Sodium-glucose cotransporter-2 inhibitor use in kidney transplant recipients

Table 1 Summary of studies on sodium-glucose cotransporter-2 inhibitor use in kidney transplant recipients

Ref.	Type, location	Follow up	Treatment arms	Inclusion/exclusion criteria	Baseline eGFR (mL/min/1.73 m2), HgbA1c (%)	Time from transplant	Result	Adverse events/treatment discontinuation	Comments
Lemke et al[10], 2022	Retrospective, United States	12 mo; 27 pts ≥ 12 mo	Cana (n = 12); Dapa (n = 3); Empa (n = 24)	T2DM or PTDM; SGLT2i; 4/2013 to 10/2020; care solely in health system	eGFR, median (IQR) 69 (54-76); HgbA1c Median (IQR) 8.4 (7.8-9.2)	Median (IQR) 28 mo (16-60)	HbA1c↓ (8.4-7.5 at 3 mo; 7.5 at 12 mo; eGFR ↔/Cr ↔ at 3/12 mo; Wt ↓1.6 kg	UTI (n = 6; 3 required hospital stay; 1 ICU). Diabetic foot ulcer (n = 2). Hypoglycemia (n = 2; insulin n = 1, glipizide n = 1). No DKA, AKI dehydration requiring IVF, Fournier gangrene, Genital infection, fractures. Discontinued tx: n = 17 [d/c after a median (IQR) 244d (117-401)], n = 6 for cost, n = 4, eGFR, n = 3 infection, n = 1 poor wound healing, n = 1, hypoglycemia, n = 1 self d/c, n = 1, death unrelated to SGLT2i	38% on ACEi/ARB at initiation. Insufficient proteinuria data; Tac levels stable. 5/6 had prior UTI, 4/6 continued SGLT2i w/o recurrence
Lim et al[13], 2022	Retrospective, South Korea	62 mo ± 42 mo	Empa (n = 150). Dapa (n = 76) vs non-SGLT2i (n = 1857)	T2DM or PTDM Pancreas Transplant Prescribed SGLT2i < 90 from transplant	eGFR at 3 mo post-transplant 66.9 ± 17.7 vs 68.4 ± 20.1. HgbA1c at 3 mo post-transplant. Both 7.3 ± 1.4	Mean 3.8 yr ± 4.5	A risk primary outcome = composite outcome of all-cause mortality, DCGF, and SCr doubling: Multivariate [aHR (0.43; 95%CI = 0.24-0.78, P = 0.006) propensity score-matched; aHR (0.45; 95%CI = 0.24-0.85, P = 0.013)]. HbA1c = NR. eGFR stable at 8 mo. ↓SCr doubling significantly in unadjusted and adjusted models. Wt = NR	UTI/genital mycotic infection: (SGLT2i 4.5 events/100 patient-year vs non-SGLT2i 6.2/100 patient-year). No DKA. Discontinued txt: NR	15.6% eGFR dip over 10% during first month. eGFR recovered thereafter. 48.7% of the SGLT2i cohort was on ACEi/ARB. Composite all-cause mortality, DCGF, or SCr doubling in KTRs
Hisadome et al[12], 2021	Retrospective observational study, Japan	48 wk	SGLT2i (n = 29); Cana (n = 9); Empa (n = 4); Dapa (n = 3); Luseo (n = 5); Ipra (n = 7); Tofo (n = 1) vs Other oral glycemic agent (n = 60); DDP4i (n = 42); meglitinides (n = 9); metformin (n = 4); SU (n = 4) α-glucosidase	ESRD patients w/T2DM nephropathy pre-transplant PO hypoglycemic. Follow up at outside centers < 1 yr follow up. Missing data	eGFR mean ± SD: 50.4 ± 13.9; 47.5 ± 13.1. HgbA1c mean ± SD: 7.7 ± 0.9; 7.6 ± 1.1	NR	HgbA1c 7.7 -> 7.6 (same) vs 7.6 to 7.5. Wt -0.7 ± 5.1 kg vs 1.6 ± 4.5 kg. eGFR 50.4 -> 51.4 vs 47.5 to 46.3. BP went up (7 mmHg ± 20 vs -3 ± 24)	UTI 2:0; CV disease 0:2. BPAR 1:1. Discontinued txt: NR	71.2% of the SGLT2i group was also on ACEi/ARB. Stable tac levels (P = 0.755)
Song et al[14], 2021	Retrospective, United States	101 d	Empa (n = 43); Cana (n =6); Dapa (n = 1)	PTDM eGFR ≥ 30. AKI in prior ≤ 30 d. UTI in prior 6 mo	eGFR at initiation: Mean 66.7; 30-45 (n = 7; 14%) HbA1c mean ± SD: 7.1 ± 0.1	Median (IQR): 319.5 d (122-696). 40% within 200 d	ΔeGFR 3 mo: -1 mL/min; 6 mo: 1 mL/min. ΔHgbA1c 0.53%. Treated UTI 7 (14%). Approximately 20% typical rate. Change in insulin (-3.7 units ± 22.8). Wt (-2.95 kg ± 3.54, 95%CI 3.53-1.5). HgbA1c ↔; eGFR ↔; Wt↓. ΔMag2+ ↑ by 0.13	UTI (n = 7). D/C txt: n = 9 (5, UTI; 1 genital infection, 1; native disease; recurrence, 1 PTDM; resolution, 1; physician preference)	80% T2DM; 98% on prednisone; UTI rate comparable to KT population (14%)
AlKindi et al[8], 2020	Retrospective case series, United Arab Emirates	Range: 3 mo to 2 yr	Empa 10 mg n = 5; 25 mg n = 1. Dapa 25 mg n = 2	Diabetic KTRs; SGLT2i between 06/16-01/19	eGFR mean ± SD: 75.8 ± 13.4; HbA1c mean ± SD: 9.3 ± 1.4	mean ± SD: 9.6 yr ± 6.41	HgbA1c↓ (9.0 at 3 mo; 8.6 at 6 mo; 7.7 at 9 mo; 7.4 at 12 mo; eGFR ↔ median eGFR 72 (range 62-76) at 12 mo. Wt (mean wt 84.82 kg -> 82.87 at 3 mo -> 82.75 at 6 mo). BP not statistically significant though 9 pt difference	UTI + hospitalization (n = 1); pt w hx of UTI no UTI w ppx. Discontinuation rate: NR	2/8 T2DM; 6/8 PTDM; all LURKTx
Halden et al[9], 2019	Prospective, double blind, RCT Norway	6 mo	Cana 10 mg (n = 22). Placebo (n = 22)	≥ 18 yr; ≥ 1 yr post-transplant. PTDM only < 20% SCr deviation in last 2 mo. ≥ 3 mo stable immunosuppression. eGFR ≤ 30; Pregnant or nursing	eGFR Median (IQR) 66(57-68): 59 (52-72). HbA1c Median (IQR) 6.9 (6.5-8.2): 6.8 (6.1-7.2)	Median (IQR) 3 yr (1-16): 3 yr (1-15)	HbA1c↓ (6.9 to 6.7 vs 6.6 to 6.9); eGFR↓ (2 mo), ↔ (6 mo)-66 to 61 vs 59 to 59. Weight↓ (92 kg to 88.8 kg vs 84 to 85 kg). No real impact on BP. Hgb increase 13.9 to 14.5. ↓Uric acid. Tac/CSA/Siro levels stable	Urosepsis 1:0 (hx of recurrent UTI), UTI 3:3, genital infection 1:0, dizziness 2:0, hematuria 1:0. Discontinued txt: n = 2 (recurrent UTI, urosepsis): 3 (withdrew consent, colon cancer, no longer PTDM)	High DPP-4i use; most were not on additional therapy
Schwaiger et al[16], 2019	Prospective	1 mo (n = 14); 12 mo (n = 8)	Empagliflozin (n = 14). Reference (n = 24)	eGFR > 30; < 40 IU/d insulin. HgbA1c < 8.5. Adequately diagnosed PTDM	Baseline. eGFR 55.6. Baseline HgbA1c 6.5	Median 69.4 ± 57.2 mo	HgbA1c 6.5-> 6.6 at 4 wk (P > 0.05). eGFR 55.6 -> 47.5 at 4 wk (P > 0.05). Average TBW↓ 1.6 kg; Waist circ ↓4 cm. ECV/TBFV decreased	UTIs: 5:9. Genital infection: 1. AKI, DKA, Fournier’s-NR	100% on steroids. Median onset of PTDM was 0.5 months. 100% on insulin
Shah et al[11], 2019	Prospective	6 mo	Canagliflozin (n = 25)	≥ 18 years old. CrCl (ml/min) > 60; HgbA1c > 6.5; T2DM; PTDM. Unstable Cr. ALT > 2 × ULN; TBili > 2 × ULN; Recent UTI/genital mycotic infection	Baseline Cr (mg/dL): 1.1 ± 0.2; Baseline HgbA1c: 8.5 ± 1.5	Mean duration of transplant = 2.7 yr (0.2-13.2)	HgbA1c: 8.5 ± 1.5 -> 7.6 ± 1. Cr: 1.1 ± 0.2 -> 1.1 ± 0.3. Weight: 78.6 ± 12.1 -> 76.1 ± 11.2 (P < 0.05). SBP (mmHg): 142 ± 21 -> 134 ± 17 (P < 0.05)	No increase in UTI/genital infections. No hypoglycemia or DKA. Fatigue (n = 3). Discontinued treatment (n = 1)	20 T2DM; 5 PTDM. Reduction of other hypoglycemics needed. 1 KTR self d/ced. Used fixed 100 mg dose. Stable tac doses

eGFR: Estimated glomerular filtration rate; pts: Patients; Cana: Canagliflozin; Dapa: Dapagliflozin; Empa: Empagliflozin; T2DM: Type 2 diabetes mellitus; PTDM: Post-transplant diabetes mellitus; SGLT2i: Sodium-glucose cotransporter-2 inhibitor; IQR: Interquartile range; HgbA1c: Glycohemoglobin; Cr: Creatinine; Wt: Weight; UTI: Urinary tract infection; ICU: Intensive care unit; DKA: Diabetic ketoacidosis; AKI: Acute kidney injury; IVF: Intravenous fluids; txt: Treatment: d/c: Discontinued; ACEi: Angiotensin converting enzyme inhibitors; ARB: Aldosterone receptor blockers; tac: Tacrolimus; SCr: Serum creatinine; DCGF: Death censored graft failure; aHR: Adjusted hazard ratio; CI: Confidence interval; NR: Not reported; KTR: Kidney transplant recipient; Luseo: Luseogliflozin; Ipra: Ipragliflozin; Tofo: Tofogliflozin; DDP4i: Dipeptidyl peptidase 4 inhibitors; ESRD: End stage renal disease; PO: Oral; SD: Standard deviation; BP: Blood pressure; CV: Cardiovascular; BPAR: Biopsy proven acute rejection; Δ: Change in; Mag2+: Magnesium; KT: Kidney transplant; hx: History; ppx: Prophylaxis: LURKTx: Living unrelated kidney transplant; Hgb: Hemoglobin; CSA: Cyclosporine; siro: Sirolimus; IU: International units; TBW: Total body weight; circ: Circumference; ECV: Extracellular volume; TBFV: Total body fluid volume; CrCl: Creatinine clearance; ALT: Alanine transaminase; ULN: Upper limit of normal; TBili: Total bilirubin; SBP: Systolic blood pressure.