Empagliflozin in posttransplantation diabetes mellitus: A prospective, interventional pilot study on glucose metabolism, fluid volume, and patient safety

Abstract

The safety and efficacy of sodium-glucose cotransporter 2 inhibitors in posttransplantation diabetes mellitus is unknown. We converted stable kidney transplant patients to 10 mg empagliflozin, aiming at replacing their insulin therapy (<40 IU/d). N = 14 participants (the required sample size) completed the study visits through 4 weeks and N = 8 through 12 months. Oral glucose tolerance test (OGTT)-derived 2-hour glucose (primary end point) increased from 232 ± 82 mg/dL (baseline) to 273 ± 116 mg/dL (4 weeks, P = .06) and to 251 ± 71 mg/dL (12 months, P = .41). Self-monitored blood glucose and hemoglobin A1c were also clinically inferior with empagliflozin monotherapy, such that insulin was reinstituted in 3 of 8 remaining participants. Five participants (2 of them dropouts) vs nine of 24 matched reference patients developed bacterial urinary tract infections (P = .81). In empagliflozin-treated participants, oral glucose insulin sensitivity decreased and beta-cell glucose sensitivity increased at the 4-week and 12-month OGTTs. Estimated glomerular filtration rate and bioimpedance spectroscopy-derived extracellular and total body fluid volumes decreased by 4 weeks, but recovered. All participants lost body weight. No participant developed ketoacidosis; 1 patient developed balanitis. In conclusion, although limited by sample size and therefore preliminary, these results suggest that empagliflozin can safely be used as add-on therapy, if posttransplant diabetes patients are monitored closely (NCT03113110).

Keywords: clinical research/practice; diabetes: new onset/posttransplant; endocrinology/diabetology; kidney (allograft) function/dysfunction; kidney transplantation/nephrology; metabolism/metabolite.

Figure 1

Study design. Glycemic profiles included blood glucose measurements 4 times daily by the patients themselves (blood glucose profiles). Renal function parameters were controlled at every visit. KTRs, kidney transplant recipients; PTDM, posttransplantation diabetes mellitus; OGTT, oral glucose tolerance test

Figure 2

Screening, enrollment, allocation, and completion of the study. KTRs, kidney transplant recipients; BG, blood glucose; eGFR, estimated glomerular filtration rate, PTDM, posttransplantation diabetes mellitus. The primary investigators of the study were able to personally screen approximately 900 of all 1120 patients for the diagnosis of posttransplantation diabetes mellitus during the inclusion period

Figure 3

Oral glucose tolerance test (OGTT) results. Blood glucose, insulin, and c‐peptide levels determined by a 75 g oral glucose tolerance test after insulin and empagliflozin treatment. Fasting and 2‐hour glucose levels increased from 111 ± 21 mg/dL and 232 ± 82 mg/dL to 144 ± 45 mg/dL (P = .005) and 273 ± 116 mg/dL (P = .06), respectively, at 4 weeks (N = 14) and to 128 ± 27 (P = .02) and 251 ± 71 (P = .41), respectively, at 12 months (N = 8). Bold lines: baseline; dotted lines: after 4 weeks of empagliflozin treatment

Figure 4

Participants' self‐monitored blood glucose profiles over 28 days. During the first 3 days of empagliflozin treatment, the insulin dosage was slowly reduced (wash‐out phase). Means and standard deviations of blood glucose levels are displayed as bold lines (blood glucose levels during the initial 4‐week period on insulin alone) and dotted lines (blood glucose levels during empagliflozin treatment). Differences in estimated means were calculated using a mixed linear model, between insulin‐ vs empagliflozin‐treated patients: Fasting: mean 114.2 ± 26.3 mg/dL vs 132.5 ± 28.8 mg/dL (95% CI −0.5 to 37 mg/dL, P = .06). Pre‐lunch: mean 131.6 ± 28.8 mg/dL vs 155.9 ± 49.7 mg/dL (95% CI −0.2 to 49 mg/dL, P = .05). Pre‐supper: mean 138 ± 37.9 mg/dL vs 158.8 ± 48.5 mg/dL (95% CI −4 to 46 mg/dL, P = .1). Post‐supper: mean 144.6 ± 43.6 mg/dL vs 152.5 ± 45.2 mg/dL (95% CI −21 to 37 mg/dL; P = .6)

Figure 5

Bacterial urinary tract infections. Kaplan–Meier curves for the study population (SP) vs the matched reference population (RP). “Proportion of event free” refers to urinary tract infections, dropping out, and end of study in the SP, but to urinary tract infections alone in the RP; P = .81 by log rank test. N, number of patients

Figure 6

Concept. OGTT, oral glucose tolerance test; KTRs, kidney transplant recipients