Introduction
Worldwide, 387 million people are diagnosed with type 2 diabetes mellitus (T2DM),
and the number continues to rise at an alarming rate in every country [1]. Despite lifestyle interventions and the increasing array of pharmacological therapies,
most patients with T2DM fail to achieve established treatment goals to prevent complications
[2]. Recently, minimally invasive endoscopic treatment options for T2DM have emerged.
Evidence from bariatric surgery and the duodenal-jejunal bypass liner highlights the
importance of the small bowel, especially the duodenum, in glucose homeostasis and
metabolic regulation [3]. If contact between the duodenal mucosa, bile, and nutrients is prevented or altered,
then insulin sensitivity improves and β-cell function increases [4]
[5]
[6]. These improvements are quickly reversed when the bypassed duodenum is re-exposed
to nutrients, underscoring the glucoregulatory role of the duodenum [4]
[7]
[8].
Duodenal mucosal resurfacing (DMR) is a minimally invasive endoscopic procedure involving
catheter-based hydrothermal ablation of duodenal mucosa [9]. DMR may offer a new minimally invasive treatment approach for insulin-resistant
metabolic diseases, including T2DM, nonalcoholic fatty liver disease (NAFLD), and
nonalcoholic steatohepatitis (NASH) [10]
[11]
[12]. The first multicenter study reported durable and substantial glycaemic improvement
in patients with T2DM as well as a decrease in liver transaminase levels [10] at 24 weeks and 12 months [11]. Here we report on and evaluate the procedural feasibility of DMR. More specifically,
we elaborate on DMR catheter development and improvements and endoscopic procedure
optimization. In addition, we provide tips and tricks for endoscopists in order to
conduct a successful DMR procedure.
Patients and methods
Study design
We evaluated endoscopic feasibility data from the first open-label, single-arm, multicenter
study (NCT02413567) conducted at seven clinical sites in the EU and Chile (Academic
Medical Center of Amsterdam, Netherlands; Erasme University Hospital Brussels, Belgium;
Policlinico Gemelli, Catholic University of Rome, Italy; University College Hospital
London, United Kingdom; CCO Clinical Center for Diabetes, Obesity and Reflux, Santiago,
Chile; King’s College Hospital, London, United Kingdom; and University Hospital Leuven,
Leuven, Belgium) [11]. At each site, a single endoscopist performed the DMR procedure after completing
initial didactic and hands-on DMR training in a porcine model. The study protocol
was approved by the independent ethics committees at each center. The study was conducted
in accordance with Good Clinical Practice Guidelines and the Declaration of Helsinki.
Patients
Eligible patients had T2DM and used oral glucose-lowering medication, were aged 28
to 75 years, had a body mass index between 24 and 40 kg/m2 and hemoglobin A1c (HbA1c) between 59 and 86 mmol/mol (7.5 %–10.0 %). Main exclusion
criteria were Type 1 diabetes (including positive GAD antibodies), use of injectable
glucose-lowering medication, previous gastrointestinal surgery that could affect the
ability to treat the duodenum (eg, Bilroth 2 or Roux-en-Y gastric bypass), history
of pancreatitis, and upper gastrointestinal bleeding. The complete eligibility list
is available in te recently published efficacy study [11]. Written informed consent was obtained from all patients at screening.
Endoscopic setting
The DMR procedure was performed under general anesthesia or deep sedation with propofol,
according to local guidelines and the endoscopists’ preference. First, a screening
gastroduodenoscopy was conducted to ensure there were no conditions that would impede
the DMR procedure (e. g., erosive esophagitis ≥ grade C, gastroduodenal ulcers, varices,
strictures, or telangiectasia). Next, the papilla of Vater was marked on the contralateral
duodenal wall using argon plasma coagulation (APC) or a hemostasis clip, to mark the
proximal margins of the intended ablation zone. Then, a guidewire (recommended: Jagwire
0.035” Stiff Shaft [Boston Scientific, Marlborough, Massachusetts, United States])
was placed past the ligament of Treitz to assist delivery of the DMR catheters. Fluoroscopy
was used to verify the delivery and positioning of the guidewire.
Initial modifications of the DMR procedure
Prior to this multicenter study, three patients from the first-in-human study developed
a duodenal stenosis within 6 weeks after the procedure [12]. The stenoses were resolved by endoscopic balloon dilatation without further sequelae.
Root cause analysis revealed that overlapping ablations and ablation of non-lifted
duodenal mucosa were the likely causes for development of these duodenal stenoses
after DMR. Therefore, the following modifications were made to the DMR procedure prior
to initiation of the multicenter study: 1) ablation was performed from proximal to
distal (instead of distal to proximal as was done in the first-in-human study) to
optimize endoscopic visualization and avoid overlapping ablation zones and minimize
the length of time elapsed between submucosal injection and ablation; and 2) mucosal
lifting was performed more extensively to avoid ablation of non-lifted mucosa. All
participating endoscopists reached a consensus on the optimal DMR procedure during
a joint meeting with hands-on training in a porcine model.
DMR procedure with double catheter system
Initially, DMR was performed with two catheters (Fractyl Laboratories, Inc., Lexington,
Massachusetts, United States): a submucosal expansion (SE) catheter and a hot fluid
(HF) catheter. The SE catheter was tracked over the guidewire into the horizontal
part of the duodenum just distal to the clip/APC mark (papilla) to measure the inner
diameter of the post-papillary duodenal lumen. The endoscope (pediatric colonoscope)
was positioned just proximal to the balloon at the tip of the catheter. Then three
vacuum-assisted needles around the tip of the SE catheter were used to inject saline
into the submucosal space. Six to nine consecutive submucosal lifting cycles were
performed to ensure submucosal lifting of the postpapillary duodenal area targeted
for ablation. Between each lifting cycle, the catheter en endoscope was positioned
1 to 2 cm distally. Then, the SE catheter was replaced with a HF catheter (with fixed
balloon diameter of 19, 21, 23 or 25 mm based on the SE catheter measurements). Three
consecutive non-overlapping hydrothermal ablations of the lifted area were performed
with a 3-cm HF balloon under endoscopic visualization. Between each ablation cycle,
the catheter and endoscope were positioned 3 cm distally. A complete DMR procedure
was defined as three ablations corresponding with a 9-cm circumferential ablation
of post-papillary duodenal mucosa.
DMR procedure with integrated catheter
During the course of this study, a single catheter ([Fig. 1]) became available that integrated submucosal lift and hydrothermal ablation functions.
The novel catheter eliminated the need for catheter exchanges during the procedure
and helped ensure that ablation was performed immediately after submucosal lift of
the same segment of duodenum ([Video 1]). The DMR catheter was introduced over the guidewire and positioned just distally
of the marking of the papilla in the duodenum. The tip of the endoscope (pediatric
colonoscope) was positioned just proximal to the balloon guided by the reference markers
on the catheter. The single integrated catheter has three vacuum-assisted submucosal
injectors around a 2-cm ablation balloon at its distal end to enable lifting of the
duodenal mucosa. To ensure optimal lifting prior to mucosal ablation, every second
lifting cycle was followed by a circumferential mucosal ablation. The catheter was
advanced proximally 1 cm distally after each lifting or lifting-ablation cycle. Five
ablations were performed to achieve a total duodenal ablation length of 10 cm, defining
a complete DMR procedure.
Fig. 1 Integrated duodenal mucosal resurfacing balloon catheter. Single ring to be positioned
just proximally of the previous ablation to perform a consequent ablation. Double
ring indicates the furthest acceptable position of the endoscope.
Video 1 Stepwise explanation of endoscopic duodenal mucosal resurfacing procedure.
Post-procedural care
Patients were discharged within 24 hours after the procedure, depending on the local
center’s guidelines. Prior to discharge, patients were prescribed a 2-week post-procedure
diet that progressed from clear liquids to solid foods to facilitate mucosal healing.
The follow-up protocol and efficacy outcomes can be appreciated from our recently
published study [11].
Outcomes
Feasibility endpoints included successful completion of submucosal expansion and mucosal
ablation, defined as three (double catheter system with ablation balloon of 3 cm)
or five (single catheter system with ablation balloon of 2 cm) ablations and procedure
time (calculated from the time of insertion of the endoscope until removal of the
guidewire and catheter). Data are presented as mean (standard deviation [SD]) or percentage
where applicable. We created a table with tips and tricks for future endoscopists
to facilitate an optimal procedure.
Results
Procedure time
In total, 46 patients underwent DMR. The first 28 patients who received double-catheter
DMR had a mean (SD) procedure time of 96 (34) minutes. Once available, the single
catheter was used for all subsequent 18 patients, which reduced the mean DMR procedure
time significantly to 71 (23) minutes (P = .031).
Successful completion
The DMR procedure was completed (i. e., 3 ablation zones totaling 9 cm) in 22 of 28
patients (79 %) in the double-catheter group. The full DMR treatment was not performed
in six patients, due to catheter failure (n = 4), tortuous anatomy (n = 1), and difficulty
with catheter positioning (n = 1). In the single integrated catheter group, the DMR
procedure was completed (i. e., 5 ablation zones totaling 10 cm) in 15 of 18 patients
(83 %). Full DMR treatment was not possible in three patients due to difficulty with
catheter handling and positioning.
A stepwise explanation of the DMR procedure, including challenges and advice for how
to overcome them, is provided in [Table 1].
Table 1
Tips and tricks for a successful DMR procedure.
|
|
Challenges
|
Don’ts
|
Photo
|
|
Step
|
Positioning of the patient
|
|
|
0
|
The preferred patient position is left lateral. In centers where general anesthesia
is used, patient position can be supine.
|
In case proximal looping is observed in the stomach or during passage into the duodenum,
turn the patient left lateral/probe.
|
|
|
|
Introduction of the catheter
|
|
|
1
|
Lubricate the tip of the catheter with PAM or other lubrication agent.
|
|
|
|
|
2
|
Avoid looping of the guidewire at the cardia during catheter advancement over this
guidewire.
|
In case the guidewire loops in the cardia, retract the guidewire slightly without
losing length in the jejunum, before the tip of the catheter turns to the fundus.
|
Guidewire loops in stomach
|
Guidewire retracted
|
|
Passage of catheter through stomach into duodenum
|
|
|
3
|
Advance catheter along the greater curvature of the stomach until passage into the
duodenum D1/D2.
|
In case the catheter loops in the stomach instead of entering the duodenum, then straighten
the catheter and introduce the endoscope into the stomach to assist advancement of
the catheter through the pylorus. Deflate the stomach as much as possible.
|
Do not advance the catheter past the clip, the endoscope will push the catheter even
further to a too distal position in the duodenum. Withdrawal of the catheter will
result in disconnecting the loop of the endoscope and catheter.
|
Catheter enters duodenum with endoscope introduced
|
|
4
|
Advance endoscope by following the catheter along the greater curvature of the stomach
and enter the pylorus.
|
|
Try not to disconnect the loop of the endoscope and the catheter during the procedure.
|
Follow catheter in greater curvature stomach
|
|
5
|
Position scope in duodenum just proximally of the single marker band on the catheter.
|
|
|
|
|
6
|
Advance scope and catheter just distally of the clip (marking level of papilla) maintaining
visualization of the orientation point on the catheter (single marker band). Move
endoscope and catheter simultaneously. Keep an eye on the guidewire.
|
|
Do not push on the balloon to advance the catheter but use the proximal plastic plot
to anchor the scope to the catheter.
|
Black marking on ablation catheter aligned with clip
|
|
7
|
Oriente and optimize X-ray so that the triangular tip of catheter is projected horizontal
in X-ray image.
|
|
Suboptimal fluoroscopic support
|
Optimal fluoroscopic support due to turn fluoroscopy unit
|
|
8
|
Store first X-ray image.
|
|
|
Balloon inflated just past clip for first lift
|
|
Start of DMR lifting and ablation cycles
|
|
9
|
Lift 1
|
|
|
First lift, just distal of clip (marking papilla)
|
|
10
|
Move scope and catheter for 2 duodenal folds distally (± 1 cm).
|
In case the catheter/endoscope does not advance in the duodenum or it meets with too
much resistance, undo the loop of endoscope and catheter in the stomach. Use the endoscope
stiffener (if available) and gentle traction on the guidewire while advancing the
scope and catheter. If this fails, change the patient’s position.
|
|
|
|
11
|
Check with X-ray and compare with the previous stored image, and store this image.
|
|
|
Catheter 1 cm distally of first lift to perform second lift
|
|
12
|
Lift 2
|
|
|
Second lift
|
|
13
|
Check with X-ray for stable position after second lift and compare with previous stored
image, and store this image.
|
When you need to reposition the scope or catheter, withdraw scope or catheter and
advance until again forward movement occurs and both loops are restored in parallel.
|
Avoid withdrawal of endoscope or catheter separately during whole DMR session. This
will uncouple the parallel loops in the stomach and scope and catheter will no longer
move one on one.
|
Stable endoscopic position to perform first ablation
|
|
14
|
Perform ablation 1.
|
|
|
First ablation, mucosa gets a white aspect
|
|
15
|
Move scope and catheter for 2 duodenal folds distally.
|
|
|
Ablated mucosa after deflation balloon
|
|
16
|
Repeat steps 9 to 15 until 5 ablations are completed.
|
If a needle port disconnects from the balloon and kinks (visible on X-ray), further
lifting cannot be performed adequately. Replace the dysfunctional catheter with a
new catheter.
|
Two ports slightly deviating (sign of disconnection)
|
Two ports kinked, catheter should be replaced
|
DMR, duodenal mucosal resurfacing.
Discussion
DMR is a promising minimally invasive endoscopic procedure that appears to elicit
robust and sustained improvements in metabolic parameters after a single treatment
in patients with T2DM. Data from the first international, multicenter study suggest
that DMR is feasible, safe, and effective in patients with T2DM that is suboptimally
controlled with oral glucose-lowering medication with a considerable glucose lowering
effect and a reduction in hepatic transaminase levels [10]
[11]. Reported AEs are reassuringly mild and consistent with what is observed with other
general upper gastrointestinal therapeutic endoscopic approaches. No cases of duodenal
stenosis were reported after the initial DMR procedure modifications prior to this
study.
Conclusions
The goal of the multicenter study was to deliver a uniform DMR to the T2DM study population.
During the study, the introduction of a new, single DMR catheter resulted in an overall
reduction in procedure time and increased ability to perform a complete DMR procedure.
DMR appears to be a safe endoscopic procedure which is feasible in the hands of experienced
endoscopists. With the introduction of the integrated DMR catheter during this study,
the system matured and is ready for more extensive studies and possibly also for the
first clinical applications. However, a procedure success rate of 83 % indicates that
technical feasibility is not a given and a reduction in procedure time is desirable.
Further optimization of the technique would be valuable prior to widespread dissemination.
Our video and the table of practical advice from experienced DMR endoscopists are
beneficial tools to increase success rate and reduce procedure time, especially for
newly trained DMR endoscopists.
Further clinical investigations, including liver imaging and histology, are currently
underway and a double-blind, sham-controlled, randomized trial is being finalized.
Mechanistic interrogation of the DMR effect also is underway in both animals and human
subjects.
