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

Armando Torres, Domingo Hernández, Francesc Moreso, Daniel Serón, María Dolores Burgos, Luis M Pallardó, Julia Kanter, Carmen Díaz Corte, Minerva Rodríguez, Juan Manuel Diaz, Irene Silva, Francisco Valdes, Constantino Fernández-Rivera, Antonio Osuna, María C Gracia Guindo, Carlos Gómez Alamillo, Juan C Ruiz, Domingo Marrero Miranda, Lourdes Pérez-Tamajón, Aurelio Rodríguez, Ana González-Rinne, Alejandra Alvarez, Estefanía Perez-Carreño, María José de la Vega Prieto, Fernando Henriquez, Roberto Gallego, Eduardo Salido, Esteban Porrini, Armando Torres, Domingo Hernández, Francesc Moreso, Daniel Serón, María Dolores Burgos, Luis M Pallardó, Julia Kanter, Carmen Díaz Corte, Minerva Rodríguez, Juan Manuel Diaz, Irene Silva, Francisco Valdes, Constantino Fernández-Rivera, Antonio Osuna, María C Gracia Guindo, Carlos Gómez Alamillo, Juan C Ruiz, Domingo Marrero Miranda, Lourdes Pérez-Tamajón, Aurelio Rodríguez, Ana González-Rinne, Alejandra Alvarez, Estefanía Perez-Carreño, María José de la Vega Prieto, Fernando Henriquez, Roberto Gallego, Eduardo Salido, Esteban Porrini

Abstract

Introduction: Despite the high incidence of posttransplant diabetes mellitus (PTDM) among high-risk recipients, no studies have investigated its prevention by immunosuppression optimization.

Methods: We 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.

Results: The 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.

Conclusion: In high-risk patients, tacrolimus-based immunosuppression with SM provides the best balance between PTDM and acute rejection incidence.

Keywords: cyclosporin A; posttransplant diabetes; posttransplant hyperglycemia; renal transplantation; steroid withdrawal; tacrolimus.

Figures

Figure 1
Figure 1
Patient disposition. CNI, calcineurin inhibitor; CsA-SM, cyclosporine A and steroid minimization; I.C., inclusion criteria; DFG: death with a functioning graft; Tac-SM, tacrolimus and steroid minimization; Tac-SW, tacrolimus and rapid steroid withdrawal.
Figure 2
Figure 2
Glucose homeostasis alterations 3 months after transplantation in each study arm. (a) Fasting plasma glucose. (b) Proportion of patients with posttransplant diabetes (PTDM) according to criterion 1. (c) Proportion of patients with PTDM according to criterion 2. CsA-SM, cyclosporine A and steroid minimization; Tac-SM, tacrolimus and steroid minimization; Tac-SW, tacrolimus and rapid steroid withdrawal. *P < 0.05 CsA-SM versus Tac-SW or Tac-SM; **P < 0.05 CsA-SM versus Tac-SW.
Figure 3
Figure 3
Glucose homeostasis alterations 12 months after transplantation (end of study) in each study arm. (a) Proportion of patients with posttransplant diabetes (PTDM) according to criterion 1. (b) Proportion of patients with PTDM according to criterion 2. (c) Proportion of patients requiring treatment with hypoglycemic drugs. CsA-SM, cyclosporine A and steroid minimization; Tac-SM, tacrolimus and steroid minimization; Tac-SW, tacrolimus and rapid steroid withdrawal. *P < 0.01; **P < 0.05; ***P = 0.06.
Figure 4
Figure 4
Evolution of glucose homeostasis alterations in each study arm from 3 to 12 months after transplantation. CsA-SM, cyclosporine A and steroid minimization; IGT, impaired glucose tolerance; PTDM, posttransplant diabetes; Tac-SM, tacrolimus and steroid minimization; Tac-SW, tacrolimus and rapid steroid withdrawal.
Figure 5
Figure 5
Cumulative incidence of biopsy-proven acute rejection (BPAR) in each study arm. Log-rank test P = 0.04. CsA-SM, cyclosporine A and steroid minimization; Tac-SM, tacrolimus and steroid minimization; Tac-SW, tacrolimus and rapid steroid withdrawal.
Figure S1
Figure S1
Noncensored graft (A) and patient survival (B) in each study arm. Log-rank test P = 0.9 and P = 0.8, respectively. CsA-SM, cyclosporine A and steroid minimization; Tac-SM, tacrolimus and steroid minimization; Tac-SW, tacrolimus and rapid steroid withdrawal.

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Source: PubMed

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