The American Society of Transplantation

In order for a generic drug to be approved by the FDA, it needs to demonstrate bioequivalence with the reference drug. In other words, the rate and extent of absorption of the generic drug can not be significantly different from the reference drug when given at the same molar dose under the same conditions. Bioequivalence for the generic drug is established in a single study of 24-36 healthy volunteers. It is determined by determining the mean AUC and Cmax for the generic drug and comparing it the reference drug. The ratio of bioavailability of the generic drug to the reference drug (T/R ratio) must fall between the confidence interval of 80-125% for the generic drug to get FDA approval.

The FDA does not usually require manufacturers of generic drugs to perform safety or efficacy studies in humans or in this particular case, transplant patients. For this reason, some transplant physicians are reluctant to use generic mycophenolate mofetil since no efficacy studies were perform in transplant patients prior to the release of these drugs into the market.

Thank you for your excellent question:

I have actually expanded your question into two parts:

1) What information does an oral glucose tolerance test provide compared to fasting glucose?
2) Can a current normal oral glucose tolerance test in the setting of a patient with other risk factors help refine the future risk of diabetes?

1)

The determinants of elevated fasting glucose and 2-h plasma glucose in an oral glucose tolerance test (2-HPG) levels differ.

Raised hepatic glucose output and a defect in early insulin secretion are characteristic of the former, and peripheral insulin resistance is most characteristic of the latter.

Therefore, concordance between the categories of IFG and IGT is limited. About half or less of people with IFG have IGT, and even a lower proportion (20-30%) with IGT also have IFG. In the majority of studies, IGT is more prevalent than IFG, and there is a difference in phenotype and gender distribution between the two categories. IFG is substantially more common amongst men and IGT slightly more common amongst women. The prevalence of IFG tends to plateau in middle age whereas the prevalence of IGT rises into old age.

Both IFG and IGT are associated with an increased risk of developing diabetes, with the highest risk in people with combined IFG and IGT. Because IGT is commoner than IFG in most populations it is more sensitive (but slightly less specific) for identifying people who will develop diabetes. The OGTT is also less reproducible than the fasting glucose test.

2)

Although research protocols for estimating the future risk of diabetes have primarily depended upon identification of impaired glucose tolerance through a 2 hour oral glucose tolerance test, other clinical, historical and laboratory measures are known risk factors for diabetes. There are no studies to my knowledge that compare risk of diabetes in patients with risk factors (such as parental history) but current normal laboratory tests. Most studies predict risk of progression to diabetes in patients with impaired glucose tolerance ( Edelstein et al).

A recent study in the Annals of Internal Medicine (Khan et al) Compared two risk scores for predicting future diabetes in adults aged 45-64 years. The first risk score was based on clinical and historical criteria only (diabetes in mother, father, sex, smoking history, hypertension, Black race, waist circumference, height, pulse, weight), while the second score also included laboratory tests including fasting glucose, triglycerides, and uric acid. NOte both scores included maternal and paternal history of diabetes.

The risk scores had reasonable sensitivity and specificity for development of diabetes over the next 10 years ( AUC 0.71 and 0.79). These risk scores could be applied to your patient.

Once the risk in your patient is determined, it is important to note that numerous studies have shown that diabetes can be prevented by lifestyle modification and potentially by the use of medications (metformin).

Your final decision to move forward should consider the baseline risk in your donor and your assessment of whether your donor can implement lifestyle changes to modify this risk.

References:

Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse
GK, et al. Predictors of progression from impaired glucose tolerance to NIDDM:
an analysis of six prospective studies. Diabetes. 1997;46:701-10.

Khan et al Ann Intern Med. 2009;150:741-751.

Most solid organ transplant programs encourage trimethoprim/sulfamethoxazole prophylaxis for approximately 3-12 months after transplantation. Although it is unknown whether prolonged prophylaxis is superior to temporary prophylaxis, extended prophylaxis beyond the specified period should be encouraged in the setting of ongoing rejection, increased immunosuppression, and/or graft dysfunction. In my opinion, lifelong trimethoprim/sulfamethoxazole prophylaxis should be considered in all transplant recipients who are able to tolerate the medication without side effects or toxicities. Potential benefits include prevention of the following infections that can occur at any point in the lifetime of a transplant recipient: Pneumocystis, Nocardia, Toxoplasma, bacterial pneumonia (e.g. Streptococcus pneumoniae), skin and soft tissue infections (e.g. MRSA), and bacterial urinary tract infections, among others.

Shirish Huprikar, MD
Mount Sinai School of Medicine
AST Education Committee Member

It is difficult to predict who will develop diabetes.
Gestational diabetes along with obesity, ethnicity and family history are all risk factors for development of mature onset diabetes.
Better tests are needed but the most predictive available tests are the fasting blood glucose, insulin levels, and the 2 hour glucose tolerance test.
In one study 35% of women who have gestational diabetes developed type 2 diabetes by 15 years after delivery.(ref 1)
A study of 241 diet treated women with GDM diagnosed between 1978 – 85 in Copenhagen found that 2-11 years later 34% had abnormal glucose (3.7% IDDM, 13.7% NIDDM, 17%IGT) in contrast to a control group where none had diabetes and 5.3% had IGT.(ref 2)

So clearly there is a risk. Importantly diet, excercise can modify this risk.

We therefore do not exclude patients simply on the basis of GDM but alo look at their current risk based on BMI at time of evaluation, and laboratories (fasting glucose and oral glucose tolerance).

The next question is what if the donor does develop diabetes. The existing data would suggest that the risk of micro and macro-albuminuria are increased. One of the most widely known studies is that of Silveiro (ref 3). Importantly microalbuminuria was noted an average of 23 years after nephrectomy, but was present as soon as five years after nephrectomy. The conclusions that can be drawn are that nephrectomy in an individual with diabetes, normal renal function and no dipstick identifiable proteinuria is likely not going to cause problems in the short term. However with time increasing proteinuria is common, and this may ultimately lead to loss of renal function and perhaps an increase in cardiovascular disease.

Putting all of this together – the key considerations are the age of your donor and an assessment of their current risk based on BMI and laboratory tests. If they are young, the risk may preclude donation, if they are older and their other risk factors are low – this may be acceptable with informed consent.

1)Linne Y et al. Br J obst and Gyne 58:193-200, 2002
2)Damm P. Dan Med Bull. 1998 Nov;45(5)495-509
3)Silviero Diabetes Care 21: 1521-24, 1998.

John Gill, MD, MS
University Of British Columbia
St. Paul’s Hospital
Member, AST Education Committee