Outcomes of SGLT2 Inhibitors Use in Diabetic Renal Transplant Patients

Outcomes of SGLT2 Inhibitors Use in Diabetic Renal Transplant Patients Fatima AlKindia,*, Hanan L. Al-Omaryb, Qutaiba Hussainc, Mohamed Al Hakimc, Ahmed Chaabanc, and Yousef Boobesc a Internal Medicine Department, Tawam Hospital, Al-Ain, United Arab Emirates; bMedical College, University of Baghdad, University of Baghdad, Iraq; and cNephrology Division, Tawam Hospital, Al-Ain, United Arab Emirates

ABSTRACT Sodium-glucose cotransporter 2 (SGLT2) inhibitors are newly introduced hypoglycemic drugs that work by inhibiting glucose reabsorption at proximal renal tubules. The use of SGLT2 inhibitors in nontransplant diabetic patients with or without cardiovascular disease has wellestablished efficacy and safety. The risks of renal graft dysfunction and urinary tract infections might be the limiting factors for their use in renal transplant patients. Data regarding the safety and long-term efficacy of SGLT2 inhibitors use in diabetic renal transplant patients is scanty. The aim of the study is to report our experience with use of SGLT2 inhibitors in 8 diabetic renal transplant patients supported by literature review. Eight diabetic renal transplant patients were recruited from Tawam hospital during the period between June 2016 and January 2019. Demographic, clinical, and laboratory data were collected and analyzed. Adding SGLT2 resulted in significant decrease in hemoglobin A1c and body mass index after 12 months of treatment. There was significant negative correlation between the duration of treatment with SGLT2 and hemoglobin A1c. Diabetic renal transplant patients with stable kidney function had better glycemic control with use of SGLT2 inhibitors. There was no deterioration of kidney function and risk of recurrent urinary tract infection was low.

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IABETES mellitus and new-onset diabetes after transplantation is prevalent among renal transplant patients [1]. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are newly introduced hypoglycemic drugs that work by inhibiting glucose reabsorption at proximal renal tubules. The use of SGLT2 inhibitors in nontransplant diabetic patients with or without cardiovascular disease has wellestablished efficacy and safety [2,3]. Recent systematic review and meta-analysis demonstrated long-term renal protective effects of SGLT2 inhibitors in diabetic patients with chronic kidney disease [4]. However, the Food and Drug Administration has issued alerts regarding increased acute kidney injury risk with 2 of them, canagliflozin and dapagliflozin. The risks of renal graft dysfunction and urinary tract infections (UTIs) might be the limiting factors for their use in renal transplant patients. Data regarding the safety and longterm efficacy of SGLT2 inhibitors use in diabetic renal transplant patients is scanty. We aimed to study the shortterm safety and efficacy of SGLT2 inhibitors in diabetic renal transplant patients supported by literature review. ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169

Transplantation Proceedings, XX, 1e4 (2019)

PATIENTS AND METHOD

A retrospective chart review study was conducted at Tawam hospital (tertiary hospital in Al-Ain, United Arab Emirates) over 2 years from June 2016 until January 2019. We included all diabetic renal transplant patients who were started on SGLT2 inhibitors during the study period. The patients were followed up regularly in renal transplant and endocrine clinics, and SGLT2 inhibitors were added by team members after explaining the potential side effects.

Statement of Ethics: Ethical approval was obtained from the institutional review board of Tawam Hospital. Disclosure Statement: The authors report no conflicts of interest. Funding Sources: The study was not funded and no research grants were received. *Address correspondence to Fatima AlKindi, Internal Medicine, Tawam Hospital, United Arab Emirates. E-mail: dr.fkendi@gmail. com 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.11.007

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The study was approved by the scientific and ethical committee of Tawam Hospital. Demographic, clinical and laboratory data were collected and analyzed using descriptive analysis using the SPSS 20 system (IBM, SPSS Statistics for Windows, Version 20.0. Armonk, New York, United States). Data were expressed in mean
SD, and comparison between them was done using analysis of variance test. A P value of less than .05 was considered as significant. Outcomes of glucose, diabetes control (hemoglobin A1c [HbA1c]), renal functions, blood pressure readings, and weight changes were collected at baseline, 3-, 6-, 9-, and 12-month intervals. Complications related to the use of SGLT2 inhibitors were monitored closely including UTIs, genital fungal infection, acute kidney injury, or graft dysfunction, symptomatic hypoglycemia, and ketoacidosis. RESULTS

A total of 8 renal transplant patients were included, 2 patients (25%) had long-standing diabetes mellitus type 2 and the remaining 6 patients (75%) had posttransplant diabetes (new-onset diabetes after transplantation). The majority were males (75%), with mean age of 56.8
13.71 years. The comorbid conditions in our cohort were hypertension (7 [87.5%]), dyslipidemia (7 [87.5%]), osteoporosis (3 [37.5%]), history of UTI (2 [25%]), and obesity body mass index >30 (4 [50%]). Median years from transplantation were 9.6 years and all patients had a transplant from living unrelated donors, with stable allograft function (estimated glomerular filtration rate [eGFR] >60). The renal transplant patients were maintained on a triple immunosuppressant therapy regime using combination of tacrolimus (62.5%), cyclosporine (37.5%), prednisolone (100%), mycophenolate (62.5%) and mycophenolic acid (37.5%). Table 1 shows the demographic data of the patients and their basic characteristics. The baseline HbA1c (mean
SD) was 9.34%
1.36% and hypoglycemic medications used included metformin (37.5%), gliclazide modified release, (62.5%), DPP4 inhibitors (linagliptin or sitagliptin) (37.5%), insulin (37.5%), and dulaglutide 1.5 mg (37.5%). SGLT2 inhibitors (empagliflozin [6 patients], dapagliflozin [2 patients]) were added for better glycemic control. Doses of SGLT2 inhibitors used in our cohort as the following: empagliflozin 10 mg (5 patients), empagliflozin 25 mg (one patient), and dapagliflozin 5 mg (two patients). The duration of their use varied, ranging from 3 months to 2 years. There was a significant reduction in HbA1c (P value of .05) over the study period as the following HbA1c after 3 months (9.025
1.28), 6 months (8.55
2.33), 9 months (7.7
1.61), and 12 months (7.41
1.44) (Table 2). None of the patients experienced any episodes of severe hypoglycemia or symptomatic ketoacidosis during the study period. No significant changes in eGFR could be observed after starting SGLT2 inhibitors. The mean of eGFR at baseline was 75.75 mL/min/1.72 m2. After 3 months of introduction

ALKINDI, AL-OMARY, HUSSAIN ET AL Table 1. Baseline Characteristics of Diabetic Renal Transplant Patients Baseline Characteristics

Mean age (y) Male sex Diabetes mellitus (n [%]) and mean duration (y) Post-transplant diabetes (NODAT), (n [%]) Type of renal transplant: LURD Mean duration of transplantation (y) Baseline hemoglobin A1c (%) eGFR (mL/min/1.73 m2) Serum creatinine (mmol/L) Baseline overweight (BMI 25-30) Baseline obesity (BMI >30) Hypertension Cardiovascular disease History of urinary tract infection

Renal Transplant Patients (N ¼ 8)

56.8
13.70 (6 [75%]) (2 [25%]), 21.5 (6 [75%]) (100%) 9.63
6.41 9.34%
1.36% 75.75
13.38 92.5
11.65 (3 [37.5%]) (4 [50%]) (7 [87.5%]) None (2 [25%])

Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; LURD, living unrelated renal donor; NODAT, new-onset diabetes after transplantation.

of SGLT2 inhibitor eGFR was (76.3 mL/min/1.72 m2), after 6 months (71.2 mL/min/1.72 m2), and after 9 months (77.75 mL/min/1.72 m2). There were no acute kidney injury events observed during the study period and SGLT2 inhibitors were well tolerated (Table 2). The effects of SGLT2 inhibitors on blood pressure were studied and it showed a nonsignificant decrease in both systolic and diastolic blood pressure (base line mean systolic blood pressure 135
9.59 mm Hg, and after 12 months it was 126.43
11.46 mm Hg). Baseline diastolic pressure was 80.62
10.13 mm Hg and after 12 months was 74.75
7.25 mm Hg (as shown in Table 2). Reduction in weight was observed in some patients with mean weight of (82.87
11.52 kg and 82.75
11.35 kg) at 3 and 6 months, respectively, from mean baseline weight of 84.82
12.83 kg. There was statistically significant (P value of .05) reduction on weight and body mass index during the study period. The incidence of acute UTI was low (only one attack of bacterial UTI) and no reported fungal infections. The 2 patients who had previous history of recurrent UTI, they were on prophylactic treatment did not experience new episodes, except one patient developed one episode of acute UTI after 1 year of SGLT2 use. DISCUSSION

Our results showed that the use of SGLT2 inhibitors among diabetic renal transplant patients was both effective and safe. These results support the limited available data to date. In review of literature, there were 4 published cases series describing the short-term use of SGLT2 inhibitors in renal transplant patients, 2 of them were abstracts (Table 3) [5e8]. Total of 43 renal transplant patients were reported. They had either diabetes mellitus (type 1 or 2) or new-onset diabetes after transplantation, with uncontrolled HbA1c

OUTCOMES OF SGLT2 INHIBITORS USE

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Table 2. Comparison Between Baseline Measurements (HbA1c, eGFR, Creatinine, Blood Pressure, and BMI) and the Following Months of Treatment (SGLT2 Inhibitors) Baseline

HbA1c (%) eGFR (mL/min/1.73 m2) Serum creatinine (mmol/L) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) BMI (kg/m2)

9.34
75.75
92.5
135
80.63
32.74


1.36 13.38 11.65 9.59 10.13 7.2

After 3 Mo

9.025
76.38
91.63
126.88
77.38
32


After 6 Mo

1.28 13.09 13.45 14.22 8.14 6.61

8.55
72.38
92.75
121.75
122.5
31.11


2.33 7.61 10.82 15.15 9.38 6.31

After 9 Mo

7.7
62
88.88
122.5
100.7
28.5


1.61 15.95 19.83 9.38 5.78 5

After 12 Mo

7.41
69.88
82.63
126.43
74.75
27.4


P Value

1.44 14.70 13.91 11.46 7.25 4.2

<.05* >.05 >.05 >.05 >.05 <.05*

Data were expressed in mean
SD. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; SGLT2, sodium-glucose cotransporter 2. * P value is significant at <.05.

ranging from 7.4% to 8.8%. Mean duration of renal transplantation ranged from 3.5 to 7 years with stable renal function (eGFR >60). The types of SGLT2 inhibitors used as add-on medication for controlling diabetes were

dapagliflozin for 26 patients, canagliflozin for 10 patients, and empagliflozin for 7 patients. There were positive effects of SGLT2 inhibitors on glycemic control with improvement on HbA1c ranging from 0.5% to 1%. Symptomatic

Table 3. Summary of Reported Studies of SGLT2 Inhibitor Use in Diabetic Renal Transplant Patients

Reference

Harindra R, 2017 N ¼ 10 KTR (n ¼ 5), SPKTR (n ¼ 5)

Guthoff M, 2017 N¼7

Beshyah, 2018 N¼1

not provided not provided

58-year-old, male 1 (DM type 2 for 25 y)

6.9 y Empagliflozin

LURD for 7 y Dapagliflozin, 10 mg/d for 2.5 y

Age, sex DM type 1, n DM type 2, n NODAT, n Mean duration of renal transplant SGLT2 inhibitors used

2 8 3.5-4.4 y Canagliflozin

not provided 3 15 7 72 (9-262) mo Dapagliflozin, 5 mg/d

HbA1C Baseline Change after SGLT2 inhibitors

7.4% in SPKTR, 8.6% in KTR (e0.84%)

7.9% 7.4%

7.6% Markedly improved, number not provided

8.8% 7.8%

eGFR Baseline Change after SGLT2 inhibitors

60 in SPKTR, 78 in KTR (e4.3 [12.2])

71.1 mL/min 71.5 mL/min at 1 y

61 mL/min Stable, details not provided

84 mL/min 95 mL/min

Not given

Not provided, but did not change 10 patients, had reduced number and/or dose of antihypertensives

Not provided

115/70

not given (e2.14 [2.8])

72.2 kg 68.1 kg (at 1 y)

not provided

Hypoglycemia (n ¼ 1) Cellulitis ( n ¼ 1) No UTI or fungal infections No AKI or graft dysfunction

Acute cystitis (n ¼ 2) Lack of efficacy (n ¼ 3)

No complications

BP Baseline Changes after SGLT2 inhibitors

Weight Baseline Changes after SGLT2 inhibitors

Complications related to SGLT2 inhibitors inhibitors

not provided

Kwon, 2017 N ¼ 25

systolic BP (e6.5 [10.8]), diastolic BP (e4.8 [12])

BP decreased transiently after SGLT2 inhibitors then increased (>130/80) 86 kg First reduced to 78 kg in 6 mo, then increased to 84 kg at 2.5 y No complications

No AKI or graft dysfunction

Abbreviations: AKI, acute kidney injury; BP, blood pressure; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; KTR, kidney transplant recipients; LURD, living unrelated renal donor; NODAT, new-onset diabetes after transplantation; SGLT2, sodium-glucose cotransporter 2; SPKTR, simultaneous pancreas-kidney transplant recipients; UTI, urinary tract infection.

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hypoglycemia was reported in one patient and no documented diabetic ketoacidosis. In our cohort, there was also significant reduction in HbA1c (from 9.3%-8.4% at 6 months) and good glycemic control with the use of SGLT2 inhibitors. The renal graft function was stable throughout the duration of SGLT2 inhibitors use without any reported episodes of acute kidney injury or rejection. The effect of SGLT2 inhibitors use on blood pressure control was variabledsome patients had reduction in dose and number of antihypertensive medications and others had transient effects. Similar findings were observed in our patients, as there was minor reduction in blood pressure. Moreover, there was a significant weight reduction after SGLT2 inhibitors use at 1 year ranging from 2 to 4 kg in published data (Table 3). Our cohort of patients had significant weight reduction of 2 kg after 6 months. In regards to infectious complications of SGLT2 inhibitor use among diabetic renal transplant patients, cystitis developed in 2 patients, cellulitis in 1 patient, and no reported genital fungal infection or recurrent UTIs (Table 3). One of our patients required hospital admission for management of acute UTI developed after one year of SGLT2 inhibitor use. Interestingly, even in patients with previous history of recurrent UTI, there was no major risk of UTI with SGLT2 inhibitors use. A large systematic review and meta-analysis included 50,820 participants from 77 randomized control trials and examined the risk of UTI and genital infections in diabetic patients using SGLT2 inhibitors [9]. The risk of genital infections was high in patients using SGLT2 inhibitors (risk ratio 3.30). On the other hand, the risk of UTI with SGLT2 inhibitors use still remains uncertain, as there was no significant difference in incidence of UTI in patients who were using SGLT2 inhibitors compared with the control group [9]. In general, our short-term data suggests that using SGLT2 inhibitors among diabetic renal transplant patients is safe and effective in improving glycemic control and weight reduction. CONCLUSION

In our diabetic renal transplant patients with stable kidney function and chronic kidney disease stage I or II (eGFR

ALKINDI, AL-OMARY, HUSSAIN ET AL

>60), the use of SGLT2 inhibitors is associated with significant improvement in glycemic control and weight reduction. There was no deterioration of kidney function and risk of recurrent UTI was low. Further studies are needed to explore the long-term safety and efficacy of SGLT2 inhibitors in diabetic renal transplant patients. ACKNOWLEDGMENTS The authors would like to thank Ms Nicole Gebran for providing list of patients and endocrine team members for managing the diabetic renal transplant patients.

REFERENCES [1] Kaposztas Z, Gyurus E, Kahan BD. New-onset diabetes after renal transplantation: diagnosis, incidence, risk factors, impact on outcomes, and novel implications. Transplant Proc 2011;43: 1375e94. [2] Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117e28. [3] Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375: 323e34. [4] Seidu S, Kunutsor SK, Cos X, Gillani S, Khunti K. For and on behalf of Primary Care Diabetes Europe: SGLT2 inhibitors and renal outcomes in type 2 diabetes with or without renal impairment: a systematic review and meta-analysis. Prim Care Diabetes 2018;12: 265e83. [5] Rajasekeran H, Kim SJ, Cardella CJ, Schiff J, Cattral M, Cherney DZI, et al. Use of canagliflozin in kidney transplant recipients for the treatment of type 2 diabetes: a case series. Diabetes Care 2017;40:e75e6. [6] Kwon HY, Kong JM. Sodium/Glucose Cotransporter 2 (SGLT2) Inhibitor for Diabetic Kidney Transplant (KT) Patients. Kidney Week 2017. New Orleans, LA, USA: American Society of Nephrology; 2017. [7] Beshyah SA, Beshyah AS, Beshyah WS, Yaghi S. Use of SGLT2 inhibitors in diabetic renal transplant recipients: a mixed method exploratory exercise. Int J Diabetes Metab 2018;21:16e21. [8] Guthoff M, Mahling M, Nadalin S, Heyne N. SGLT2 inhibition in kidney transplant recipients with diabetes. Am J Transplant 2017:17. [9] Liu J, Li L, Li S, Jia P, Deng K, Chen W, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep 2017;7: 2824. https://doi.org/10.1038/s41598-017-02733-w.