Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus

Abstract

IntroductionDespite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization.MethodsWe conducted an open-label, multicenter, randomized trial testing whether a tacrolimus-based immunosuppression and rapid steroid withdrawal (SW) within 1 week (Tac-SW) or cyclosporine A (CsA) with steroid minimization (SM) (CsA-SM), decreased the incidence of PTDM compared with tacrolimus with SM (Tac-SM). All arms received basiliximab and mycophenolate mofetil. High risk was defined by age >60 or >45 years plus metabolic criteria based on body mass index, triglycerides, and high-density lipoprotein–cholesterol levels. The primary endpoint was the incidence of PTDM after 12 months.ResultsThe study comprised 128 de novo renal transplant recipients without pretransplant diabetes (Tac-SW: 44, Tac-SM: 42, CsA-SM: 42). The 1-year incidence of PTDM in each arm was 37.8% for Tac-SW, 25.7% for Tac-SM, and 9.7% for CsA-SM (relative risk [RR] Tac-SW vs. CsA-SM 3.9 [1.2–12.4; P = 0.01]; RR Tac-SM vs. CsA-SM 2.7 [0.8–8.9; P = 0.1]). Antidiabetic therapy was required less commonly in the CsA-SM arm (P = 0.06); however, acute rejection rate was higher in CsA-SM arm (Tac-SW 11.4%, Tac-SM 4.8%, and CsA-SM 21.4% of patients; cumulative incidence P = 0.04). Graft and patient survival, and graft function were similar among arms.ConclusionIn high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Balancing Immunosuppressive Efficacy and Prevention of Posttransplant Diabetes—A Question of Timing and Patient Selection

“…Similar to the study by Torres et al. , 1 older patients are frequently transplanted with organs from older donors with age-related chronic damage that can be further worsened by ischemia-reperfusion injury and delayed graft function. In this context, calcineurin inhibitor minimization is probably the best intervention to avoid the added detrimental effect of chronic calcineurin inhibitor nephrotoxicity on an already damaged graft.…”

“…In conclusion, the study by Torres et al. 1 provided additional evidence that cyclosporine is considerably less diabetogenic than tacrolimus but is associated with a higher incidence of acute rejection, particularly when used at a relatively low dose in association with systematic steroid withdrawal by 6 months. In this setting, tacrolimus-based immunosuppression with steroid withdrawal after the early posttransplant phase provides the optimal immunosuppressive regimen for the large majority of patients.…”

“…The prospective and randomized multicenter study from Spain by Torres et al. 1 in the present issue of KI Reports is a significant contribution in this respect, and provides important information on the potential pitfalls.…”

“…In the quest to balance the risk of adverse graft outcomes and metabolic side effects, systematic steroid withdrawal like in the trial by Torres et al. 1 is probably not the best choice in the majority of patients at risk for PTDM.…”

Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets

“…In that study, the low-dose VCS group had similar efficacy to TAC in controlling acute rejection with a significantly decreased incidence of NODAT (1.6% vs 16.4%, respectively; P = 0.031) ( 4 ). In the AURA study for lupus nephritis, 1.1% of patients receiving VCS (23.7 mg) and 1.1% of patients in the placebo group reported diabetes ( 5 ), contrasting with NODAT in 25.7% of patients while taking a standard dose of TAC for 1 year ( 6 ). Thus, there is an unexplained difference between the clinical diabetes seen after treatment with VCS versus the currently prescribed immunosuppressants TAC and CsA.…”