SGLT2 Inhibitors in Solid Organ Transplant Recipients with Type 2 Diabetes Mellitus

The increasing prevalence of type 2 diabetes in recent decades is the primary factor accounting for the substantial global increase in kidney failure. Currently, more than 3 million people worldwide are estimated to be receiving treatment for kidney failure, with predictions that the number will increase to more than 5 million by 2035 (1). Sodium-glucose cotransporter 2 (SGLT2) inhibitors were developed to lower blood glucose levels in patients with type 2 diabetes. These agents were studied in trials to meet the regulatory requirements for cardiovascular safety; in fact, they were found to reduce cardiovascular events. Further analysis of these trials suggested that SGLT2 inhibitors might improve kidney outcomes. The CREDENCE trial was designed to study SGLT2 inhibitors in diabetic kidney disease (DKD) patients with proteinuria, who are at high risk for microvascular and macrovascular complications. For the first time in two decades since renin-angiotensin system blockade was approved for use in DKD patients, this trial with SGLT2 inhibitors has revolutionized their treatment (1).

The three large population-based controlled trials with SGLT2 inhibitors were conducted primarily to assess for cardiovascular safety: 1) the Empagliflozin, Cardiovascular outcomes, and Mortality in type 2 diabetes (EMPA-REG OUTCOME) trial showed that empagliflozin was superior to placebo (2); 2) the Dapagliflozin Effect on Cardiovascular events–Thrombolysis in Myocardial Infarction 58 (DECLARE–TIMI 58) trial showed that dapagliflozin was noninferior to placebo (3); and 3) the Canagliflozin Cardiovascular Assessment Study (CANVAS) trial showed a lower risk of cardiovascular events in patients treated with canagliflozin than in those who received a placebo (4). A greater risk of amputation, primarily at the level of the toe or metatarsal area, was noted in these studies, and physicians were cautioned (4). Owing to the mechanism of SGLT2 inhibitors, glycosuria leads to an increased incidence of genitourinary infections (both bacterial and fungal) and an initial small decline in estimated eGFR as with renin-angiotensin aldosterone inhibitors (14).

The CREDENCE trial specifically studied the role of canagliflozin in DKD and showed a 30% lower risk in the event rate of ESRD, in comparison with the placebo group; doubling of serum creatinine; and cardiovascular death in the treatment group, which also had a lower risk of hospitalization for heart failure, cardiovascular death, myocardial infarction, or stroke, and hospitalization for heart failure. However, this trial excluded patients with nondiabetic kidney disease, with glomerulonephritis treated by immunosuppressive agents, or with a kidney transplant (1).

After solid organ transplantation, there is an increased risk of DKD, because of the recurrence of both pre-transplantation diabetes and post-transplantation diabetes mellitus (PTDM). PTDM has been reported to occur in 4% to 25% of kidney transplant recipients, 2.5% to 25% of liver transplant recipients, 4% to 40% of heart transplant recipients, and 30% to 35% of lung transplant recipients. PTDM occurred in 34.7%, 46.9%, and 56.2% of liver transplant patients at their 1-year, 3-year, and 5-year follow-up visits (5). This leads to substantial microvascular and macrovascular complications after transplantation. These complications eventually reduce the survival of allografts and patients.

SGLT2 inhibitors are an attractive therapeutic option for DKD patients after solid organ transplantation because this population has the most to gain. However, trials and consensus guidelines regarding the use of SGLT2 inhibitors are lacking; hence, they are not used for these patients. Lacking clinical trial data with reported adverse effects, the transplantation community is holding back on prescribing this therapy. In terms of clinical data, only a handful of case series or trials with SGLT2 inhibitors for solid organ post-transplantation patients with DKD, that analyze their efficacy, kidney outcomes, and safety, are available.

A single-center, prospective, double-blind randomized study with empagliflozin in 22 kidney transplant (KT) recipients (22 empagliflozin/22 placebo, 34 male patients) over 24 weeks showed a median change in glycated hemoglobin (HbA1c) by −0.2% (compared with −0.1% in the placebo group) and a reduction of 2.5 kg body weight versus a gain of 1 kg in the control group, with no significant differences in adverse events, interactions with immunosuppressants, or eGFR (6).

A case series of 10 post-KT recipients with PTDM but stable graft function and no recurrent urinary tract infections, treated with empagliflozin in addition to preexisting antidiabetic treatment, showed a stable median eGFR during follow-up for 12 months (7). The median HbA1c decreased by 0.2%. Two patients had urinary tract infections (UTI) with no long-term effect on kidney function, 1 patient had a creatinine increase of 0.3 mg/dL with no incidence of ketoacidosis, and 1 patient experienced a diabetic ulcer, which healed even during therapy with SGLT2 inhibitors.

A report of 10 KT and simultaneous kidney-pancreas transplant recipients who were given canagliflozin, with a follow-up time of >80.5 patient-months, showed a decrease in body weight by 2.1 kg, lower systolic and diastolic blood pressure (−6.5/−4.8 mm Hg), and decreased HbA1c by 0.84% (8). There were no increases in urinary or mycotic infections, acute allograft rejection, or acute kidney injury. A small change in eGFR (4.3 mL/min), similar to that in the general population, was observed.

In a case series, 8 living unrelated KT recipients (2 with a history of diabetes) received SGLT2 inhibitors (empagliflozin and dapagliflozin) and were followed up at 3 and 6 months. Their kidney function remained stable, with minor changes in HbA1c and body weight. Again, no increased incidence of UTI or fungal infection was reported (9).

In the only available report of SGLT2 inhibitors in heart transplant recipients (study group 22, control patients 79), transplant recipients receiving empagliflozin were followed up for 12 months and showed a reduction in body weight (−2 kg median body weight), body mass index (−1.3 kg/m2), and HbA1c, and a reduced need for diuretics (10). There were no large changes in blood pressure or kidney function. This group experienced three adverse events, including dizziness, acute kidney injury, and urinary symptoms, but no UTIs were noted.

None of these case series or studies demonstrated an increased risk of amputation, as reported in CANVAS (4). In the CREDENCE trial there was no significant difference in the risk of lower-limb amputation or rates of fracture (1

The Dapagliflozin in Chronic Kidney Disease (DAPA-CKD) results presented at the European Society of Cardiology Congress 2020 are the first to include nondiabetic CKD patients (32%). The study included 4304 participants from 21 countries randomized to Dapagliflozin and placebo. The primary outcome showed slower eGFR decline with improved ESKD outcomes and renal or CV death (hazard ratio 0.61; number needed to treat, 19). The side effect profile was not observed to be different from placebo. A few post-kidney transplant patients were part of the study. It will be interesting to see the analysis on this small cohort of patients and their baseline characteristics once the study is published.

In conclusion, SGLT2 inhibitors are no doubt an effective therapy for DKD, but their benefits regarding primary or secondary outcomes in solid organ transplant recipients are unclear. Theoretically, they appear to be a reasonable therapeutic choice in solid organ transplant recipients and can potentiate the benefit of transplantation in patient survival. SGLT2 inhibitors can be considered 6 months after transplantation, once allograft function is stable and kidney function is in a steady state.

Randomized controlled trials with SGLT2 inhibitors are warranted to better study the kidney and cardiovascular outcomes in all solid organ transplant recipients. These studies should be able to guide us in timing the initiation of therapy and in analyzing its efficacy, safety, drug–drug interactions, and its long-term impact on the immunologic makeup of individual patients. Both kidney and cardiovascular outcomes along with patient and allograft survival.

Notes

[1] Special thanks to Rakesh Gulati, MD, professor of nephrology, and Pooja Singh, MD, associate professor of nephrology, at Thomas Jefferson Hospital.

References

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October-November 2020 (Vol. 12, Number 10 & 11)