Interventional procedure overview of endoscopic duodenal mucosal resurfacing for insulin resistance in type 2 diabetes
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Evidence summary
Population and studies description
This interventional procedures overview is based on 214 people from 1 RCT, 2 prospective cohort studies (1 study with 2 publications) and 1 proof of concept study. Of these 214 people, 157 people had the procedure. This is a rapid review of the literature, and a flow chart of the complete selection process is shown in figure 1. This overview presents 5 studies as the key evidence in table 2 and table 3, and lists 4 other relevant studies in table 5.
Mingrone (2022) was a multicentre double-blind sham-controlled RCT for DMR for people with T2D. The study was done across 11 sites in Europe (9) and Brazil (2), with 56 people having the DMR procedure and 52 having the sham version of the procedure. The baseline characteristics of subgroups were broadly similar. The Brazil subgroup was split close to 50% men and 50% women, while men made up around 76% of patients in European centres. Mean age across the study was 58 years and the follow up was 24 weeks.
The study by van Baar (2022) was a prospective single-arm study for DMR for people with T2D with a 2-year follow up. The study was done across 7 sites in the Netherlands, Belgium, Italy, the UK and Chile. Forty-six people were included for the treatment, but the analysis was only done for up to 33 people. From the baseline set of people (n=34), the mean age was 56.2 years and 64.7% were men.
van Baar (2021) was a prospective cohort study for DMR combined withGLP-1 RA) to stop insulin in T2D. It was carried out in the Netherlands and included 16 people with T2D. The median age of this cohort was 61 years and 63% were men. People were followed up for up to 18 months.
Meiring (2022) was based on the same prospective study as van Baar (2021) but with a focus on cardiovascular health. Cardiovascular outcomes were captured at baseline and at 6 months after DMR.
Rajagopalan (2016) was a phase 1 first-in-human non-randomised proof-of-concept study in a single centre in Chile. It investigated the efficacy and safety of DMR in a cohort of 44 people with T2D. The mean age was 53.4 years and 64% were men. Thirty-nine people had the treatment and were followed up for 6 months.
Table 2 presents study details.
* Results of Mingrone (2022), van Baar (2021) and Meiring (2022) are median (IQR).
Procedure technique
Of the 4 studies, 1 study detailed the procedure technique and devices used in the paper and 3 studies referred to procedure details in referenced studies.
The procedure involves endoscopic exploration under general anaesthetic or deep sedation, followed by submucosal expansion with saline and the hydrothermal ablation of the duodenal mucosa under direct vision with endoscopic or fluoroscopic guidance. The circumferential ablations are done up to 5 times along the length of the post-papillary duodenum. The aim of the hydrothermal ablation is to cause the mucosa to regenerate and treat duodenal dysfunction, which is thought to contribute to insulin resistance.
The device used for this procedure (the Revita system DMR technology) consists of a console and a novel single-use balloon catheter. The console is used to monitor the procedure, while clinicians use the catheter to access the duodenum and do the DMR procedure in an outpatient setting.
The sham procedure (Mingrone, 2022) involved placing the DMR catheter over the guidewire into the stomach and leaving it in place for 30 minutes before removing it from the patient.
Rajagopalana (2016) did 2 variations of DMR: LS-DMR and SS-DMR. The long version, LS-DMR, ablated about 9.3 cm of duodenum tissue, while the short version, SS-DMR, ablated about 3.4 cm of tissue.
Efficacy
Glycaemic endpoints
HbA1c was reported in all 4 studies. The RCT (Mingrone, 2022) found no statistically significant difference in HbA1c change at 24 weeks between the overall DMR and sham groups. The change from baseline in median HbA1c in the Europe subgroup was 6.6 mmol/mol after DMR compared with 3.3 mmol/mol after sham at 24 weeks (p=0.033). Median changes in the Brazil subgroup at 24 weeks were not statistically significant (p=0.104). The PP analysis found that DMR reduced median HbA1c in patients with baseline FPG 10 mmol/litre or higher by 14.2 mmol/mol at 24 weeks compared with 4.4 mmol/mol with the sham procedure (p=0.002) in the whole population and by 13.1 mmol/mol compared with 1.6 mmol/mol after sham in the Europe subgroup (p=0.005). There was no statistically significant difference between treatments in the Brazil subgroup or any group in which baseline FPG was less than10 mmol/litre. Mean HbA1c improvements from baseline of -0.9% to -1.2% were seen at 6 months (van Baar, 2022, p<0.001; Rajagopalan, 2016, p<0.001) and remained at 12, 18 and 24 months (van Baar, 2022, p<0.05). One study (van Baar, 2021) found no statistically significant change in median HbA1c up to 18 months, other than a median HbA1c reduction from 7.5% at baseline to 6.7% at 6 months in the PP analysis (p=0.008, n=11). The LS-DMR group (Rajagopalan, 2016) had greater reductions than the SS-DMR group at 3 months (2.5% compared with 1.2%, p<0.05). The differences were not statistically significant at 6 months (1.4% compared with 0.7%, p=0.30).
FPG was reported in all 4 studies. There was no statistically significant difference between median FPG change from baseline across DMR and sham groups in Europe and Brazil subgroups (Mingrone, 2022). Mean reductions in FPG from baseline were seen at 6, 12, 18 and 24 months (p<0.001). There was a mean reduction of 2.1 ± 2.7 mmol/mol at 6 months and -1.9 ± 2.0 mmol/mol at 24 months (van Baar, 2022). Median FPG was statistically significantly different from baseline at 6, 12 and 18 months (van Baar, 2021). FPG was 10.1 mmol/litre at baseline and reduced to 8.0 at 6 months (p=0.039), 7.1 at 12 months (p=0.006) and 7.3 at 18 months (p=0.011). LS-DMR produced lower FPG at 1 and 3 months than SS-DMR (Rajagopalan, 2016; p<0.05).
HOMA-IR was reported in 3 studies. In the RCT (Mingrone, 2022), DMR reduced HOMA-IR by 1.3 compared with 0.4 after sham in the Europe PP analysis (p=0.047). Statistically significant reductions of HOMA-IR of at least 2.9 were seen for median HOMA-IR at 6 and 18 months (van Baar, 2021; p<0.05) and for mean HOMA-IR at 6 and 12 months (van Baar, 2022; p<0.05).
Fasting C-peptide was reported in 2 studies. After DMR, mean fasting C-peptide had reduced from baseline by 0.8 ± 1.1 ng/mL at 6 months and 0.7 ± 1.0 ng/mL at 24 months (van Baar, 2022; p<0.05). van Baar (2021) found no statistically significant changes to fasting C-peptide at any follow up.
FPI was reported in 2 studies. van Baar (2021) found that DMR with GLP1-RA reduced median FPI from the baseline value of 104 (49 to 178) pmol/litre to 42 (26 to 64) pmol/litre at 6 months (p=0.001), 71 (45 to 121) pmol/litre at 12 months (p=0.116) and 63 (34 to 110) pmol/litre at 18 months (p=0.036). Rajagopalan (2016) reported FPI for the LS-DMR group (n=28) and found no statistically significant change from baseline at 3 and 6 months after DMR.
Postprandial insulin was reported in 1 study (Meiring, 2022). Median postprandial insulin was measured at intervals of 15 to 60 minutes for the first 4 hours after mixed meal tolerance testing. The median values at intervals in the 4 hours after the start of the mixed meal test were all lower at the 6 months after DMR test than they were at the baseline test.
Diabetic medication use was reported in 1 study. At 24 months after DMR, 3% (1/34) of patients had reduced their medication usage, 50% (17/34) of patients' medication had remained unchanged and 47% (16/34) had increased their medication dosage, added an oral medication or added insulin (van Baar, 2022).
Metabolic endpoints
Weight was reported in 4 studies. In the RCT (Mingrone, 2022), median weight loss after DMR was -2.8 kg (IQR=4.5) at 24 weeks; a greater weight loss than in the sham group of -1.5 kg (IQR=3.3; p=0.021). Weight loss was greater in DMR groups than sham groups for the Europe and Brazil subgroups but only statistically significantly different in the Europe subgroup (p=0.012). Average weight loss was seen at various time points after DMR. Mean change from baseline after DMR was -2.6 ± 3.7 kg at 12 months (p<0.001) and -3.1 ± 6.0 kg (p=0.010; van Baar, 2022). Median change at 6, 12 and 18 months after DMR and GLP1-RA was about -7 kg (van Baar, 2021; p=0.001). In the LS-DMR group (Rajagopalan, 2016), weight loss of 3.9 ± 0.5kg was seen at 3 months after DMR (p<0.001) and 2.5 ± 0.1kg at 6 months (p=0.05). Rajagopalan (2016) found no correlation between weight loss and magnitude of HbA1c improvement.
BMI was reported in 2 studies. Median BMI reductions from baseline were seen in both studies (Mingrone, 2022; van Baar, 2021). The RCT found a statistically significantly greater reduction in BMI after DMR than after sham at 24 weeks (p=0.025). In the van Baar (2021) study, median BMI reduction was 2.3 kg/m2 at 6 months, 1.1 kg/m2 at 12 months and 2.4 kg/m2 at 18 months (all p=0.001).
Pancreatic or liver markers were reported in 3 studies. PDFF was reported in 2 studies (Mingrone, 2022; van Baar, 2021). Mingrone (2022) found that, for people with a baseline FPG of 10 mmol/litre or more, DMR produced greater reductions in PDFF at 12 weeks than the sham procedure in the overall group (7.6 compared with 3.1, p=0.01) and the Europe subgroup (8.0 compared with 2.1, p=0.006) but not in the Brazil subgroup (5.4 compared with 6.7, p=0.006). For people with a baseline FPG of less than 10 mmol/litre, there was no statistically significant difference between DMR and sham groups. Baseline median PDFF in van Baar (2021) was 8.1%, which reduced to 5.3% at 6 months (p=0.053) and 5.6% (p=0.035) at 12 months. van Baar (2022) reported on AST and ALT. Statistically significant reductions in AST of 3.7 to 5.7 U/litre after DMR were seen at 6 and 12 months (p<0.05). Statistically significant reductions in ALT of 8.5 to 10.2 were seen at 12 and 24 months (p<0.05).
VAT/SAT were reported in 1 study. Median VAT reduced from 248 cm2 at baseline to 188 cm2 at 6 months after DMR (Miering, 2022; p=0.002). Median SAT reduced from 152 cm2 at baseline to 121 cm2 at 6 months after DMR (Meiring, 2022; p=0.002).
Cardiovascular markers
Cardiovascular outcomes were reported in 1 study (Meiring, 2022). Median daytime systolic blood pressure reduced from 132 (119 to 148) mmHg at baseline to 127 (115 to 137) at 6 months after DMR (p=0.001). Daytime diastolic blood pressure reduced from a median value of 83 (73 to 89) mmHg at baseline to 79 (72 to 86) mmHg at 6 months after DMR (p=0.037). Daytime MAP reduced from 104 (95 to 115) mmHg at baseline to 100 (93 to 109) mmHg at 6 months after DMR (p<0.001). Median heart rate increased from 78 (67 to 84) bpm at baseline to 81 (73 to 89) bpm at 6 months after DMR (<0.001). No statistically significant differences were seen for changes in nighttime or 24-hour measures of systole, diastole and MAP between baseline at 6 months after DMR. Fourteen of 16 patients had no change in their blood pressure lowering medication over the 6 months follow up. One patient started amlodipine 5 mg 3 months after DMR and 1 patient stopped hydrochlorothiazide 3 months after DMR.
Median total cholesterol was statistically significantly lower after DMR (p=0.008). Median cholesterol was 3.64 (3.34 to 4.89) mmol/litre at baseline and reduced to 3.48 (3.18 to 3.97) at 6 months after DMR.
Median LDL reduced from 1.92 (1.49 to 2.30) mmol/litre at baseline to 1.79 (1.49 to 2.30) mmol/litre at 6 months after DMR (p=0.044). Median HDL reduced from 1.21 mmol/litre at baseline to 1.15 at 6 months after DMR, but this was not a statistically significant difference.
Urine microalbumin test revealed lowering of albumin after DMR. The median value at baseline was 7 (3 to 27) mg/litre at baseline and reduced to 4 (3 to 8) mg/litre at 6 months after DMR (p=0.018).
The ASCVD scores indicated that DMR reduced the median risk of atherosclerotic cardiovascular disease. At baseline, the median ASCVD score was 13.6% (5.7 to 26.0) and at 6 months after DMR the median score was 11.5% (4.2 to 22.5). The median scores at both time points indicate intermediate risk of cardiovascular disease. The number of patients considered at high risk (ASCVD scores of 20% or above) reduced from 6 at baseline (37.5%) to 4 at 6 months after DMR (25%).
The DIAL model predicted 82 (81 to 83) ASCVD-free life years at baseline. At 6 months after DMR, the predicted value was 83 (81 to 84).
Treatment satisfaction
DTSQ was reported in 1 study (van Baar, 2022). The mean DTSQ score improved from 27.5 ± 6.6 at baseline to 31.1 ± 5.3 at 12 months (p=0.0039), and 30.1 ± 6.1 at 24 months (p=0.0699).
Safety
Safety outcomes were reported in all 4 studies. Across studies, 157 patients were treated with DMR and 229 AEs were reported (including 7 SAEs).
Metabolic symptoms
In the Mingrone (2022) RCT (n=56 for DMR), 68 of 94 AEs were instances of hypoglycaemia. For people in the sham arms (n=52), there were 80 instances of hypoglycaemia out of 89 AEs. One case of hypoglycaemia and 1 case of hyperglycaemia were reported by van Baar (2022; n=46). van Baar (2021) reported 1 case of either hypo/hyperglycaemia (n=16) and none were reported by Rajagopalan (2016).
SAEs
Three SAEs in 1 paper were haematochezia, haemorrhoid and jejunal perforation (Mingrone, 2022; n=56 for DMR).
GI symptoms
GI-related AEs were described in 4 studies. Mingrone (2022) reported abdominal pain (16), nausea (3), diarrhoea (2) and vomiting (2) for their 56 patients having DMR. van Baar (2022) reported abdominal pain (13), diarrhoea (11), nausea (7), oropharyngeal pain (5), constipation (2), vomiting (2), throat irritation (1) and 1 other GI symptom. One study reported 31 non-specific GI symptoms (van Baar, 2021; n=16). Rajagopalan (2016) reported 8 instances of abdominal pain and 3 instances of duodenal stenosis which presented as epigastric pain and vomiting.
General symptoms
General symptoms such as malaise and fatigue were detailed by 2 studies. van Baar (2022; n=46) reported 3 instances of musculoskeletal pain, 2 instances of malaise and 1 instance for each of fatigue, rash, influenza-like illness, body temperature increase and C-reactive protein increase. The other study reported 17 general symptom AEs and 16 infections (van Baar, 2021; n=16).
Anecdotal and theoretical AEs
Expert advice was sought from consultants who have been nominated or ratified by their professional society or royal college. They were asked if they knew of any other AEs for this procedure that they had heard about (anecdotal), which were not reported in the literature. They were also asked if they thought there were other AEs that might possibly occur, even if they had never happened (theoretical).
They listed the following anecdotal AEs:
Difficulty swallowing
Perforation
Stenosis
Sore throat
Stricture
Bleeding
Abscess formation
Anaesthesia complication
Duodenal perforation/haemorrhage
Pancreatitis.
They listed the following theoretical AEs:
Device-related risks, such as:
Allergic reaction
Device dysfunction
Disarticulation of component from the device
Device/component lost in GI tract or wall
Puncture damage to surrounding structures (for example, liver, pancreas).
Six professional expert questionnaires for this procedure were submitted. Find full details of what the professional experts said about the procedure in the specialist advice questionnaires for this procedure.
Validity and generalisability
Across studies, the direction of the evidence mostly supports the efficacy of DMR in the reduction of HbA1c and other T2D-associated factors.
The outcomes differed in measurement (median compared with mean) or units across studies, so comparisons of outcomes between studies should be done with care.
Across outcomes in the Mingrone (2022) RCT, values differed to support either DMR or the sham procedure across the Europe and Brazil subgroups. The baseline characteristics of the 2 subgroups were broadly similar, but it is believed that the Brazilian population had a more intensive approach to treatment of diabetes and dieting, which explains some of the HbA1c treatment effects.
van Baar (2022) discussed that changes in insulin resistance in their study were, in large part, driven by reductions in FPG.
Rajagopalan (2016) found no correlation between weight loss and magnitude of HbA1c improvement.
The sample sizes of people having DMR ranged from 16 to 56 patients. The procedure is somewhat novel (earliest paper 2016), but these are small samples to draw strong conclusions from.
The demographic characteristics were similar across studies. They seem somewhat representative of the T2D population in England (National Diabetes Audit), although men are slightly overrepresented as study participants.
Follow up ranged from 24 weeks to 24 months. Where reductions were seen in the shorter term (3 to 6 months), some papers were able to present sustained reductions from baseline in a given outcome in the longer term (12 to 24 months).
The 2 most recent studies, Mingrone (2022) and van Baar (2022), included centres in the UK.
There is overlap in authorship across the included studies.
All 4 of the included studies included, at least 1 author who has worked for or had connections to Fractyl Laboratories.
Inclusion criteria were similar across the studies.
An RCT study NCT04419779 is enrolling up to 560 people for this procedure compared with sham and is due to be completed in January 2025.
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