RE: The Efficacy and Safety of SGLT2 Inhibitor in Kidney Transplant Recipients With Diabetes : Transplantation

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RE: The Efficacy and Safety of SGLT2 Inhibitor in Kidney Transplant Recipients With Diabetes

Lim, Jeong-Hoon MD, PhD1; Cho, Jang-Hee MD, PhD1

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Transplantation 107(3):p e80-e81, March 2023. | DOI: 10.1097/TP.0000000000004471
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We appreciate the comments of Gaynor et al1 on our recent study,2 which demonstrated the beneficial effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on mortality and graft function in kidney transplant recipients (KTRs) with diabetes. The beneficial effects and safety of SGLT2i have been confirmed for the first time, to our knowledge, in a number of KTRs.

Large-scale randomized controlled trials (RCTs) have recently confirmed the renal and cardiovascular advantages of SGLT2i.3-5 Of course, RCTs are the best way to objectively confirm the effect of a specific medication, but there are limitations to conducting an RCT because it requires significant resources in terms of cost and staffing, as well as a long observation period. Many observational studies based on real-world data have been conducted to overcome these limitations.6 Our observational study was similarly designed to confirm the effect of a new antidiabetic medication that is currently in the spotlight, SGLT2i, in a special cohort, but there are inevitable limitations in this observational study design. In particular, it is difficult to identify the effectiveness of specific medications among diabetes patients because many of them take multiple antidiabetic medications.

Differences in baseline characteristics between groups and the problem of immortal time bias are major issues in observational cohort studies, and they are the main shortcomings to overcome.7,8 We used multivariate models and a propensity score-matching model to balance the baseline differences between the groups. However, our study design could not completely avoid immortal time bias; therefore, we conducted the current analyses in conjunction with internal discussions involving a statistician, specifically to reduce bias and objectively confirm the effectiveness of SGLT2i.

KTRs with diabetes usually take metformin as a first-line antidiabetic medication and then take additional medications such as SGLT2i if glycemic control is poor. As a result, the initiation time of SGLT2i medication is inevitably delayed compared with other antidiabetic drugs, such as metformin, potentially leading to an advantageous selection bias in the SGLT2i user group. In addition, KTRs have a high incidence of mortality or acute rejection during the early period of transplantation; therefore, the time span between kidney transplantation (KT) and SGLT2i initiation may affect the outcomes. Considering these points, the starting time for both groups was set as the first use of antidiabetic medication after KT.

SGLT2i, a recent antidiabetic, has not been used for as long as other antidiabetic medications, such as metformin. However, in the present study, more than half of the SGLT2i users took SGLT2i for >1 y, and the longest took SGLT2i for >4 y. Furthermore, our results showed that SGLT2i significantly reduced proteinuria over a short period of 8 mo in KT patients. Because the effect of SGLT2i has been confirmed from the early stage of SGTL2i medication in previous RCTs,3-5 the duration of SGLT2i medication in this study was considered sufficient to confirm the effectiveness and safety of SGLT2i in a specific user group, KTRs.

McGuire et al9 conducted a meta-analysis of 6 landmark RCTs of SGLT2i. Such well-designed RCTs are strictly controlled for the inclusion and exclusion criteria. Therefore, the results of these RCTs cannot be compared with those of the current observational cohort study. Moreover, all KTRs are taking maintenance immunosuppressants and are in functional single-kidney status, causing more changes in kidney function than in nontransplant type 2 diabetes patients. A laboratory study also confirmed the effect of SGLT2i in reducing tacrolimus-induced renal injury.10 Taken together, the renal outcomes of SGLT2i in KTRs may differ from those in nontransplant patients.

This observational study could not definitively demonstrate the effects of SGLT2i. However, our study is meaningful in that we confirmed the efficacy and safety of SGLT2i using a large KT cohort with diabetes. The results of our study will help reduce concerns about the use of SGLT2i in KTRs and are expected to be a cornerstone for future RCTs in KTRs.

REFERENCES

1. Gaynor JJ, Tabbara MM, Ciancio G. Time-dependent bias existing in their statistical analysis must be properly controlled/avoided prior to drawing any conclusions. Transplantation. 2023;107:e78–e79.
2. 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.
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8. Kwon S, Kim CT, Lee JP. The long-term effects of metformin on patients with type 2 diabetic kidney disease. Diabetes Care. 2020;43:948–955.
9. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6:148–158.
10. Jin J, Jin L, Luo K, et al. Effect of empagliflozin on tacrolimus-induced pancreas islet dysfunction and renal injury. Am J Transplant. 2017;17:2601–2616.
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