (n = 43), canagliflozin (n =  6) or dapagliflozin (n = 1)	At 6 months:
				• Weight reduction of −2.95 kg (SD 3.54)
				• 14% of patients had a UTI (similar to the rate reported in KTRs)
				• No significant changes in renal function
				• Therapy discontinued in nine patients
Lim et al. 2022 [8]	Observational retrospective (226 KT)	KT with T2DM on SGLT2i		• Mean follow-up 69.2 months (SD 42.2)
				SGLT2 group had:
				• Lower risk of primary composite outcome (all-cause mortality, death-censored graft failure and serum creatinine doubling)
				• Initial eGFR dip after initiation in 15.6% of KTRs, but eGFR recovered thereafter and remained stable
Lemke et al. 2022 [17]	Observational retrospective (39 KT)	KT on SGLT2i (T2DM or PTDM)	Canagliflozin (n = 12), dapagliflozin (n = 3), empagliflozin (n =  24)	At 12 months:
				• No significant change in kidney function
				• 25% of patients experienced an adverse event, with UTI the most common
				• HbA1c decline from a median of 8.4% (IQR 7.8–9.2) to 7.5% (6.8–8.0)
				• 17 patients (43%) discontinued the drug. The most common reasons were the cost of the drug and kidney function decline

IQR: interquartile range; PAD: diastolic blood pressure; PAS: systolic blood pressure; SPKT: simultaneous pancreas–kidney transplantation; UACR: urinary albumin:creatinine ratio.

In the current issue, Sánchez-Fructuoso et al. [5] present a multicentric observational study with 339 diabetic KTRs treated with SGLT2is, the largest cohort of KTRs in the current literature. Patients in this cohort were treated with SGLT2is if they had poor glycaemic control, cardiovascular risk or kidney risk factors. The most common SGLT2i used was empagliflozin and 60% of the patients were diagnosed with PTDM while the rest had T2DM. The main outcome of the study is a safety one, described as the incidence of UTIs or mycoses. The incidence of UTI at 6 months was 10.3% and at 12 months was 14%. The authors also found the UTI incidence 6 months before starting SGLT2i was similar. Previous studies have compared UTI frequency in an untreated KTR control group, also showing no differences [6–8]. These findings support the idea that KTRs on SGLT2is do not have a higher risk of UTI. At 12 months, genital mycoses occurred in 1.5% of the patients, concordant with findings from previous studies [6].

Sánchez-Fructuoso et al. [5] report a modest decrease in haemoglobin A1c (HbA1c) of −0.36% (95% confidence interval −0.51 to −0.21). The magnitude of the glucose-lowering effect varies among reports, from as low as no decrease [7] to >1% in others [9]. However, we should take into consideration that studies had a different range of baseline HbA1c, concomitant medications and different purposes. Moreover, HbA1c changes should be interpreted together with estimated glomerular filtration rate (eGFR), since in native kidneys it has been demonstrated that the glucose-lowering effect depends on kidney function.

A reduction in body weight of 2–4 kg has been consistently reported in KTRs treated with SGLT2is, as well as a decrease in systolic and diastolic blood pressure. However, data on kidney outcomes are still scarce. Some studies [6, 7, 10] report an initial eGFR decline similar to that described in non-transplanted kidneys. Sánchez-Fructuoso et al. [5] describe a slight clinically non-significant reduction in eGFR during the 6 months of follow-up. A reduction in proteinuria was only seen in the subgroup that had a baseline urinary protein:creatinine ratio >300 mg/g (30 patients). Another report also showed a reduction in proteinuria [8]. Sanchez-Fructuoso et al. [5] report some additional interesting effects. Hyperuricaemia, hypomagnesaemia and anaemia are frequent complications after kidney transplantation that can be attenuated by the use of SGLT2is, as has been described in non-transplanted patients with CKD and heart failure [11, 12].

The current evidence, including the study by Sánchez-Fructoso et al. [5] regarding the use of SGLT2is in kidney transplantation, is coming from observational studies describing associations rather than demonstrating causality. However, they provide some valuable clues to design further studies aimed at demonstrating the safety and efficacy of these drugs to reduce cardiovascular events and kidney function decline in kidney allograft recipients with and without diabetes. The results of this study encourage the use of SGLT2is in diabetic KTRs in terms of safety and efficacy for body weight reduction and blood pressure control. However, it remains unknown the effect on long-term nephroprotection and graft survival in KTRs. New randomized controlled trials might help fill these information gaps on these promising drugs in KTRs.

ACKNOWLEDGEMENTS

We thank the CERCA Program/Generalitat de Catalunya and Instituto Salud Carlos III (ISCIII)’, Kidney Disease RICORS RD21/0005/0021 and NextGenerationEU.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

L.O. performed the database search literature review. L.O., N.M. and J.M.C. prepared and revised the article.

DATA AVAILABILITY STATEMENT

The data underlying this article will be shared upon reasonable request to the corresponding author.

CONFLICT OF INTEREST STATEMENT

J.M.C. is member of the CKJ editorial board. The other authors declare no conflicts of interest.