ForePass outperforms Semaglutide in weight control, glucose metabolism, and gut microbiota in swine

Aims: This study evaluated the metabolic efficacy of ForePass-a novel, incision-free, reversible, endoscopically delivered device that mimics biliopancreatic diversion-in growing pigs. The primary aim was the superiority of ForePass over Semaglutide in improving insulin sensitivity (S₈). Secondary aims included effects on weight gain, endogenous glucose production (EGP), disposition index (DI), oral glucose rate of appearance, plasma metabolomics, and faecal microbiota. Materials and methods: Over 30 days, 12 young Landrace pigs (46. 7 ± 1. 1 kg) received ForePass, twice-weekly Semaglutide, or sham endoscopy. Sample size was calculated a priori for the primary endpoint (Δ = 0. 6 min^-1·pM^-1, SD = 0. 3, α = 0. 05, 80% power), yielding n = 4 per group. Body weight was monitored, and oral glucose tolerance testing (OGTT) with stable isotope tracers assessed hepatic glucose disposal. S₈, insulin secretion, glucose rate of appearance (R₀), metabolomics, and faecal microbiota were analysed. Results: ForePass improved S₈ more than Semaglutide (2. 75 ± 0. 37 vs. 1. 34 ± 0. 21 min^-1·pM^-1) and sham (0. 78 ± 0. 46; p <0. 05). Weight gain was 2. 0 kg (4%) with ForePass, versus 16. 3 kg (36%) with Semaglutide and 21. 1 kg (47%) with sham (p <0. 0001). Semaglutide reduced weight gain by 11% versus sham (p <0. 05). DI was 2. 6-fold higher with ForePass than Semaglutide and 3. 5-fold higher than sham. ForePass reduced oral glucose R₀ by 40% versus Semaglutide and 30% versus sham, while EGP 46% was lower than Semaglutide and 51% lower than sham (p <0. 0001). Metabolomics showed ForePass increased ketogenic and branched-chain amino acids, whereas Semaglutide raised lactate and alanine. Only ForePass increased faecal Akkermansia muciniphila. Conclusions: ForePass produced superior insulin sensitivity and weight outcomes versus Semaglutide. Its distinct effects on glucose disposal, metabolomics, and microbiota support development as a reversible, incision-free endoscopic therapy that may bridge the gap between pharmacological and surgical options for obesity and type 2 diabetes.