麻豆传媒

CHICAGO -- A novel approach to revitalizing the duodenal mucosa as a means to restore normal insulin sensitivity in people with type 2 diabetes is showing strong promise in early studies, according to results presented here.

In two single-arm trials of a , reported at Digestive Disease Week (DDW), patients with either poorly controlled or insulin-dependent type 2 diabetes showed improved glycemic control, reduced insulin resistance, and lost substantial amounts of weight, with only minimal adverse effects.

Most patients in one of these trials, who also received semaglutide (Ozempic), were able to end their daily insulin while still achieving all those other improvements, according to Jacques Bergman, MD, PhD, of Amsterdam University Medical Center in the Netherlands.

The ReCET treatment involves snaking a catheter down the esophagus into the duodenum to deliver high-frequency pulses of electrical energy that essentially punch holes in the outer membrane of epithelial cells. Called electroporation, it's the same basic technology to insert novel genetic material into plant cells. Here, however, the goal is to induce apoptosis in dysfunctional duodenal epithelial cells, which are then replaced by new and more active ones.

Underlying this approach is recognition that the duodenum is not an inert pipeline but an active and critical regulator of metabolic activity, an organ that responds to nutrients and other substances passing out of the stomach. In type 2 diabetes, its reactivity goes haywire. Thus the idea is that forcing the duodenal lining to renew itself may restore its normal function.

Bergman has headed other efforts in this direction. In 2019, his group with a thermal ablation device in 46 patients, showing marked improvements in HbA1c levels and reduced insulin resistance lasting the full 12 months of follow-up. However, the procedure wasn't completed successfully in 10 of the 46 patients (the investigators blamed the device's novelty and endoscopists' unfamiliarity with it), and half of the rest experienced adverse effects (severe in one patient) related to the thermal ablation. As electroporation literally does not bring heat, and its depth of penetration can be controlled precisely, it's hoped that it will be better tolerated.

That seems to have been borne out in the new studies. The larger of the two, reported here by Adrian Sartoretto, MBBS, of The BMI Clinic in Double Bay, Australia, has so far yielded results in 41 patients, whose HbA1c averaged 8.7% at baseline with mean insulin resistance values of 5.5. They were allowed to continue on background medications such as metformin.

Sartoretto said there were "no device or procedure-related" serious adverse events. Nineteen did report mouth and throat pain, resulting from the peroral endoscopy, and 10 reported diarrhea. But rates of diarrhea and other gastrointestinal symptoms decreased during follow-up, when patients were recommended to follow a standard diabetic-management diet.

Partway into the study, interim findings led the investigators to double the number of ablations and to up the voltage somewhat. This did not increase the rate of adverse effects, Sartoretto said. It did, however, increase the procedure's efficacy. Among 12 patients receiving the single 600V dose, mean HbA1c declined 0.4 percentage points at week 12, and by week 24 it was only 0.3 points less than at baseline. With double doses, the mean decline from baseline was 1.0 point at week 12 and 0.8 at week 24.

Similarly, the double dose led to lasting decreases in fasting plasma glucose (by about 2 mmol/L), while the single dose had only a small effect on this parameter. Even more interesting was that while both the single and double doses induced loss of about 3.5% of total body weight at week 12, by week 24 body weight had returned almost to baseline in the single-dose group whereas it increased further to about 4.2% below baseline with the double dose.

Bergman's study in the Netherlands was conducted a bit differently. Fourteen patients with type II diabetes using basal insulin daily (<1U/kg/day), but with HbA1c of 8.0% or less, were enrolled. Following electroporation, participants were kept on an isocaloric liquid diet for 2 weeks, and then semaglutide was started with gradual escalation to 1 mg/week.

In contrast with the thermal ablation, this time procedural success was 100%, with no serious adverse effects related to the device. One patient did experience a hypoglycemic episode during follow-up but it did not require medical treatment.

Within 3 months, 12 of the 14 patients were able to end their daily insulin and they were able to stay off it through 12 months. HOMA-IR values declined from a mean 5.84 at baseline to 2.47 at month 6 (the only time point reported), and mean fasting plasma glucose fell by 2.0 mmol/L to 6.8.

Weight loss was substantial too: from an average 90.7 kg at baseline to 77.6 at month 6; similarly, mean BMI declined from a baseline average of 28.8 to 24.9.

At a DDW press conference held prior to the conference, Bergman commented that this approach has several advantages over conventional management of type 2 diabetes. Not least of these is that it doesn't require much in the way of patient compliance, as opposed to daily or weekly drug-taking. Maintaining long-term adherence is key to success, but this has proved difficult to impossible for most people.

Moreover, Bergman said, duodenal ablation "is disease-modifying [for] insulin resistance, as opposed to drug therapy which, at best, is disease-controlling." In a separate talk here, the senior investigator on Sartoretto's team, Barham Abu Dayyeh, MD, of the Mayo Clinic in Rochester, Minnesota, speculated that the resurfacing could be repeated "every 1 or 2 years" if necessary to maintain the effects, as the electroporation creates no lasting tissue damage or scarring.

Bergman said a double-blind controlled trial of the ReCET device is now underway, although Clinicaltrials.gov has no current listing for it.