Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 7 1506-1514, 2007.

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New-onset diabetes is a significant comorbidity in patients who undergo what otherwise would be a life-extending procedure, namely resumption of normal kidney function by transplantation. The differences between standard immunosuppressive calcineurin inhibitors cyclosporine and tacrolimus have been pointed out before. Somewhat paradoxic, cyclosporine increases other risk factors for cardiovascular disease, such as hypertension and LDL cholesterol, compared with tacrolimus, which increases new-onset diabetes. This study compared de novo renal transplant patients who were on a regimen of basiliximab, mycophenolic acid, steroids, and either cyclosporine microemulsion or tacrolimus. The cyclosporine therapy was monitored by C2 sampling, and the tacrolimus was monitored by trough levels. This study was an attempt to compare the two most commonly used calcineurin inhibitors in terms of their metabolic consequences because cardiovascular death, presumably associated with abnormal risk factors in these patients, is the most common cause of death with a functioning transplant. Findings. This was an intention-to-treat study of 682 patients, 336 of whom were treated with cyclosporine microemulsion and 346 with tacrolimus. A total of 567 did not have diabetes at the baseline visit, and their risk for diabetes including steroid doses was similar at baseline. The end point was new-onset diabetes after transplantation or impaired fasting glucose at 6 mo. This was a multicenter study, and a variety of steroid protocols were used in these patients. It is pointed out by an editorialist for these articles that the dosages of steroids and target tacrolimus trough levels may be higher than is currently used in clinical practice and may partially account for the results obtained (1). The primary efficacy end point was biopsy-proven acute rejection, graft loss, or patient death at 6 mo. Renal function was estimated by the Cockcroft-Gault formula. There was statistically more diabetes in the tacrolimus patients, 96 of whom developed the end point of new-onset diabetes or fasting glucose intolerance. This represents 33.6% of the patients. Seventy-three cyclosporine microemulsion patients achieved this end point for a 26% prevalence. Efficacy was no different between the groups with an end point occurring in 43 (12.8%) cyclosporine microemulsion patients and 34 (9.8%) tacrolimus patients. Renal function as estimated by the formula was no different. BP was no different, but total cholesterol and LDL cholesterol were higher in cyclosporine compared with tacrolimus patients. It should be noted that the study was supported financially by Novartis. Commentary. This large, well-done clinical study points out what has been thought by transplant physicians, namely that the price for effective immunosuppression with both calcineurin inhibitors is an increased incidence of posttransplantation diabetes, which is obviously a major risk factor for cardiovascular disease. A recent review of this subject has appeared in the pages of the Clinical Journal of the American Society of Nephrology (2). Efficacy between the two immunosuppressive drugs is similar as noticed in previous studies. The trend toward less rejection with tacrolimus is again noted. The major criticism of this study is the higher steroid burden and the trough levels and thus the increased exposure to tacrolimus provided by the protocol. Both steroids and tacrolimus cause insulin resistance, contributing to the risk for posttransplantation diabetes. Thus, the differences between the two drugs are not terribly surprising and do favor the sponsor's compounds. For the physician contemplating which calcineurin inhibitor to use, the choice should be based on individual patient factors. These include the immunologic risk of the patients versus the risk for cardiovascular and metabolic complications. Individual choices can then be rationalized. We have two effective calcineurin inhibitors, and their differences and similarities should be considered in prescribing for the individual patient.