Onset and progression of diabetes in kidney transplant patients receiving everolimus or cyclosporine therapy: an analysis of two randomized, multicenter trials

Claudia Sommerer, Oliver Witzke, Frank Lehner, Wolfgang Arns, Petra Reinke, Ute Eisenberger, Bruno Vogt, Katharina Heller, Johannes Jacobi, Markus Guba, Rolf Stahl, Ingeborg A Hauser, Volker Kliem, Rudolf P Wüthrich, Anja Mühlfeld, Barbara Suwelack, Michael Duerr, Eva-Maria Paulus, Martin Zeier, Martina Porstner, Klemens Budde, ZEUS and HERAKLES study investigators, Claudia Sommerer, Oliver Witzke, Frank Lehner, Wolfgang Arns, Petra Reinke, Ute Eisenberger, Bruno Vogt, Katharina Heller, Johannes Jacobi, Markus Guba, Rolf Stahl, Ingeborg A Hauser, Volker Kliem, Rudolf P Wüthrich, Anja Mühlfeld, Barbara Suwelack, Michael Duerr, Eva-Maria Paulus, Martin Zeier, Martina Porstner, Klemens Budde, ZEUS and HERAKLES study investigators

Abstract

Background: Conversion from calcineurin inhibitor (CNI) therapy to a mammalian target of rapamycin (mTOR) inhibitor following kidney transplantation may help to preserve graft function. Data are sparse, however, concerning the impact of conversion on posttransplant diabetes mellitus (PTDM) or the progression of pre-existing diabetes.

Methods: PTDM and other diabetes-related parameters were assessed post hoc in two large open-label multicenter trials. Kidney transplant recipients were randomized (i) at month 4.5 to switch to everolimus or remain on a standard cyclosporine (CsA)-based regimen (ZEUS, n = 300), or (ii) at month 3 to switch to everolimus, remain on standard CNI therapy or convert to everolimus with reduced-exposure CsA (HERAKLES, n = 497).

Results: There were no significant differences in the incidence of PTDM between treatment groups (log rank p = 0.97 [ZEUS], p = 0.90 [HERAKLES]). The mean change in random blood glucose from randomization to month 12 was also similar between treatment groups in both trials for patients with or without PTDM, and with or without pre-existing diabetes. The change in eGFR from randomization to month 12 showed a benefit for everolimus versus comparator groups in all subpopulations, but only reached significance in larger subgroups (no PTDM or no pre-existing diabetes).

Conclusions: Within the restrictions of this post hoc analysis, including non-standardized diagnostic criteria and limited glycemia laboratory parameters, these data do not indicate any difference in the incidence or severity of PTDM with early conversion from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes.

Trial registration: clinicaltrials.gov , NCT00154310 (registered September 2005) and NCT00514514 (registered August 2007); EudraCT ( 2006-007021-32 and 2004-004346-40 ).

Keywords: Diabetes; Everolimus; Kidney transplantation; PTDM; Post-transplant; TOR inhibitor.

Conflict of interest statement

Ethics approval and consent to participate

All patients provided written informed consent. The study protocols were conducted in compliance with German law and approved by the independent ethics committee or institutional review board for each center, and the procedures followed in the trials were in accordance with the Declaration of Helsinki 1975, as revised in 2008.

Consent for publication

Not applicable.

Competing interests

Claudia Sommerer has received honoraria from Novartis, Chiesi and Sanofi, and her institution has received research funding from Chiesi, Astellas and Novartis.

Oliver Witzke has received research funds and/or honoraria from Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Janssen-Cilag, MSD, Novartis, Pfizer, Roche and Shire.

Frank Lehner has received research funds and/or honoraria from Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Hexal, Novartis, Pfizer and Roche Pharma.

Wolfgang Arns has received research funds and/or honoraria from Alexion, Astellas, Chiesi and Novartis.

Petra Reinke has received research funds, honoraria, advisory board from Teva, ThermoFisher, Pfizer, Astellas, Amgen, Baxalta; MSD and Pluriste.

Ute Eisenberger has received honoraria and/or travel expenses from Novartis Pharma, Astellas and Amgen.

Bruno Vogt has no conflicts of interest to declare.

Katharina Heller has no conflicts of interest to declare.

Johannes Jacobi has received honoraria from Roche.

Markus Guba has no conflicts of interest to declare.

Rolf Stahl has no conflicts of interest to declare.

Ingeborg A Hauser has received honoraria from Alexion, Astellas, Chiesi, Fresenius, Hexal, Novartis, Roche, Sanofi and Teva.

Volker Kliem has received honoraria and fees from Astellas, Novartis, Raptor and Fresenius.

Rudolf P Wüthrich has received fees for scientific advice from Astellas, Novartis, Roche and Wyeth (now Pfizer).

Anja Mühlfeld has no conflicts of interest to declare.

Barbara Suwelack has no conflicts of interest to declare .

Michael Duerr has received research funds from Bristol–Myers Squibb and travel grants from Novartis and Roche.

Martin Zeier has received research funding from Dietmar Hopp-Stiftung.

Martina Porstner is an employee of Novartis Pharma GmbH.

Eva-Maria Paulus is employee of Novartis Pharma GmbH and holds stock options.

Klemens Budde has received research funds and/or honoraria from Abbvie, Alexion, Astellas, Bristol-Myers Squibb, Chiesi, Fresenius, Genentech, Hexal, Novartis, Otsuka, Pfizer, Roche, Shire, Siemens, and Veloxis Pharma.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Patient disposition in (a) the ZEUS study (b) the HERAKLES study (safety populations). PTDM, posttransplant diabetes mellitus
Fig. 2
Fig. 2
Occurrence of posttransplant diabetes mellitus (PTDM) in (a) the ZEUS study (b) the HERAKLES study (Kaplan-Meier estimates) CsA, cyclosporine
Fig. 3
Fig. 3
Mean random blood glucose concentrations from time of transplant to month 12 in (a) the ZEUS study and (b) the HERAKLES study. CsA, cyclosporine; PTDM, posttransplant diabetes mellitus

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