Long-term freedom from insulin may be achieved with duodenal electroporation plus semaglutide

The combination of re-cellularization via electroporation therapy (ReCET) plus semaglutide appears to improve glucose control and metabolic health and eliminate the need for insulin therapy in most patients with type 2 diabetes (T2D), with the effects maintained up to 2 years, according to the follow-up data from the single-arm, dose-finding, first-in-human EMINENT trial.

In EMINENT, 14 patients with T2D underwent a single ReCET procedure under deep sedation followed by a 2-week isocaloric liquid diet. They were then initiated on semaglutide, which was titrated up to 1 mg/week. At baseline, the patients were overweight (average weight 90.7 kg, average BMI 28.8 kg/m², average waist circumference 107 cm) and were receiving 27 insulin units daily.

The efficacy endpoint of the percentage of patients off insulin while maintaining adequate glycaemic control (HbA1c ≤7.5 percent) was 100 percent (n=14) at 3 months (100 percent), then slightly dropped to 86 percent (n=12) at 6 and 12 months. [EASD 2024, abstract 669]

Presenting the 24-month data at EASD 2024, lead investigator Dr Celine Busch from the Amsterdam University Medical Center (UMC) in Amsterdam, the Netherlands, pointed out that the two patients in whom insulin was needed again at 6 months received the lowest ablation dose (600 V).  

Results for glycaemic parameters showed significant improvements from baseline to 12 months in fasting glucose (from 8.8 to 6.6 mmol/l; p=0.003), HbA1c (from 7.1 percent to 6.5 percent; p=0.010), HOMA-IR (from 5.84 to 1.78; p=0.002), and time in range (from 73 percent to 89 percent; p=0.011). At 24 months, only the change in HOMA-IR remained significant (3.16 percent; p=0.008).

As for the metabolic parameters, the significant reductions observed from baseline to 12 months were maintained through 24 months for weight (from 90.7 to 74.0 kg and 73.0 kg; p=0.002 and p=0.003, respectively), BMI (from 28.8 to 22.6 kg/m² and 23.6 kg/m²; p=0.002 and p=0.003, respectively), and liver fat (from 9.2 percent to 4.2 percent and 3.9 percent; p=0.016 and p=0.006, respectively).

These findings indicate that in patients with T2D, a single ReCET procedure combined with a GLP-1 receptor agonist (RA) led to durable insulin elimination up to 24 months in 100 percent of the responders while maintaining glycaemic control, even though the glycaemic parameters slightly worsened at 24 months than at 12 months, Busch said. Moreover, metabolic health was improved.

Duodenal ablation safety

Duodenal ablation is an endoscopic procedure known to have positive effects on hyperglycaemia, which leads to the need for exogenous insulin therapy in many patients, according to Busch. A novel approach to this procedure is ReCET, wherein electrical pulses are sent through the mucosa to induce natural cell death without generating heat and to promote duodenal mucosal renewal, she added.

“The benefit is mainly that there is no risk of damaging the deeper layers of the duodenum,” Busch said.

All 14 patients (average age 62 years, 57 percent male) in EMINENT underwent ReCET at Amsterdam UMC. Given the dose-finding nature of the study, the dosage of ablation was increased in every four patients, with patients 1–4 receiving single 600-V ablations, patients 5–7 receiving single 750-V ablations, and patients 10–14 receiving double 750-V ablations.

ReCET had a technical success rate of 100 percent, with a median axial treatment length of 12 cm. The procedure took a median of 58 minutes to complete.

No procedure-related serious adverse events (AEs) or severe hypoglycaemic events were reported. In the first year of follow-up, one patient had a hypoglycaemic event that did not require third-party assistance. Mild procedure-related AEs occurred, including nine cases of sore throat and two cases of obstipation.  

Meanwhile, a total of 24 mild-to-moderate GLP-1 RA-related AEs were documented, including five cases each of nausea and loss of appetite. These events were consistent with the known side effects of semaglutide. All but one patient (93 percent) tolerated the maximum dose of semaglutide.

“At the second year of follow-up, the only thing we saw was a moderate GLP-1 RA-related AE,” namely diarrhoea, Busch said.

The investigator shared that she and her team used EMINENT as a basis for the sham-controlled trial, EMINENT-2, that they are currently conducting. She added that they are considering the potential benefits of repeated ReCET procedures on glycaemic control.

When asked whether the majority of the benefit seen in EMINENT wasn’t just due to semaglutide, Busch responded that while she cannot definitively say, the current sham-controlled trial aims to determine if ReCET alone has a significant effect. She added that previous duodenal ablation studies have shown benefits from the procedure itself, but in EMINENT, ReCET was combined with semaglutide, which makes it challenging to isolate the specific contribution of each component.