Study confirms duodenal mucosa as therapeutic target in T2D

Removing the excessive layer of the duodenal mucosa via hydrothermal ablation is safe and effective in type 2 diabetes (T2D) patients with or without nonalcoholic liver disease, improving glycaemic control and reducing liver fat content, especially in patients with high fasting plasma glucose (FPG), according to the REVITA-2 feasibility trial.

Known as duodenal mucosal resurfacing (DMR), the procedure cleanses the duodenal mucosa by taking out the extra layer that has developed due to consumption of foods high in fat and sugar. It is minimally invasive and performed in an outpatient setting using a system that consists of a console and a novel single-use balloon catheter, the investigators said.

Physicians use the catheter to access the duodenum and perform hydrothermal ablation, with the console serving to monitor the procedure. A full procedure consists of five sequential ablations of 2 axial centimetres each, starting within 3 centimetres distal to the Ampulla of Vater towards the Ligament of Treitz, adding up to 10 axial centimetres of circumferentially ablated tissue in the duodenum during a single endoscopic session. [Endosc Int Open 2019;7:E685-E690]

The randomized REVITA-2 trial included 108 patients with poorly controlled T2D (HbA1c, 59–86 mmol/mol; fasting insulin >48.6 pmol/L; ≥1 oral antidiabetic medication) from Europe and Brazil. They were 58 years of age on average, and their mean body mass index was 31 kg/m².

A total of 56 patients were assigned to the DMR arm and 52 to the sham arm. This procedure consisted of placing the DMR catheter over the guidewire into the stomach and leaving it in place for 30 minutes before removing it from the patient.

At week 24 post-treatment, patients in the DMR arm saw numerically greater reductions in their HbA1c levels compared with those in the sham arm (median change, −10.4 vs −7.1 mmol/mol; p=0.147). [Gut 2021;doi:10.1136/gutjnl-2020-323608]

In the subgroup of patients with nonalcoholic liver disease (liver MRI proton-density fat fraction [MRI-PDFF] >5 percent; DMR, n=48; sham, n=43), DMR reduced liver fat by 5.4 percent at week 12 post-treatment. This was significantly larger than the 2.9-percent decrease seen in the sham arm (p=0.096).

Prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063). Subsequently, the investigators stratified the results by region.

In the European cohort, both endpoints proved superior in the DMR vs the sham arm. Changes in HbA1c at week 24 were –6.6 vs –3.3 mmol/mol (p=0.033), while those in liver fat at week 12 were –5.4 percent vs –2.2 percent (p=0.035).

The results in the Brazilian cohort showed a trend towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect.

In the entire population, patients with high baseline fasting plasma glucose (≥10 mmol/L) had significantly greater HbA1c reductions with DMR vs sham (p=0.002).

DMR was well tolerated, with most adverse events (AEs) being mild and transient. Common AEs included abdominal pain, diarrhoea, hyperglycaemia, hypoglycaemia, nasopharyngitis, and headache.

“These data provide insight into a potential therapeutic opportunity for DMR to favourably impact both T2D and nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis in a manner that can modify the natural history of these chronic and progressive diseases,” according to the investigators.

They are expecting the release of 48-week follow-up data on the DMR soon, with a pivotal study in T2D insulin-treated patients already in the pipeline. “This will be important research to confirm the metabolic benefits seen thus far in patients with T2D with or without NAFLD, provide long-term follow-up (including biopsies of the duodenal mucosa to further understand the long-term morphological changes), and provide the opportunity to understand the biological mechanisms likely behind the benefit of DMR on the treatment of these pathological conditions.”