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New-onset diabetes after renal transplantation: comparing ciclosporin and tacrolimus

Original article Vincenti F et al. (2007) Results of an

international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 7: 15061514

S Y NO P S I S
keywords ciclosporin, impaired fasting glucose, new-onset diabetes, renal transplantation, tacrolimus

defined by the American Diabetes Association and the WHO), evaluated in patients who were nondiabetic at transplantation. The primary efficacy end point was a composite of biopsy-proven acute rejection, graft loss and death, evaluated in the entire study population. Both end points were assessed 6months after transplantation.
RESULTS

BACKGROUND

Meta-analyses and registry data imply that tacrolimus is associated with a greater incidence of new-onset diabetes after transplantation (NODAT) than is ciclosporin.
OBJECTIVE

To compare the effects of ciclosporin and tacrolimus on the rate of development of glycemic abnormalities in renal transplant recipients.
DESIGN

Adults aged 70years who were scheduled to receive a first or second renal transplant were recruited for the open-label, international DIRECT study. Recipients of grafts from nonheartbeating donors and from donors with hepatitis B or C were excluded.
INTERVENTION

After stratification according to ethnicity (white or nonwhite) and the presence or absence of diabetes, participants were randomized on a 1:1 basis to receive tacrolimus (starting dose 0.2mg/kg/day) or ciclosporin microemulsion (starting dose 10mg/kg/day) in addition to steroids, mycophenolate and basiliximab. Ciclosporin C2 (2-hour post-dose) targets were 1,600ng/ml during month 1, 1,400ng/ml during months 2 and 3, and 1,000ng/ml thereafter; tacrolimus C0 (trough) targets were 1015ng/ml during the first 3months and 510ng/ml thereafter. Analysis was by intention to treat.
OUTCOME MEASURES

The intention to treat population comprised 682 patients, most of whom (83% [567]) were nondiabetic at transplantation. There were no significant differences in baseline demographic or clinical characteristics between the patients who were randomized to receive ciclosporin (n=336) and those who were randomized to receive tacrolimus (n=346). Median cumulative steroid doses were also similar in the two groups. There were 36 cases of study discontinuation or loss to follow-up. The safety end point occurred less often in ciclosporin-treated patients than in tacrolimus-treated patients (26.0% [73] vs 33.6% [96]; P=0.046); the efficacy end point occurred in similar proportions of patients in the two groups (12.8% [43] and 9.8% [34], respectively; P=0.211). Noninferiority testing confirmed that ciclosporin was noninferior to tacrolimus for the efficacy end point. Mean Cockcroft Gault-estimated glomerular filtration rates were similar in the ciclosporin group and the tacrolimus group at 6months (63.6ml/min/1.73m2 and 65.9ml/min/1.73m2, respectively). In total, 71 (21.1%) patients discontinued ciclosporin and 39 (11.3%) discontinued tacrolimus. Peripheral edema and cytomegalovirus infection were more common in the ciclosporin group (P=0.003 for both); diarrhea and tremor occurred more often in the tacrolimus group (P<0.001 and P=0.022, respectively).
CONCLUSION

The primary safety end point was development of NODAT or impaired fasting glucose (IFG; as

Compared with ciclosporin, tacrolimus is associated with a higher risk of developing NODAT or IFG during the first 6months after renal transplantation.

20 nature clinical practice NEPHROLOGY

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CO M M ENTARY Richard Moore

The DIRECT study is the first trial undertaken specifically to compare the risks of NODAT in patients receiving ciclosporin and those receiving tacrolimus. The findings are consistent with those of a previous large-scale registry analysis, which indicated that NODAT develops in up to one-fifth of renal transplant recipients.1 In the DIRECT trial, almost 30% of patients developed NODAT or IFG within 6months after transplantation. Diabetes is associated with a 63% increase in the risk of graft loss in renal transplant patients and an increase of almost 90% in the risk of death, largely because of excess cardiovascular mortality.1 Systematic screening for abnormalities of glucose metabolism should now be routine, both in patients awaiting renal transplantation and in the post-transplantation population. International guidelines2 recommend that wait-listed patients regularly undergo fasting plasma glucose (FPG) evaluation and oral glucose tolerance testing to identify those who have overt diabetes or are at high risk of developing NODAT. FPG testing should be routinely performed after transplantation regardless of previous diabetic status. Oral glucose tolerance testing is mandatory in transplant recipients with abnormal FPG, and should preferably be undertaken regularly in all patients as it is more sensitive and specific than FPG for diagnosing diabetes3 and (unlike FPG testing) it can detect impaired glucose tolerance. Diagnosis of impaired glucose tolerance is important as this condition is more predictive of increased cardiovascular risk than is FPG. The DIRECT study used the diagnostic criteria for diabetes and IFG established by the American Diabetes Association and the WHO, which should be adopted by all transplantation centers. The DIRECT study indicates that the risk of NODAT or IFG during the first 6months after transplantation is significantly lower with ciclosporin than with tacrolimus. This finding is consistent with that of a recent meta-analysis of earlier trials.4 No apparent difference in efficacy was observed between the two agents, although more patients discontinued ciclosporin than tacrolimus. Thus, in patients with overt diabetes and those who have IFG with other

risk factors for NODAT (e.g. obesity), de novo immunosuppression with ciclosporin instead of tacrolimus might be appropriate. The choice of immunosuppressant does need, however, to take into account the higher rate of acute rejection observed with ciclosporin-based regimens than with tacrolimus-based regimens in other clinical trials. Interestingly, the corticosteroid dose in DIRECT was significantly higher among ciclosporin-treated patients who developed NODAT or IFG than among those who did not, underscoring the need to taper corticosteroids as early as possible in patients at high risk of diabetes who are receiving ciclosporin. Steroid dose does not seem to affect the risk of diabetes in tacrolimus-treated individuals. The DIRECT findings imply that there is a difference between the diabetogenic mechanisms of the two calcineurin inhibitors. Insulin secretion was reduced to a greater extent with tacrolimus than with ciclosporin (as has been reported previously invitro5). Insulin sensitivity was, however, similar in the two treatment groups. The DIRECT study highlights the high incidence of abnormalities of glucose metabolism in renal transplant recipients. It reinforces the importance of protocol-based surveillance of wait-listed and post-transplantation patients for such abnormalities, to allow individualized modification of immunosuppression that takes into account the diabetic risk status of each patient and the likelihood of graft rejection.
References 1 Kasiske BL et al. (2003) Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 3: 178185 2 Davidson J et al. (2003) New-onset diabetes after transplantation: 2003 international consensus guidelines. Proceedings of an international expert panel meeting. Barcelona, Spain, 19 February 2003. Transplantation 75 (Suppl): SS3SS24 3 Sharif A et al. (2006) The use of oral glucose tolerance tests to risk stratify for new-onset diabetes after transplantation: an underdiagnosed phenomenon. Transplantation 82: 16671672 4 Webster AC et al. (2005) Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 331: 810814 5 Redmon JB et al. (1996) Effects of tacrolimus (FK506) on human insulin gene expression, insulin mRNA levels, and insulin secretion in HIT-T15 cells. J Clin Invest 98: 27862793

Acknowledgments
The synopsis was written by Chlo Harman, Associate Editor, Nature Clinical Practice.

Competing interests
The author declared associations with the following companies: Astellas, Novartis, Roche, Wyeth. See the article online for full details of the relationships.

Correspondence
University Hospital of Wales Transplant Unit Heath Park Cardiff CF14 4XW UK richard.moore@ cardiffandvale.wales.nhs.uk
Received 15 August 2007 Accepted 6 September 2007 Published online 16 October 2007
www.nature.com/clinicalpractice doi:10.1038/ncpneph0640

PRACTICE POINT

R Moore is a Consultant Nephrologist and Clinical Director of Nephrology and Transplantation at the University Hospital of Wales, Cardiff, UK.

Screening for abnormalities of glucose metabolism should be routine in patients before and after renal transplantation; immunosuppression should be modified according to the risk of new-onset diabetes mellitus and the likelihood of acute rejection

January 2008 vol 4 no 1 

nature clinical practice NEPHROLOGY 21