Combined effects of SGLT2 inhibition and GLP-1 receptor agonism on food intake, body weight and central satiety and reward circuits in obese T2DM patients

SGLT2 inhibitors promote the renal excretion of glucose and lower elevated
blood glucose levels in patients with type 2 diabetes (T2DM), independent of
insulin action. Furthermore, SGLT2 inhibitors are associated with a decrease in
body weight, caused by the chronic urinary calorie loss. However, the observed
weight loss has been consistently less than expected from the amount of urinary
glucose excretion. Recently, it has been shown that there is a mean weight loss
of 3 kg during treatment with a SGLT2 inhibitor, whereas the observed calorie
loss through glycosuria was predicted to result in a weight loss of 11 kg. As
studies have shown that acute or chronic treatment with an SGLT-2 inhibitor
does not alter energy expenditure, the discrepancy between observed and
expected weight loss implies that patients increased their energy intake. These
findings are supported by studies in animals that show compensatory hyperphagia
in response to SGLT2 inhibition.
It is important to understand the mechanisms whereby glycosuria may
influence appetite regulation and food intake. In addition, it is of interest
to investigate whether the effects of SGLT2 inhibitors on weight could be
improved by combining SGLT2 inhibitors with interventions aimed at reductions
in appetite and food intake.
It has been hypothesized that excessive eating due to changes in CNS
satiety and reward responses to the consumption of food is fundamental in the
development of obesity and T2DM. We and others have demonstrated altered
responses within CNS satiety and reward circuits (including striatum, amygdala,
orbitofrontal cortex, anterior cingulate cortex, insula, hypothalamus) in obese
and T2DM relative to non-obese individuals, and these responses were shown to
predict future weight gain. SGLT2 inhibitors may influence appetite and food
intake through direct or indirect effects on the CNS, but the effects of SGLT2
inhibitors on these reward and satiety centers have not been investigated.
Interestingly, GLP-1 receptor agonists have been shown to decrease
appetite, food intake and body weight through effects on central reward and
satiety circuits. Preliminary data show that when SGLT-2 inhibitors are
combined with GLP-1 receptor agonists, the increased food intake during
treatment with SGLT-2 inhibitors may be prevented. However, the effects of
combined administration of SGLT2 inhibitors and a GLP-1 receptor agonist on
central reward and satiety circuits, food intake and body weight have not been
investigated.

Hypothesis: treatment with SGLT2 inhibitors is associated with alterations in
central reward and satiety circuits in response to food related stimuli,
leading to increased appetite and food intake. In addition, we hypothesize that
adding a GLP-1 receptor agonist to treatment with an SGLT2 inhibitor may
increase weight loss and prevent the increased food intake during treatment
with SGLT2 inhibitors due to effects on neuronal activity of central satiety
and reward circuits in response to food-related stimuli in obese patients with
T2DM

Primary objective:
To investigate the separate and combined actions of the SGLT2 inhibitor
dapagliflozin and GLP-1 receptor agonist exenatide on activity in central
reward and satiety circuits in response to food related stimuli in obese
patients with T2DM

Secondary objective:
To investigate the separate and combined actions of the SGLT2 inhibitor
dapagliflozin and GLP-1 receptor agonist exenatide on quantitative and
qualitative aspects of food intake, energy expenditure, body measurements,
resting state brain activity networks, cardiovascular autonomic nervous
function, renal function and plasma/serum biomarkers

Safety objectives:
To evaluate the safety and tolerability of the separate and combined actions of
the SGLT2 inhibitor dapagliflozin and GLP-1 receptor agonist exenatide

Exploratory objectives:
-to study the possible influence of concomitant changes in several important
hormones and novel hormone measurements that may become available in the near
future.
-to allow the study of the effects of human genetic variation on the endpoints
in the future
- drug effects on microbiome
- changes in overall food intake, measured by a fooddiary

Double blind placebo-controlled randomized trial

Subjects will be randomized in one of the following arms:

1) SGLT2 inhibitor dapagliflozin 10 mg/day in combination with placebo GLP-1
receptor agonist exenatide twice daily,
2) GLP-1 receptor agonist exenatide twice daily in combination with placebo
dapagliflozin,
3) combination of dapagliflozin 10 mg/day and exenatide twice daily, or
4) placebo dapagliflozin and placebo exenatide twice daily

We are aware of the possible demand that may be imposed on the participants in
this study. After the screening visit participants will travel 4 times to the
study location. The total duration of the 3 test visits is aproximately 4
hours, the screeningvisit will take aproximately 2hours, the safety control
visit aproximately 1 hour and the telephone consultations 15 min. The total
amount of blood will be 150 ml in the total study (4 months). The risks
associated with participation are the risks of venous blood drawing.
The fMRI, calorimetry, cardiac autonomous nervous system function test are
considered to be safe. No invasive procedures are involved. Participants could
experience discomfort while being in a supine position while testing.
Both study medications haven been approved for blood glucose lowering treatment
in type 2 diabetes patients and based on currently available data are
considered to be safe. Side effects of exenatide including hypoglycaemia (in
combination with SU), nausea, vomiting and diarrhea are usually mild and
transient. Side effects of dapagliflozine including genital (fungal) infections
and hypoglycaemia (in combination with SU) are usually mild and transient.
Three of the four intevention groups will have benefit from treatment, possibly
weight reduction and better glucose regulation. The placebo group will not have
a benefit from treatment in this study.
We have built in different ways to alleviate the burden for participants,
including clear, repeated communication, frequent contacting, 24-hour
availability of the research staff and study, travel reimbursement and during
test-days we provide meals.