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

Diabetic nephropathy is now the most frequent indication for kidney transplantation, accounting for approximately a third of kidney transplants in the US [1], and is set to grow in frequency as the prevalence of diabetes continues to grow [2, 3]. Additionally, under conventional immunosuppressive regimens, up to 20% of kidney transplant recipients develop posttransplant diabetes mellitus (PTDM) [4‐6]. Both pre-existing diabetes [7, 8] and PTDM [9] are associated with an increased risk of cardiovascular events [9, 10] and inferior long-term survival, as well as morbidity from diabetes-related complications [7, 11]. The diabetogenic effect of calcineurin inhibitors (CNIs), particularly tacrolimus [4, 12] and steroids [5], can be compounded by maintenance steroid therapy, especially pulsed steroid therapy for the treatment of rejection [13]. In this unfavorable context, novel immunosuppressive regimens must be carefully evaluated in terms of their diabetogenic potential.

The mammalian target of rapamycin (mTOR) inhibitor agents sirolimus and everolimus have been widely assessed within a variety of regimens for de novo or delayed initiation following kidney transplantation [14]. mTOR inhibitors offer the potential for CNI sparing, which might be expected to lower the risk for PTDM [15]. However, results from the early era of sirolimus therapy in kidney transplantation raised concerns that the class may have an inherent diabetogenic effect [16, 17]. In a large randomized trial of sirolimus published in 2006, Vitko et al. reported an increased rate of PTDM in patients randomized to a loading dose (6 mg) and a fixed dose of 2 mg/day versus mycophenolate mofetil when both were administered in combination with standard-dose tacrolimus and steroids [18]. Although smaller trials using fixed sirolimus dosing [19, 20] or high sirolimus exposure targets [21] did not demonstrate any effect, an analysis of United States Renal Data System data from over 20,000 patients undergoing kidney transplantation during 1995–2003 concluded that patients treated with sirolimus were at increased risk of PTDM whether administered in combination with a CNI or an antimetabolite [22]. In contrast, a large meta-analysis published in 2006 found that use of mTOR inhibitors was not associated with any increased risk of developing insulin-treated PTDM compared to antimetabolite therapy [23].

As experience with mTOR inhibitors has grown, fixed dosing has been replaced by progressively lower trough concentration targets, and concomitant CNI exposure has been reduced [14]. Loading doses for sirolimus have typically become smaller, and no loading dose is required for everolimus due to its shorter half-life. In large, randomized trials undertaken recently, no increase in the rate of PTDM was observed in the sirolimus [24, 25] or everolimus [26, 27] treatment arms.

Conversion to an mTOR inhibitor from CNI therapy after the first 3–12 months post-transplant is an appealing immunosuppressive strategy, harnessing the potent immunosuppressive effect of CNIs during the period of highest risk for rejection but taking advantage of the reduced nephrotoxicity associated with mTOR inhibitors [28]. To date, no analyses are available concerning the impact of conversion to an mTOR inhibitor on PTDM or the progression of pre-existing diabetes. We report here a post hoc analysis of diabetic parameters in two large, multicenter trials (ZEUS [29] and HERAKLES [30]) in which de novo kidney transplant recipients were randomized to either convert to everolimus in a CNI-free regimen or to remain on a standard cyclosporine (CsA)-based regimen, or in one study to alternatively switch to everolimus with reduced-exposure CsA.

Results from this post hoc analysis of two large randomized studies do not suggest any difference in the incidence or severity of PTDM in patients who were converted early post-transplant from a CsA-based regimen to everolimus, or in the progression of pre-existing diabetes. Kaplan-Meier estimates showed comparable rates of PTDM in the different treatment cohorts after randomization in both studies to month 12, with similar patterns of random blood glucose concentration over time in the subpopulations with or without PTDM or pre-existing diabetes. The number of patients who developed PTDM after randomization was identical in the everolimus group or the standard CsA group, but absolute numbers were very low, even within this large pooled cohort, so firm conclusions cannot be drawn.

The progressive renal deterioration which is frequently associated with diabetes in the general population has also been documented in patients with PTDM [33, 34], so any potential benefit for preservation of renal function may be particularly relevant in this subpopulation. Here, the change in eGFR from randomization to month 12 in patients receiving everolimus within a CNI-free regimen which was achieved in the overall study populations at month 12 [29, 30] was also observed in the subpopulation of patients with PTDM, although the small numbers of patients precluded any statistical differences. Mean eGFR in patients randomized to CNI-free therapy with everolimus in patients with PTDM improved by 14 mL/min/1.73m² in the ZEUS study and by 4.9 mL/min/1.73m² in HERAKLES by month 12. Among patients with pre-existing diabetes, there was a numerically greater improvement in renal function from randomization to month 12 in the CNI-free cohorts of both trials versus the comparator groups.

Certain aspects of the analysis should be taken into account. First, PTDM was included from the time of transplant, with few events in either group after randomization, and the onset of PTDM was collected by standard adverse event reporting, with no pre-specified criteria. In the DIRECT study [4], in which data on HbA1_c, insulin level and oral glucose tolerance testing were collected prospectively to month 6 in patients receiving a standard CsA-based regimen, the incidence of treated PTDM was 7.4% but a further 7.4% had untreated PTDM based on American Diabetes Association criteria (14.8% overall) [35]. Based on the 6.8–8.0% incidence of PTDM reported by 12 months in the current studies, it is likely that the standard reporting adverse event techniques did not capture all cases of PTDM. However, since it seems reasonable to assume that centers applied the same procedures for monitoring and defining PTDM regardless of patients’ immunosuppressive treatment, it is unlikely that this will have biased diagnosis rates between treatment arms. Second, oral glucose tolerance tests were not recorded and HbA1_c levels were not measured, with the only available laboratory test being random blood glucose levels. This is a weakness of the analysis. The presence of hyperglycemia could be recorded as an adverse event by investigators, but no strict reporting checks for this value were in place, hence reporting of hyperglycemia is not fully reliable. Information on antidiabetic therapy was captured by standard documentation of concomitant medication, and may have been incomplete despite the strict external monitoring. Third, the analysis does not address the relative diabetogenic effect of everolimus and CsA during the very early post-transplant period (up to month 3), when the rate of onset of glucose metabolism disturbances, hyperglycemia and onset of PTDM can be highest [4, 36]. Fourth, the results presented here apply only to conversion from CsA (not tacrolimus) to everolimus after the initial weeks post-transplant. Tacrolimus, now the dominant CNI, is widely regarded to be more diabetogenic than CsA [37, 38]. Fifth, the studies were not powered to detect differences within subpopulations for the primary endpoint (eGFR at month 12) or to detect differences in any of the endpoints which were specified post hoc. Indeed, even with this large pooled dataset, the number of patients who developed PTDM after randomization was very small, restricting interpretation. Lastly, the follow-up period (a maximum of nine months after randomization) was too short to assess any long-term effect of CNI administration on late-onset PTDM or progression of pre-existing diabetes.

Within the limitations of this post hoc analysis, including an absence of pre-specified diagnostic criteria for PTDM or extensive laboratory data, conversion from a CsA-based regimen to everolimus in combination with mycophenolic acid and steroids within the first six months after kidney transplantation does not appear to affect the subsequent risk of developing PTDM, or adversely affect the progression of pre-existing diabetes. This finding from the subgroup analysis adds to the observed benefit on renal function after switching to everolimus-based therapy with CNI-withdrawal seen from the main study analyses.