Sitagliptin Therapy in Kidney Transplant Recipients With New-Onset Diabetes After Transplantation

New-onset diabetes after transplantation (NODAT) remains a frequent and serious complication after kidney transplantation (1). We previously reported NODAT in our postkidney transplant population at a frequency of more than 50%, using the definition established by the 2003 International Guidelines (2). This high rate of posttransplant diabetes has serious negative consequences for future cardiovascular risk and survival after kidney transplant (3). Many factors contribute to NODAT, including age, genetic background, obesity, and the use of immunosuppressants (2, 4). Despite the elimination of chronic glucocorticoids and minimization of immunosuppressants, NODAT remains a difficult problem (4). An ideal agent should stimulate beta-cell function, improve insulin resistance, be easily administered, and well tolerated without hypoglycemia. Finally, as our data have shown, NODAT occurs within the first 3 months posttransplant, so any pharmacologic intervention must be given soon after transplantation (2). The incretin class of agents may be suitable as treatment, or even prevention, for NODAT. These agents include glucagon-like peptide-1 agonists and the dipeptidyl peptidase (DPP)-4 inhibitors. They stimulate beta-cell function, slow gastric emptying, and decrease insulin resistance (5). The glucagon-like peptide-1 agonists also suppress appetite but may cause nausea and cannot be used with a low glomerular filtration rate (GFR). This leaves the orally administered DPP-4 inhibitors as potential candidates because they can be used with low GFR, infrequently cause nausea, and have a low hypoglycemia potential (6). We designed a 3-month pilot study to demonstrate the feasibility of using the DPP-4 inhibitor, sitagliptin, in a population of renal transplant recipients who had been diagnosed with NODAT. The primary endpoints included the effect of sitagliptin on tacrolimus and sirolimus levels and changes to renal function. Secondary endpoints included side effects and change in HbA1c. Fifteen patients were recruited for a 3-month study through the University of Nebraska Medical Center (UNMC) Clinical Research Center. The study was approved by the UNMC Institutional Review Board. All patients met the definition of NODAT (1). Patients had an estimated GFR (eGFR) more than 30 ml/min according to the Modification of Diet in Renal Disease study, were free of other chronic illnesses, and had a HbA1c of 6.5% to 10.0%. Our immunosuppression regimen was free of glucocorticoids and used low-dose tacrolimus (target levels 2–4 ng/mL) and sirolimus (target levels 4–6 ng/mL) (7). Patients were treated with sitagliptin at a standard dose of 100 mg orally each day with dosing adjusted based on eGFR, per package insert. Tacrolimus and sirolimus levels and serum creatinine were obtained weekly, while HbA1c was measured at 0 and 12 weeks. Patients were aged 52.1±4.0 years (mean±SD), 11 of 15 were male, 12 of 15 were whites, and body mass index was 34.0±1.8 kg/m2. They had been diagnosed with NODAT 1.8±0.3 years and were 4.7±1.0 years posttransplant. Mean blood pressure on entry was 139±5/78±3 mm Hg. Figure 1 demonstrates that over the course of the study, there was no significant change in tacrolimus or sirolimus levels, using nonparametric repeated measures analysis of variance testing. Similarly, there was no change in eGFR over the course of the study. eGFR was 58.9±4.4 mL/min at entry and 60.5±5.6 mL/min at week 12. Neither tacrolimus nor sirolimus doses changed over the study. HbA1c improved from a baseline of 7.2%±0.1% to 6.7%±0.2% (P=0.002).FIGURE 1.: Mean drug levels for sirolimus, tacrolimus, and eGFR over time. eGFR, estimated glomerular filtration rate.No patient discontinued the use of sitagliptin because of side effects. No patients had symptomatic hypoglycemia, although some were on more than one agent for NODAT. Side effects included mild abdominal discomfort, loose stools, nausea, and headaches. It should be noted that the highest rates of NODAT occur in patients who receive calcineurin inhibitors for immunosuppression (1). In addition, sirolimus has also been associated with NODAT (4). It is interesting to note that despite exposure to tacrolimus and sirolimus, there was an improvement in HbA1c similar to that seen in other patients with type 2 diabetes (8). These results suggest that further studies should be pursued with DPP-4 inhibitors in patients with NODAT, as part of a comprehensive treatment plan. This might even extend to treatment of patients without NODAT during the first 6 months after transplant, when immunosuppressant exposure is the greatest. In conclusion, we have shown that sitagliptin, in a pilot study, is capable of inducing a clinically significant decrease in HbA1c in patients who have NODAT after kidney transplant, without altering tacrolimus or sirolimus drug levels or eGFR and with minimal side effects. James T. Lane1 David E. Odegaard1 Claire E. Haire1 Dean S. Collier2 Lucile E. Wrenshall3 R. Brian Stevens3 1 Department of Internal Medicine University of Nebraska Medical Center Omaha, NE 2 College of Pharmacy University of Nebraska Medical Center Omaha, NE 3 Department of Surgery University of Nebraska Medical Center Omaha, NE