Dr.Robin Maskey,MD,Internal MedicineFellow, EndocrinologySir Gangaram Hospital

IntroductionEpidemiologyDefination and Diagnosis of NODATPathogenesis of NODAT Risk Factors for NODATSequelae of NODATManagementControversies and Areas of

Uncertainty

Posttransplant diabetes, or new-onset diabetes after transplantation(NODAT), is observed after transplantation of kidney, liver, lung, heart, and other solid organs, as well as bone marrow and hematopoietic stem cells.

Also as Secondary type of diabetes mellitus

Among renal transplant patients, the risk of NODAT peaks within the first year, with incidence rates as high as 15%;thereafter, the annual incidence rate falls to6%.

(J Clin Endocrinol Metab 96: 3289–3297, 2011 )

• The incidence of NODAT ranges from approximately 4% to 25% of renal allograft,2.5 to 25% of liver transplant,4 to 40% of heart transplant and 30 to 35% of lung transplant recipients.

• The variation is due to lack of standard defination, duration of follow up, presence of

of risk factors and type of organ transplant.

Diabetes,Metabolic Syndrome and Obesity:Targets and Therapy,2011:4 175-186

• The true incremental incidence of diabetes occurs mainly during the first 6 months posttransplantation, when patients are treated with high doses of immunosuppression.

Approximately 50% of people diagnosed with NODAT experience improvement in glucose tolerance after the immunosuppressive agents have been decreased or tapered to maintenance doses.

• The most accurate incidence of NODAT under calcineurin inhibitor (CNI) therapy is provided by the prospective study of Vincenti et al. reporting an incidence of NODAT reaching 20.5% within the first 6 months postrenal transplantation

(J Clin Endocrinol Metab 96: 3289–3297, 2011 )

DIABETES CARE,VOLUME 36,MAY 2013

WHO AND 2003 updated ADA criteria : Symptoms of diabetes mellitus + casual PG

≥200mg/dl(11.1 mM) or

FPG ≥ 126 mg/dl (7.0 mM) or

2-hr PPG ≥200mg/dl(11.1 mM) during OGTT

The use of glycosylated hemoglobin (HbA1c) for diagnosis of diabetes or prediabetes during the peritransplant period is not recommended.

Diabetes,Metabolic Syndrome and Obesity:Targets and Therapy,2011:4 175-186

DIABETES CARE,VOLUME 36,MAY 2013

Immunosuppressive agents

Pathogenic mechanisms Comments

Corticosteriods • Decrease Peripheral insulin sensitivity•Inhibit pancreatic production & secretion•Increase Hepatic gluconeogenesis•lipolysis

•Dose dependant•Impact of complete withdrawl of ch low dose steriods unclear•Potenital NODAT risk decreased in steroid free regimens

Cyclosporine •Decreased insulin secretion(CsA>Tac)•Decreased insulin synthesis•Decreased β cell density

•Dose dependant•Diabetogenic effect increased with increase steroid dose

Tacrolimus •Decreased insulin secretion

Same as cyclosporine

Sirolimus •Impair pancreatic β cell response

•increased Diabetogenic effect with CNIs

In addition to the risk of developing the well-known long term complications of diabetes, NODAT also identifies patients at high risk for adverse clinical outcomes:

loss of the renal allograft, infections, cardiovascular events, and increased mortality among renal transplant patients

Among liver transplant recipients, NODAT is associated with increased cardiovascular morbidity and mortality, more fatal infections more neuropsychiatric complications, higher rejection rates, and poorer graft survival

Among lung transplant recipients, cytomegalovirus (CMV) infection and acute rejection episodes

(J Clin Endocrinol Metab 96: 3289–3297, 2011 )

Pretransplant periodDocument baseline blood glucose

statusAssess diabetes risk factors Identify high-risk subjects Initiate lifestyle interventionDietary counselingExercise counseling

J Clin Endocrinol Metab, November 2011, 96(11):3289–3297

Insulin infusion can be used, as appropriate, to manage perioperative stress hyperglycemia.

Once patients begin to eat after surgery, the regimen can be changed to sc insulin (basal or basal-bolus, as appropriate).

With a decline in postoperative stress and reduction of steroid doses, many patients can be weaned off insulin before discharge.

J Clin Endocrinol Metab, November 2011, 96(11):3289–3297

Posttransplant period Immunosuppressive regimenMinimize steroid doseMinimize calcineurin inhibitor exposure

Treat hyperglycemia beginning in the peritransplant period

Close follow-up of all patients, especially those with prediabetes

J Clin Endocrinol Metab, November 2011, 96(11):3289–3297

Patients discharged without hyperglycemia should have FPG testing at least weekly during the first month, then every 3 months for 1 yr, and annually thereafter.

Once a blood glucose-based diagnosis of NODAT has been established in a patient who is more than 3 months posttransplant, the HbA1c can be used to monitor glycemic control .

Posttransplant period For those who develop NODAT Diabetes education Appropriate medical therapy based on severity

of hyperglycemia Surveillance for microvascular complications Optimize insulin therapy during episodes of

high-dose steroid exposure Evaluate and control comorbid conditions Hypertension Dyslipidemia Hyperuricemia OtherJ Clin Endocrinol Metab, November 2011, 96(11):3289–

3297

Depending on the organ transplanted and the state of kidney, liver, and cardiac function, some oral antidiabetes drugs may be absolutely or relatively contraindicated. In such instances, insulin often becomes an early option.

Careful attention must be paid to the toxicity profiles of antidiabetes agents in the transplant population

The pancreatic b-cell is exposed to several stressors immediately after kidney transplant surgery, including the surgical procedure itself, high-dose corticosteroids, and initiation of CNIs.

Thus, resting the b-cell with basal insulin and optimizing b-cell protection with tighter control to near-normoglycemic treatment goals could further reduce the number of patients with future impaired glucose tolerance and NODAT.

The standard regimens (basal insulin, split-mix, basal-bolus) are all applicable in the management of NODAT.

Steroid-sparing or steroid- free regimens appear to be associated with decreased risk of NODAT

Tacrolimus, a potent inhibitor of insulin secretion, has been associated with a greater risk of NODAT compared with cyclosporine

Belatacept, a selective inhibitor of T-cell activation, is a parenteral immunosuppressant that replaces CNIs. Studies suggest that transplant recipients who receive belatacept have a better metabolic profile and a lower incidence of NODAT compared with those who receive CNIs .

The calcineurin inhibitors cyclosporine and tacrolimus are known to increase cholesterol levels, so patients may require adjustment of statin dose after transplant.

Pravastatin and fluvastatin, which are not metabolized by CYP3A4, tend to be used preferentially in transplant patients with dyslipidemia.

Sirolimus and glucocorticoids are associated with hypertriglyceridemia that may require treatment with fibrates.

The National Kidney Foundation recommends that blood pressure control be maintained at below 130/80 mm Hg in renal transplant recipients

The beta- blockers and calcium channel blockers appear to be well tolerated and effective .

Microalbuminuria is a predictor of renal allograft loss and increased mortality

Besides the risk of gout, hyperuricemia is associated with cardiovascular disease, inflammation, insulin resistance, and decreased renal graft survival

Primary prevention of NODATOptimal immunosuppressive

regimenOptimal glycemic management

J Clin Endocrinol Metab, November 2011, 96(11):3289–3297

The current recommendation is to identify high-risk patients during the pretransplant period.

Once identified, such highrisk subjects can empirically be offered lifestyle intervention to decrease obesity and increase physical ctivity, as appropriate.

The use of medications to prevent type 2 diabetes has been well documented in the general population,but not yet in transplant recipients

Type 2 diabetes mellitus and NODAT share similar risk factors, especially obesity.

Obesity prevention may also benefit patients who already have received a transplant because there is an observed weight gain of 10% during the first year after transplant .

Earlier studies documented a survival benefit associated with higher BMI in dialysis patients .

Recent studies suggest that it is higher muscle mass, rather than higher fat mass, that predicts longer survival in dialysis patients.

Thus, a lifestyle intervention aimed at lowering fat mass may be appropriate for the prevention of NODAT.

Toxicities from antirejection immunosuppressive medications constitute the strongest trigger for NODAT

Aiming for the lowest effective dose of corticosteroids in the posttransplant patient minimizes the risk of dysglycemia.

Also, there are limited data showing benefit of substituting cyclosporine for tacrolimus in immunosuppressive regimens

NODAThas been identified as a risk factor for graft rejection, long-term graft failure, and decreased patient survival, the mechanisms linking hyperglycemia to these adverse outcomes remain to be determined.

Improved glycemic control decreases infections in liver transplant recipients

NODAT is a common complication after solid organ transplant and has variably adverse impact on patient and allograft outcomes.

The most important risk factor predisposing to the development of NODAT is the immunosuppressive drugs.

Risk stratification and intervention to minimize risk should be integral part of the management of NODAT patients.

Thank you