Proximal intestinal mucosal ablation (PIMA) is a metabolic endoscopic procedure that aims to replicate the glycaemic benefits of gastric bypass surgery in patients with type 2 diabetes (T2D). This is achieved by endoscopically ablating up to 60 cm of the abnormal, hypertrophied intestinal mucosa. PIMA is completed with the through-the-scope, radiofrequency vapor ablation (RFVA) mesh-tip catheter. In our first in-human study, we investigated RFVA as a modality of duodenal mucosal ablation for the treatment of T2D, which is limited to 15 cm of treated duodenum. We hypothesised that a longer ablation length could lead to an improved and more durable glycemic response without compromising safety. Accordingly, we report the first-in-human evaluation of PIMA, which aimed to assess its safety, tolerability, feasibility, and early efficacy.

A prospective, single-centre first-in-human study evaluating PIMA using RFVA for the treatment of uncontrolled T2D (glycated haemoglobin [HbA1c] 7.5-10.0%) despite ≥1 oral glucose-lowering agent (GLA) within Clinica Colonial, Santiago (NCT05887635). After screening, patients underwent a 4-week run-in period to ensure stable glycaemic control before undergoing PIMA between September 2024 and May 2025, alongside standard lifestyle advice for T2D and no change in GLAs. PIMA was performed via an adult colonoscope (Olympus HQ190L) with the circumferential through-the-scope mesh-tip RFVA catheter under general anaesthesia. RFVA was delivered at a dose of 250-275J with double application (2X) to the post-ampullary intestinal mucosa. Patients were discharged within 24 hours on a modified day for 14 days. Technical success was defined as ≥20 cm of ablated post-ampullary mucosa. The primary outcomes were safety (serious adverse events), tolerability (visual analogue score [VAS] for pain post-procedure), feasibility (procedure time and ablation length), and reduction in HbA1c at 3- and 6-months. Secondary exploratory outcomes included change in body mass index (BMI) and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). 

In total, 13 patients (38.5% female) with an average age of 52 years (IQR 45-61) underwent PIMA. The average T2D disease duration was 6 years (IQR 5-9), the baseline HbA1c was 9.3% (SD 0.7), BMI was 31.4 kg/m2 (SD 2.5), and the average number of GLAs was 1 (IQR 1-2). PIMA was successful in all patients with an average treatment length of 54 cm (IQR 44-60) and 40.8 (SD 10.7) ablations. Six patients were treated with a 250 J dose, and seven patients with 275 J. The average procedure time was 62.2 minutes (SD 14.4) and catheter time 51.3 minutes (SD 19.2). PIMA was well-tolerated with a maximum median VAS score of 1 (IQR 0-2) on day 2. All patients reached six months follow-up, and there were no adverse events related to the procedure or episodes of hypoglycaemia. Follow-up enteroscopy with biopsy was normal in all patients. The median reduction in HbA1c at 3- and 6-months was 2.5% (IQR 1.4-2.9; p<0.0001) and 2.2% (IQR 1.0-2.5; p=0.0001), respectively. Over the same period, we observed a non-significant reduction in BMI by 0.6 kg/m2 (SD 1.3; p=0.13) and 1.0 kg/m2 (SD 1.9; p=0.08), as well as reductions in HOMA-IR by -2.7 (SD 3.3; p<0.05) and -2.0 (SD 3.3; p=0.05), respectively.

PIMA appears to be a safe, feasible, and well-tolerated metabolic endoscopic procedure that leads to major reductions in glycated haemoglobin comparable to modern injectable pharmacotherapies.