iPAVE - imaging Pituitary ActiVation by Exendin

68Ga-NODAGA-exendin PET/CT offers a unique opportunity to further elucidate the
effects of GLP-1RA on the pituitary and to gain more insight into the
mechanisms leading to GLP-1RA treatment failure. If we achieve positive results
in this project, this would form the basis for a completely new research line
aiming at defining the role the HPA axis plays in treatment of T2D. An improved
understanding of the role of the HPA might also change our view of the
development of obesity/metabolic syndrome and T2D and help to define new
strategies for medical intervention, for example by specifically modulating the
HPA axis.
It has been hypothesized that the improved outcome of combined
GLP-1RA/glucagon/GIP treatment relay on the combination of positive dominant
effects of the single compounds, thus overruling negative effects of the
others. Such combined treatment regimens may proof efficient in patients with
HPA oversensitivity, for example by lipolytic effects of glucagon counteracting
the effects of HPA activation on adipose tissue.
Such results may change the treatment of obesity/T2D and would create new
possibilities for development of novel therapeutic strategies or novel drugs
improving the health of the population. The outcomes of this project have the
potential to boost innovation in diabetes/endocrinology research, which is of
special importance in view of the ever-increasing rate of obesity and the
associated morbidity and the subsequent healthcare costs, expected to rise to
up to 40% of the annual healthcare budget in high prevalence countries.

The study objective is to compare the pituitary uptake of 68Ga-NODAGA-exendin
in patients with and without adequate response (based on HbA1c or weight loss
or classification by the treating diabetologist) to GLP-1R agonist treatment,
to increase understanding of the role of the HPA axis in T2D, which could
contribute to the improvement of treatment strategies.

Subjects with T2D will be recruited from the outpatient clinic of the
Department of Internal Medicine of the Radboud university medical center
(Radboudumc) or through advertising (websites, social media). The subjects must
have a minimum age of 18 years. After recruitment, subjects will visit the
Department of Radiology and Nuclear Medicine in the Radboudumc in Nijmegen.
After informed consent, metabolic characterization is perrformed that will
consist of laboratory parameters and oral glucose tolerance testing. The second
visit includes an ACTH assay and is performed after the stimulation with 10
microgram of GLP-1RA intravenously. Also, daily (unstimulated) cortisol
excretion in 2 x 24h urine samples will be determined, these samples will be
collected by the participant at home (creatinine excretion as internal
control). All samples that are taken will be destroyed after analysis.
68Ga-NODAGA-exendin PET/CT scans will be performed in 10 patients with improved
glycaemic control (decreased HbA1c of >=5 mmol/mol) or weight loss (>=5%) within
one year of GLP-1RA treatment and in 10 patients without treatment response (as
classified by the treating diabetologist). All patients will be injected with
100-150 MBq 68Ga-NODAGA-exendin, PET/CT scans will start with injection and
dynamic image acquisition will be performed for one hour. One hour p.i., an
additional static scan of the upper abdomen will be performed for determination
of pancreatic uptake as measure for beta cell mass for reference to metabolic
parameters/insulin production capacity. In 5 patients with high
68Ga-NODAGA-exendin uptake, an additional brain MRI will be performed for
improved anatomical referencing.
Quantitative analysis of the scans will be performed for determination of
binding capacity and absolute uptake in the pituitary and absolute uptake in
the pancreas. Analysis of patient data (imaging, metabolic testing, cortisol
production) will be performed and descriptive statistics will be obtained.
A fourth visit is required for 5 out of 20 patients, who will receive a MRI
scan without contrast for anatomic correlation with the tracer uptake.

The patients will need to visit the Department of Radiology and Nuclear
Medicine of the Radboudumc in Nijmegen 3 times in total. One visit is required
for the stimulated ACTH assay, the second visit for the metabolic
characterization (laboratory parameters and oral glucose tolerance testing) and
during the third and last visit the PET/CT scan will be performed. All visits
require an intravenous catheter, but will reduce the number of required
venipunctures. Due to the placement of intravenous catheters, there is a small
chance of bruising, pain and inflammation at the site of catheter placement.
The (unstimulated) cortisol excretion will be determined in 2 x 24h urine
sample. The participant will need to collect these samples at home.
The PET/CT scan will be performed in 20 patients. In 5 patients with a high
uptake in the pituitary gland, an additional MRI scan will be done (fourth
visit). For the PET/CT scan, 100-150 MBq 68Ga-NODAGA-exendin-4 will be
administered intravenously. High doses of Byetta® (exenatide) may result in
nausea and headaches as has been reported in clinical trials studying the
therapeutic effect of Byetta®. Nausea with a single event of vomiting has been
observed in only 3 out of 103 cases in imaging studies after the administration
of this radiopharmaceutical. In addition, single cases of low blood pressure
and low blood glucose levels have been described after application of
therapeutic or higher doses of Byetta®. Although low blood glucose levels only
occurred after accidental heavy overdosing of Byetta®, patients will be closely
monitored. In this study, we will administer 100 to 150 MBq
68Ga-NODAGA-exendin-4, corresponding to an exendin dose of 4 to 7 µg.
Therefore, no (serious) adverse events will be expected. In case of
administering 68Ga-NODAGA-exendin-4, the expected radiation exposure will be
0.023 mSv/MBq. In addition, 1.25 to 2 mSv will be received due to the low-dose
CT. The total radiation exposure will be 3.6 to 5.5 mSv and is therefore
considered minimal to little.
Despite the radiation exposure, 68Ga-exendin PET can be used to provide in vivo
visualization and quantification of tissues expressing the GLP-1 receptor. This
study will contribute to an improved understanding of the role of HPA axis in
T2D treatment and can provide more insights regarding the mechanism leading to
treatment failures in case of GLP-1 receptor agonist therapy.