The GATE trial: Endoscopic sutured Gastroplasty in Type 2 diabetic, obese patients using the Endomina device - a randomized controlled trial, and its effect on incretin hormones

Diabetes mellitus is a chronic disease often associated with long-term
macrovascular and microvascular complications (e.g., heart disease, stroke and
renal failure) and decreased life expectancy. (2) Approximately 70% of patients
with type 2 diabetes mellitus (DM2) is overweight or obese. (3) Findings from a
national cohort of US adults showed that the risk for DM2 increases with 4.5%
for every kilogram increase in weight. (4) Besides DM2, obesity is associated
with impaired quality of life, cardiovascular diseases, arthrosis, cancer and
reduced life expectancy. (5)

Weight loss benefits several aspects of DM2, such as improved glycemic control,
increased insulin sensitivity and reduced fasting insulin. This results in a
reduction of glycated hemoglobin. In addition, coexisting disorders such as
hypertension and dyslipidemia improve as well. (2)

Interventions for weight loss in patients with DM2 include lifestyle
interventions (diet, exercise), but also pharmacotherapy and bariatric surgery.
Bariatric surgery is indicated at a BMI > 35 kg/m², in combination with other
comorbidities such as DM2, hypertension or sleep apnea, or a BMI >40 kg/m² with
or without any comorbidities. (6) It is associated with better glycemic control
and more weight reduction, compared to intensive medical treatment alone, with
more than 90% of patients in the surgical group having glycemic control without
using insulin. (7) However, it is associated with perioperative and long-term
complications, 6% of patients requiring revision surgery, and a mortality risk
of 0.1-2%. (8-10) Also, literature shows that only 1% of eligible patients
actually undergo bariatric surgery. This is mainly due to the change in anatomy
and the fear of operative risks. (11) Therefore, less invasive and safer
techniques are needed.

Endoscopic bariatric therapies are techniques with much less-invasive features
(as it does not cross the border of the GI tract) and without the significant
risks associated with surgery. Especially, for patients with not adequately
controlled DM2 with a BMI between 30 and 35 kg/m², the therapeutic gap could be
filled by one of the currently available endoscopic therapies. These therapies
can be categorized in three different techniques:
1) inserting of a (temporarily) space-occupying device (balloon) in the stomach
aiming to reduce the stomach*s capacity
2) redirecting calories away from the stomach by aspiration therapy or,
3) decreasing the stomach size by endoscopic suturing. (12, 13)

Endoscopic sutured gastroplasty is one of the techniques that decreases the
stomach size. This technique can be performed with different devices currently
available, e.g., the Incisionless Operating Platform (USGI Medical),
Overstitch Endoscopic Suturing System (Apollo Endosurgery) or Endomina (Endo
Tools Therapeutics). Previous studies, including meta-analyses have shown a
positive effect of ESG on weight loss. (14) However, there is a paucity of data
showing the effect of ESG on metabolic comorbidities including DM2. (14) Also,
most studies have been performed with the Overstitch device. Therefore, this
study aims to compare the efficacy and safety of ESG with the endomina device
on glycemic control.

Effect on hormones
Bariatric surgery leads to a greater chance of DM2 remission compared to
similar weight loss without surgery. (15) There are several theories on the
mechanism that attributes to improved glycemic control after bariatric surgery.
These theories can be divided into 4 pathways: 1) cellular alterations, 2)
changes in microbiome, 3) histological changes, and 4) hormonal shifts. (15)
The latter theory can be further exemplified by several gut hormones, including
incretin hormones (GLP-1 and GIP) and ghrelin. These hormones are responsible
for the regulation of gastric emptying, feeling of satiety and insulin
secretion.

The hormone studied most within this field is GLP-1. This gut hormone is
secreted by intestinal L-cells primarily in the distal ileum and colon. L-cells
are stimulated by several factors, including nutrient and endocrine factors.
Quickly after ingestion of food, particularly when it contains lots of fat and
carbohydrates, GLP-1 secretion is stimulated. (16) This has an incretin effect:
a stronger stimulation of insulin secretion after oral glucose intake compared
to intravenously glucose administration. (17) Other effects of GLP-1 are
regulation of glucagon secretion, slowing gastric emptying and providing the
feeling of satiety. (18) It is known that the incretin effect is reduced or
even absent in patients with DM2. (19)

The effect of bariatric surgery on this incretin effect can possibly explain
its benefits on DM2. It is extensively confirmed that GLP-1 levels rise after
bariatric surgery. (20-24) Firstly, Roux-and-Y gastric bypass provides the
stomach to empty nutrients into the distal part of the small intestine. This
equals the location of most L-cells, where GLP-1 secretion is stimulated. (19)
Secondly, due to a sleeve gastrectomy the gastric emptying accelerates and
delivers nutrients faster in the small intestine, which stimulates GLP-1
secretion. (19) Ghrelin levels on the contrary fall after a meal. It causes the
feeling of hunger and appetite and regulates the use of energy. (24, 25) The
effect of bariatric surgery on ghrelin levels remains unclear. Theoretically,
the levels of ghrelin would reduce after surgical sleeve gastrectomy, since the
part of the stomach is removed that is the location of the most ghrelin
secreting cells. (25)

The question raises, if the same hormonal changes occur in bariatric endoscopy
as seen in bariatric surgery. The effect on GLP-1 is mainly analyzed for the
duodenal-jejunal bypass sleeve (DJBS), which shows an increase in GLP-1 after 7
days and 24 weeks. (26) Lopez-Nava et al. showed a minimal decrease in ghrelin
levels, but no difference in GLP-1 levels before and 6 months after ESG (with
an intact fundus). (27) Abu Dayyeh et al. analyzed the effect of ESG on GLP-1
after 3 months, which showed no significant changes. (28) However, both are
small non randomized controlled studies. Vargas et al. found a significant
increase in total ghrelin 12 months after ESG compared to baseline, although no
differences between the intervention (ESG) and control (lifestyle intervention)
group were seen. At 18 months, both total ghrelin as GLP-1 were significantly
increased compared to baseline. (29) Due to the inconsistent results regarding
different hormones, the aim of this sub-study is to analyze the effect of ESG
on GLP-1 and ghrelin blood levels within our randomized study population with
obesity and diabetes mellitus type 2.

The primary objective of this study is to evaluate the efficacy of endoscopic
sutured gastroplasty with the endomina device (EndoTools Therapeutics S.A.) on
glycemic control (reduction in insulin dose), in obese insulin treated type 2
diabetes patients after 12 months.
Secondary objectives are:
- To evaluate the effect of ESG on:
o HbA1c
o Weight loss
o Blood pressure, in patients with hypertension at inclusion
o Quality of life, measured with the quality-of-life questionnaires EQ-5D-5L
and Diabetes Treatment Satisfaction Questionnaire (DTSQ)
after 1 month, 3, 6, and 12 months of follow-up
- To evaluate the possibility and safety of performing ESG under procedural
sedation (with propofol).

Substudy:
To evaluate the effect of ESG on GLP-1 and ghrelin blood levels, 1 month and 6
months after ESG.

Type of study
This study is designed as a prospective randomized controlled trial, conducted
in Rijnstate Hospital (Arnhem).

Summary of study design
Screening patients will be performed in several phases:
- Patients (previously) known at the Internal Medicine outpatient population
from Rijnstate Hospital or Radboudumc with DM2 will be screened for eligibility
using CTcue. Patients diagnosed with DM2, with a BMI between 30 and 40 kg/m2
and treated with insulin are eligible for inclusion.
- After this first screening, a multidisciplinary meeting will be held with the
coordinating researcher, a gastroenterologist and an internist to discuss
eligibility of the patient (e.g. are there any (already known)
contraindications precluding ESG).
- If a patient seems eligible for inclusion, an information letter will be sent
to patient*s home address, followed by telephonic contact by their treating
physiscian to provide additional information. If the patient seems still
eligible and he/she is interested, han outpatient clinic visit will be
scheduled with the coordinating researcher to discuss the study in detail.
Afterwards, the patient will have 7 days to consider participation and if
wanted discuss participation with the treating physician.
- After 7 days, informed consent will be obtained and, a blood test will be
performed to check HbA1c. Subjects will be screening failures when the HbA1c
is < 7.0% or >11.0%, and will be excluded for enrollment. In addition, subjects
will be screened by a psychologist from Vitalys (Bariatric Center Velp), and an
anesthesiologist. If this leads to a negative advice, the subject will be
excluded from the trial as well. If the HbA1c is between 7.0% and 11.0%, and
they passed the screening, subjects will be included in the study and
randomized in a 1:1 ratio to either the intervention or control group.

Subjects in the intervention group will receive the ESG, followed by follow-up
visits at the outpatient department and one appointment by a dietician from
Vitalys to provide information about diet after ESG (e.g. smaller portions,
multiple times a day).
Subjects in the control group will receive standard diabetic care, which
includes consultation with a dietician for patients with DM2 under insulin
therapy. Further standard care will be provided by one of the trial researchers
instead of a treating physician. If indicated, consultation with the treating
physician will be performed.

The intervention group will have a telephonic follow-up 7 days post-procedure
and outpatient department follow-up visits at 14 days, 1 month, and at 3, 6, 9
and 12 months after ESG. The control group will have videocalls at 14 days
after randomization, 1, 6 and 9 months, and follow-up visits at 3 and 12 months
after baseline visit. During these visits/calls, primary and secondary
endpoints will be assessed.

Substudy:
In addition to the main study procedures, subjects will undergo a Mixed Meal
Tolerance Test (MMTT) 3 times during follow-up to measure changes in GLP-1 and
ghrelin concentrations before and after bariatric endoscopy.

The first test will take place at baseline, for the intervention group at the
utmost of 2 weeks prior to the procedure. Subjects have to withdraw their oral
anti-diabetic medication 12 hours before admission, skip their morning dose of
insulin at the day of admission, but can continue their evening insulin dose
the day before admission. In addition, they have to fast for 12 hours before
the test.

Blood samples will be collected for GLP-1 and ghrelin measurements before the
start of the test. Then, the subject has to eat a standardized meal in 15
minutes (2 slices of bread, 10grams of margarine, 1 slice of cheese, 1 slice of
ham, 1 cup of tea without sugar), and the measurements will be repeated at 30,
60, 90 and 120 minutes. The MMTT will be repeated after 1 month and 6 months.

Subjects in the intervention group will be treated with an ESG with the
endomina ® and TAPES devices (Endo Tools Therapeutics S.A.), both CE-marked for
endoscopic gastroplasty. The endomina is a device that can be attached to an
endoscope and allows remote actuation of the device during a peroral
intervention. Thanks to a therapeutic channel that can be angled
perpendicularly to the axis of vision of the endoscope, it allows the
possibilities of making transoral full thickness tissue apposition and
performing, via a transoral route, large plications with tight serosa to serosa
apposition in the stomach. (Figure 1) This suturing will be done from the
incisura to the upper body of the stomach, along the great curvature (Figure 2)
with TAPES, a single use needle preloaded with suture (Figure 3).
In addition to the endomina device, any other required endoscopic accessories
can be used during the procedure (e.g., grasping forceps, loop cutter).

See chapter 7.3 in the protocol for a more detailed description of the
procedure.

Subjects in the intervention group will receive one meeting with a dietician
from Vitalys, to provide information about adjusting their diet to the reduced
stomach capacity (e.g. eating smaller portions, multiple times a day). Study
follow-up visits will replace standard diabetic care during follow-up.
Subjects in the control group will receive standard diabetic care. At baseline,
one of the researchers will emphasize the importance of guidance by a
dietician.

Adjustments in glucose lowering medication doses (including insulin) will be
performed according to the local protocol.

Benefits:
Several studies have been published evaluating the safety and efficacy of ESG
with the endomina device. The efficacy mainly focussed on weight loss. One case
report published in 2018 showed 2 patients that underwent ESG with the endomina
device. Both patients had a BMI > 35 kg/m². After 3 months, both patients had
relevant weight loss of 7kg and 14kg respectively. No long-term follow-up is
available. Another safety and feasibility study showed a mean percentage excess
weight loss of 9% after 1 month, and 41% after 6 months. No adverse events were
observed. A multi centre prospective trial in 45 obese patients showed a 29%
excess weight loss, and 7% total weight loss after ESG with the endomina. No
adverse events occurred during follow-up. Lastly, a randomized trial presented
the short-term safety and effectiveness of the endomina system on weight loss
in 71 patients with a BMI of 30-40 kg/m². This study showed a 25% better excess
weight loss after 6 months in patients that underwent a combination of
lifestyle modification and endoscopic suture gastroplasty with the endomina,
compared with lifestyle modification alone. This also led to a substantial
improvement in quality of life. No procedure-related or device-related severe
adverse events were seen. In 2022, it was shown that weight loss is independent
from the suturing pattern in a prospective randomized trial evaluating 3
different patterns.

Other studies are published evaluating the effect of ESG using other devices
than the endomina device. Recently, Abu Dayyeh et al. published a RCT doing
ESG with the Apollo device. They mainly focussed on weight loss as well, which
showed a significant difference in mean excess weight loss of 49.2% (SD 32.0)
for the ESG group and 3.2% for the control group (SD 5.0) (p<0.0001). As a
secondary outcome measure they evaluated diabetes related outcomes as well,
showing a significant improvement in HbA1c levels in the intervention group
compared to the control group. However, a decrease in dose of glucose lowering
medication or diabetes remission was not mentioned.

Risks:
Previous studies have shown small periprocedural adverse events of ESG with the
endomina, consisting of small self-contained bleedings, which all stopped when
the knot was tightened. For suturing, a needle is attached to a suture and a
pre-tied knot. First, the needle is pushed through 2 layers of the gastric wall
and the suture and pre-tied knot are released. Then a second plicature is made
on the other side of the stomach. Afterwards, the pre-tied knot is tightened.
The small bleedings occurred only in between these 2 steps.
Adverse events shortly after the procedure were transient abdominal cramps
(79.4%), transient nausea (66.2%), or vomiting (66.2%). In 71 patients, 1
aspiration pneumonia occurred at extubation, which did not require longer
hospitalization or antibiotic treatment. (16) No severe adverse events were
observed, no surgical intervention or readmission were needed, and no mortality
occurred.

In addition, a meta-analysis evaluating 9 studies (1772 patients) using the
Overstitch device for ESG, has shown a severe adverse event rate of 2.2% and no
mortality. Reported severe advents were pain and nausea requiring
hospitalization (1.08%), upper gastrointestinal bleeding (0.56%), perigastric
leak or collection (0.48%), pulmonary embolism (0.06%) and pneumoperitoneum
(0.06%).

Procedural sedation has a low risk of adverse events. In a prospective
observational study in the Netherlands, almost 12.000 patients were included
who received procedural sedation. Minimal adverse events (e.g., vomiting,
muscle rigidity, or agitation) were seen in 1517 (12.8%), minor adverse events
(e.g., oxygen desaturation 75-90% for less than 60s, airway obstruction, or
hypotension) in 113 (1.0%), and major adverse events (e.g., oxygen desaturation
<75% or 75-90% for more than 60s, aspiration, or cardiac arrest) in 80 patients
(0.7%). Five unfavourable patient relevant outcomes (0.07%) occurred within
this study. This included admission to ICU, cardiac arrest and asystole
secondary to pneumodilation of the oesophagus. Another retrospective cohort
included 2937 procedures, in which no catastrophic events and a low rate of
severe events (1.09%) occurred. The most common severe events were severe
desaturation (0.6%) and hypertension (0.2%). Moreover, the most common events
with potential adverse health consequences were significant desaturation (1.6%)
and significant hypotension (8.8%). Nonetheless, no patient experienced health
consequences on the long term.

Substudy:
Most common adverse symptoms of the MMTT are hunger (14%), stomach discomfort
(6%), and belching (7%). These symptoms disappear after finishing the test.