New guidelines offer clues on managing posttransplant diabetes

Treatment guidelines for new-onset diabetes in transplant patients, developed by an international consensus panel of experts and published recently in a supplement to the journal Transplantation, emphasize the importance of screening for and managing the condition pre- and posttransplant. Studies suggest that posttransplant diabetes mellitus (PTDM) increases the risk for organ failure and cardiovascular complications and may adversely affect the quality of life and survival of the transplant recipient.

Research has also shown that immunosuppressive therapies may play a large role in the development of PTDM, and particular agents are more diabetogenic than others. "Corticosteroids and calcineurin inhibitors, such as Prograf [tacrolimus, Fujisawa USA], probably play the most significant role in increasing a patient's risk of developing PTDM," said David J. Taber, Pharm.D., BCPS, clinical pharmacy specialist and assistant professor, Medical University of South Carolina (MUSC).

It is the use of higher doses of these drugs that put a patient at higher risk of developing the condition, according to Taber. The guidelines suggest reducing steroid doses as soon as possible posttransplant and switching from tacrolimus to cyclosporine if diabetes has developed and is difficult to control.

Consideration of the risk of developing PTDM should be weighed against the risk of acute rejection when choosing an immunosuppressive regimen for each patient, according to the guidelines. "Optimally balancing a patient's regimen to effectively prevent rejection while trying to reduce the risk of developing PTDM is like walking a very thin, very high tightrope," said Taber's colleague at MUSC, Elizabeth Ashcraft, R.Ph., a clinical pharmacist who sees quite a bit of PTDM at the outpatient clinic where she helps treat kidney, pancreas, and liver transplant recipients.

"A regimen that uses cyclosporine instead of tacrolimus and includes either a steroid-sparing regimen or a rapid steroid taper is probably most appropriate for a patient who has multiple risk factors for PTDM," suggested Ashcraft. If the patient is also at high risk for acute rejection, antibody induction therapy with a lower dose of tacrolimus, Rapamune (sirolimus, Wyeth), and a rapid steroid taper might be more appropriate, she added.

Risk factors that predispose a patient to PTDM include age over 40 years, African-American and Hispanic ethnicity, history of diabetes among first-degree relatives, history of gestational diabetes, hepatitis C infection, and obesity. Patients with cardiovascular risk factors such as smoking, a family history of cardiovascular disease (CVD), and dyslipidemia are also more likely to develop both diabetes and CVD after transplantation.

"One size does not fit everyone," said Ali Olyaei, Pharm.D., BCPS, associate professor of medicine and clinical pharmacotherapist, Oregon Health Sciences University, referring to the best way to treat PTDM. Olyaei agrees that some studies suggest that different immunosuppressant regimens account for PTDM but believes that in clinical practice, the overall incidence of PTDM is more closely related to the dose of the drug. In early clinical studies, she pointed out, higher incidences of PTDM were reported in the tacrolimus group. However, after lowering the target plasma concentrations of tacrolimus, the diabetogenic effect was very similar in both the tacrolimus and cyclosporine group.

Once identified, management of PTDM should follow the American Diabetes Association recommendations for the treatment of Type 2 diabetes, according to the new guidelines, and follow a step-wise approach. Encouraging lifestyle changes and providing counseling for patients on the importance of losing weight, eating a healthy diet, and increasing physical activity are important first steps that can help reduce insulin resistance.

If glycemic control targets are not achieved, the guidelines recommend starting oral agent monotherapy with a drug chosen on the basis of its safety in that particular patient. Among the choices are the alpha-glucosidase inhibitors, for example, Precose (acarbose, Bayer); the biguanide metformin; meglitinides, for example, Prandin (repaglinide, Novo Nordisk); sulfonylureas; and the thiazolidinediones, for example, Avandia, (rosiglitazone maleate, GlaxoSmithKline). Consideration should be given to the potential side effects of each class of medication in different types of patients.

"Although we usually initiate our drug therapy with a sulfonylurea agent, meglitinides are the drug of choice for older patients and those with impaired renal function," said Olyaei. "Although weight gain and hypoglycemia are less likely to occur with metformin than with sulfonylureas and thiazolidinediones, it is important to avoid metformin in renal transplant patients due to the risk of serious lactic acidosis," she added.

Taber emphasized that early in the posttransplant period, when there is rapid tapering of both corticosteroids and calcineurin inhibitors, if a patient develops PTDM, he or she could have rapidly changing plasma glucose concentrations and the use of an oral antidiabetic or a long-acting insulin might actually predispose a patient to developing hypoglycemia. "During this time, the use of a sliding-scale insulin regimen may be most appropriate," he said. Once the patient is fairly stable on his immunosuppressant regimen (two to four months posttransplant), various other agents are considered to reach glycemic goals, he added. The guidelines recommend oral combination therapy and use of insulin with or without an oral agent if glucose levels are not adequately controlled with monotherapy.

The guidelines also suggest conducting pretransplant baseline evaluations to determine who is at risk for PTDM. Blood glucose, fasting plasma glucose, lipid, and A1c (glycosylated hemoglobin) levels should be measured and assessed routinely following transplant. Dyslipidemias should be aggressively treated to reduce the risk of heart disease in PTDM patients, and blood pressure controlled to a target value of 130/80 mm Hg.

Studies suggest the incidence of PTDM may be as high as 53%. Because PTDM adversely affects a patient's quality of life and increases the risk for graft failure and death, "developing specific protocols to standardize the prevention, detection, and treatment of PTDM should greatly improve patient outcomes posttransplant, said Taber.