Abstract and Introduction
Abstract
DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2 Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novo renal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C2 monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft-Gault) was 63.6 ± 20.7 mL/min/1.73 m in the CsA-ME cohort and 65.9 ± 23.1 mL/min/1.73 m with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.
Introduction
Development of new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) after renal transplantation increases the risk of cardiac events, peripheral vascular disease, graft failure and death. Indeed, diabetes confers a higher risk of ischemic heart disease than hypertension, smoking or severe hyperlipidemia in renal transplant patients, and onset of diabetes after transplantation is associated with more than a 60% increase in risk of graft failure and an almost a 90% increase in risk of death. Less severe hyperglycemic abnormalities are also associated with increased cardiovascular risk. In the general population, the DECODE study in 25 413 individuals has shown conclusively that fasting glucose level is significantly related to 5- and 10-year cardiovascular mortality, while in the renal transplant setting Cosio et al. have demonstrated that IFG (5.6-6.9 mmol/L) is associated with a significantly higher incidence of posttransplant cardiac events and peripheral vascular disease compared to normoglycemic recipients. However, since few studies have used the American Diabetes Association (ADA) or World Health Organization (WHO) definitions for NODAT or IFG, and fewer have employed oral glucose tolerance testing (OGTT), the incidence of glucose metabolism abnormalities in the renal transplant population is underestimated.
Established risk factors for NODAT following renal transplantation include increasing age, obesity, black or Hispanic ethnicity, family history, hepatitis C and cytomegalovirus (CMV) infection, steroid use and type of calcineurin inhibitor. NODAT is caused by insufficient insulin release in response to an increase in insulin resistance. Since calcineurin inhibitors are commonly used with steroids, it is difficult to identify whether diabetes in a posttransplant setting is due to steroids, calcineurin inhibitors or both. Steroids are known to increase peripheral insulin resistance. Tacrolimus also appears to inhibit insulin production. In vitro, tacrolimus depletes pancreatic beta-cell insulin mRNA and protein in a dose-dependent manner and, consistent with this, tacrolimus-based regimens are associated with more marked beta-cell morphological changes and inhibit insulin secretion to a greater extent than CsA-based regimens during the first 3 months post-transplant. Meta- and registry analyses have indicated that tacrolimus is associated with increased incidence of NODAT. To date, however, no randomized trial of the two agents has been designed with NODAT or other glycemic abnormalities as a primary endpoint.
The DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2 Monitoring Versus Tacrolimus) study was designed to address this question by using a combined primary endpoint of NODAT or IFG, selected because both conditions are predictive for poor patient outcomes. A co-primary endpoint was the prevention of biopsy-proven acute rejection (BPAR) or graft loss or death, since any benefit in diabetogenic risk must be balanced against immunosuppressive efficacy.