Chances and risks of sodium-glucose cotransporter 2 inhibitors in solid organ transplantation: A review of literatures

Table 1 Criteria for the diagnosis of diabetes mellitus in patients with and without solid organ transplantation

Criteria for the diagnosis of diabetes
FPG	≥ 126 mg/dL (7.0 mmol/L), fasting means no caloric intake for at least 8 h
2-h PG	≥ 200 mg/dL (11.1 mmol/L) during OGTT
HbA1c	≥ 6.5% (48 mmol/L)
	Random plasma glucose ≥ 200 mg/dL (11.1 mmol/L), in a patient with classic symptoms of hyperglycaemia or hyperglycaemic crisis

At least one of the above-named criteria must be fulfilled for the diagnosis of diabetes. 2-Hpg: 2-h-plasma glucose; FPG: Fasting plasma glucose; HbA_1c: Haemoglobin A1c; OGTT: Oral glucose tolerance test.

Table 2 Retrospective studies, case series and prospective randomised and non-randomised studies investigating sodium-glucose cotransporter 2 inhibitors in solid organ transplantation recipients

Ref.	Type	Patients	Endpoint	Findings
Lo et al[13]	Review of 7 intervention studies	KTRs: 3: Insulin therapy (more or less intensive); 3: Dipeptidylpeptidase 4-inhibitors for new-onset diabetes after transplantation; 1: Pioglitazone with insulin to insulin alone for treating pre-existing diabetes	Effectiveness and safety of glucose-lowering agents in this population.	Safety and efficacy of glucose-lowering agents in transplant recipients are uncertain due to data being limited and of poor quality; more studies are required to confirm the effectiveness and safety of glucose-lowering agents.
Schwaiger et al[51]	Prospective, nonrandomised interventional pilot study	KTRs (n = 14, all received exogenous insulin therapy [< 40 IU per day (total)]	Intra-individual difference in 2-h glucose level between first OGTT at baseline and second OGTT after 4-wk empagliflozin monotherapy.	Glucose control under empagliflozin monotherapy was clinically inferior compared to prior exogenous insulin treatment (glucose levels during second OGTT higher than baseline); statistically significant reduction in body mass index, body weight and waist circumference; bacterial urinary tract infections in 3 patients during study period; empagliflozin can safely be used as add-on therapy, if PTDM patients are monitored closely.
Halden et al[50]	Single-centre, prospective, randomised, placebo con-trolled, double blinded study	KTRs (n = 49)	Investigation whether empagliflozin can be used safely to improve glucose metabolism in KTRs with PTDM.	Glycaemic control significantly improved compared with placebo; empagliflozin treatment was associated with a concomitant, significant reduction of body weight; one case of urosepsis observed, but relationship to drug treatment is uncertain; no significant differences between groups in adverse events, immunosuppressive drug levels or estimated glomerular filtration rate.
Cehic et al[52]	Retrospective, nonrandomised single-centre observational study	Heart transplant recipients (total n = 101, 22 empagliflozin, 79 alternative glucose-lowering therapies)	Investigate the safety of empagliflozin in postheart transplant diabetic population; focus on incidence of genitourinary infections; long-term (after 12 mo) effectiveness.	No genitourinary tract infections in the empagliflozin-treated group compared with 9 urinary infections in the control group; significant reduction in median body weight, median body mass index and median furosemide dose after 12 mo of treatment with empagliflozin; HbA1c was reduced in the empagliflozin group, during patients in the control group experienced a mean increase in HbA1c; although the reduction in HbA1c was not statistically significant (P = 0.07), data suggest empagliflozin was efficacious for improving glycaemic control; overall, empagliflozin was well tolerated and can be safely used as a long-term option.
AlKindi et al[53]	Case series supported by literature review	KTRs (n = 8)	Description of the short-term experience of KTRs treated with empagliflozin (n = 6) and dapagliflozin (n = 2).	Significant reduction in HbA1c, weight and BMI; no episodes of severe hypoglycaemia or symptomatic ketoacidosis during the study period; the use of SGLT2 inhibitors among diabetic renal transplant patients was both effective and safe.
Rajasekeran et al[54]	Case series (n = 10)	KTRs (n = 6) and SPKTR (n = 4)	Description of the short-term experience of KTR and SPKTR treated with canagliflozin.	No urinary or mycotic infections diagnosed during treatment; one patient experienced hypoglycaemia that did not require hospitalization; one patient developed cellulitis; no patients experienced acute rejection or acute kidney injury. In this small cohort, canagliflozin was generally well tolerated. They observed an overall improvement in glycaemic control, weight and blood pressure.
Peláez-Jaramillo et al[55]	Literature review	LTR	Current knowledge on the epidemiology, pathogenesis, course of disease and medical management of PLTDM.	PLTDM should be screened for, timely diagnosed and intensively managed. Clinicians in charge of caring for LTR should bear in mind key concepts about PLTDM.
Cigrovski Berkovic et al[56]	Literature review	LTR	Exploration of the relationships and mechanisms between diabetes mellitus and liver disease bevor and after liver trans-plantation, especially in the term of non-alcoholic fatty liver disease.	The pharmacological management of PTDM is still complicated because there are no published randomised clinical trials about effectiveness and safety of antihyperglycaemic agents.
Attallah et al[57]	Case series (n = 8)	KTRs	Description of the short-term experience of KTR treated with empagliflozin.	The use of empagliflozin to manage diabetes mellitus after kidney transplantation was tolerated; small number and in general mild side effects.
Beshyah et al[58]	Mixed methods: Case report, surveys of physicians’ opinions, and a review of the literature	KTRs	Case report: Off-label use of dapagliflozin in a patient with diabetes mellitus and renal transplantation.	The index case suggests the safe use of SGLT2 inhibitors by renal transplant recipients. It seemed that physicians are willing to use SGLT2 inhibitors in such patients if the renal function is satisfactory.

BMI: Body mass index; HbA_1c: Haemoglobin A1c; KTR: Kidney transplant recipient; LTR: Liver transplant recipients; OGTT: Oral glucose tolerance test; PLTDM: Post-liver trans-plant diabetes mellitus; PTDM: Post-transplant diabetes mellitus; SGLT2: Sodium-glucose cotransporter 2.