DANIEL LEJOURNAL CLUB

JANUARY 26 T H , 2016

New Onset Diabetes After Transplantation (NODAT)

Introduction about NODAT

More common in African American and Hispanic

Risk factors: elderly patients, obese patient, history of infection with hepatitis C and CMV

Immunosuppression such as CNI and Corticosteroids, especially tacrolimus increase the risk of NODAT

Purpose of the Study

Look deeper into the frequency , timing of development and risk associated with NODAT

With a double-blinded, placebo controlled trial with early corticosteroid withdrawal

Eight definitions of NODAT was used to analyzed the results as well as the recent American Diabetes Associated (ADA) definition of NODAT

Study Design

The participants of this study was randomized 1:1, participants who are African American were also divided evenly between the two groups, as well as donor types (living or decreased)

The two groups was the Corticosteroid withdrawal or the Chronic Corticosteroid group

Similarities-Tacrolimus

Tacrolimus dosing : was on ABW, dose was 0.15- 0.2 mg/kg/day initiated within 72 hours post-transplant

Target trough was 10-20 ng/mL post-transplant day 7 to 90, beyond 90 target level were 5-15 ng/mL

Similarities- MMF

All patient received MMF 1 g preoperatively and 2-3g/day postoperatively from PTD 3 -14

After that the dose was reduce to 2g/day

Similarities- Induction Therapy

The agent that was used for induction therapy was chosen by the preference of the testing center

Basiliximab, Daclizumab or Thymoglobulin

How the Groups differ

All the participants received unblinded corticosteroids for the first 7 days after transplant

On PTD 8 patients received the blinded drugThe CSWD group got placeboWhile the CCS group received a prednisone

taper

The Taper

Prednisone dosing in the CCS group was:- PTD 8-14 (0.4 mg/kg)

- PTD 15 -29 (0.3mg/kg) - PTD 30-89 (0.2mg/kg) - PTD 90-119 (0.15mg/kg) - PTD 120- 180 (0.1mg/kg) - PTD > 180 5mg daily

HbA1c and Blood Sugar

HbA1c was obtained at baseline and months 6,12,24,36,48, 60

Fasting blood Sugar was obtained at baseline, daily for the first 7 days PTD, and at weeks 2,4,6,8 and at months 3,6,12,24,36,48,60

The definition of treatment of diabetes was the use of insulin and/or hypoglycemic agent

Statistical Analysis

Kaplan- Meier time to event analysis were measured by log-rank test

Life-table analysis was used to analyzed each of the 8 definition of NODAT

The Eight Definitions of NODAT

1. ADA criteria, fasting blood glucose (FBG) > or equal to 126 mg/dl two times or glucose > or equal 200 mg/dL one time, or HbA1c > or equal to 6.5 % two times, or glucose > 126 mg/dl and HbA1c > or equal to 6.5 % simultaneously one time

2. FBG > or equal to 126 mg/dL on two separate occasions during follow-up

3. FBG > 126 mg/dL on two separate occasions or treatment with oral hypoglycemic agents or insulin during follow-up

4. HbA1c > or equal to 6.0% on two separate occasions during follow-up

5. HbA1c > or equal to 6.5% on two separate occasions during follow-up

6. Treatment with oral hypoglycemic agents or insulin during follow-up7. Teat with insulin during follow-uo8. Treat with oral hypoglycemic agents during follow-up

Results

Total of 277 non-diabetic transplant patients (CCS 135, CSWD 142)

No difference were observed at 5 years in patient survival or in death-censored graft survival

Rates of death and graft loss in subjects with NODAT were not in different to those without NODAT in both groups

Results- Drug Levels

Tacrolimus trough levels stayed within the target range in the two groups at all times

MMF dosing was lower in the CSWD group between 4 weeks and 3 years, but not after.

Results –Insulin and hypoglycemic agents

At the 5 year follow up, there was more insulin use in subjects not diabetic at baseline with CCS than with CSWD

There was no significant difference in the use of oral hypoglycemic agents between the two groups

Discussion- Benefits

This study had a follow up of 5 years which is longer than most randomized studies only follow participants for 1 year

Which allows more of a in depth look at the participants

Conclusions

Low-dose corticosteroids (5mg/day) with immunosuppression such as MMF and tacrolimus had little effect on NODAT risk

At 5 years, insulin use was significantly higher in the CCS group (11.1 %) vs. CSWD group (6.3%)

Besides insulin use none of the other 8 NODAT definition had significant difference between the two groups

Implications for treatment

Corticosteroids are a critical component of post-transplant immunosuppression regimens

Based on the results of this study corticosteroids should be prescribed postoperatively, with tapering to prevent withdrawal

The Positive Benefit of the Study

Doubled blinded, control randomized, 1:1 ratio

Evenly match groupsLong duration (5 years) Multiple sites Multiple Variant analysis Clear and specific definitions of NODAT ( 8

total) Close follow-up of participants

Limitations

Participants are low-risk of develop diabetes This study did not look into patients with high

risk of rejectionUse ADA definition diabetes might have

influence participants qualification for this study since fasting glucose results may be transient

Questions