Post-Transplant Diabetes Mellitus The Role of Immunosuppression

Abstract

Immunosuppressive agents increase the risk of death due to coronary disease or stroke by their ability to cause 3 different adverse effects: dyslipidaemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants. As recipients of organ transplants survive longer, the secondary complications of diabetes mellitus have assumed greater importance. There is a need for a precise definition of post-transplant diabetes mellitus to facilitate inter-centre comparison and to study the natural history of post-transplant diabetes mellitus. We recommend broad criteria to define hyperglycaemia, as a fasting blood glucose level of > 400 mg/dl at any point or > 200 mg/dl for 2 weeks, or a need for insulin treatment for at least 2 weeks. We also recommend serial measurements of HbA1c. Cyclosporin and tacrolimus cause post-transplant diabetes mellitus by a number of mechanisms, including decreased insulin secretion, increased insulin resistance or a direct toxic effect on the beta cell. For corticosteroids, the induction of insulin resistance seems to be the predominant factor. However, few studies have examined the mechanism of diabetogenicity at the molecular level. This may hold the key for pharmacological manipulation of current immunosuppressive regimens which may result in decreased metabolic complications. Corticosteroid sparing regimens have been shown to reduce the metabolic complications of immunosuppressants including post-transplant diabetes mellitus. However, their use should be balanced against the increased incidence of transplant rejections. Post-transplant diabetes mellitus may be organ-specific irrespective of the immunosuppressant used. Tacrolimus causes a high incidence of post-transplant diabetes mellitus in recipients of kidney transplants (upto 20% in some reports); the diabetogenicity of cyclosporin-based regimens is comparable with that of tacrolimus-based regimens in recipients of liver transplants. A few clinical studies in which attempts were made to discontinue cyclosporin resulted in an unacceptable loss of the transplant. In the case of tacrolimus, complete withdrawal of immunosuppression may be possible in selected patients with liver transplants. However, post-transplant recipients who may benefit from this approach are difficult to identify. In some early series, patients received doses of tacrolimus that were approximately 2 to 3 times higher than those currently used, which may have resulted in a higher incidence of post-transplant diabetes mellitus. More recently, it has been shown that tacrolimus was successful in salvaging whole pancreatic grafts which were maintained on cyclosporin. Tacrolimus-based immunosuppression as primary therapy was also used with remarkable success in solitary whole pancreas transplants. Strategies to reduce the metabolic complications of immunosuppressants should be pursued aggressively as this will directly lead to a decrease in long term cardiovascular adverse effects.

Impact of Diabetes Mellitus on Survival Rates After Heart Transplantation

“…A relationship with diabetogenic drugs included in the immunosuppressive regimen was shown more than half of a century ago 4 . As reported by Jindal 5 , immunosuppressive agents increase the risk of death due to coronary artery disease or stroke by their ability to cause 3 different adverse effects: dyslipidemia, hypertension and hyperglycaemia. Post-transplant diabetes mellitus has emerged as a major adverse effect of immunosuppressants.…”

Long-term management of the liver transplant patient: Diabetes, hyperlipidemia, and obesity

“…11 Aside from differences in the definitions and timing used among the different studies, the explanation for the discrepant data on the prevalence of long-term posttransplant diabetes probably lies in the balance between the following: (1) the extent to which insulin resistance is reversed by removing the cirrhotic liver 11 ; (2) the degree of continuing pancreatic insulin secretory failure 11 ; and (3) the magnitude of the anti-insulin (diabetogenic) effects of obesity and the principal immunosuppressive medications, namely corticosteroids and the calcineurin inhibitors. [26][27][28][29] Corticosteroids induce insulin resistance in a dose-dependent manner, whereas cyclosporine and tacrolimus decrease insulin synthesis and secretion and/or induce insulin resistance and hyperinsulinemia. The other immunosuppressives (azathioprine, mycophenolate mofetil, and sirolimus) are not diabetogenic.…”

Influence of Early Posttransplantation Prednisone and Calcineurin Inhibitor Dosages on the Incidence of New-Onset Diabetes

“…Although reductions in steroid dosages, combined with azathioprine, reduced NOD incidence (5), approximately 25% of patients still developed NOD. The introduction of calcineurin inhibitors (CNI) facilitated further reductions in steroid dosages but were soon found to have diabetogenic effects of their own (6). National registry analyses suggest that 15 to 20% of renal transplant patients who do not have diabetes and receive a CNI currently develop NOD within 1 yr of transplantation (2,3).…”