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 (S$_{I}$). 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. S$_{I}$, insulin secretion, glucose rate of appearance (R$_{a}$), metabolomics, and faecal microbiota were analysed. Results: ForePass improved S$_{I}$ 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 R$_{a}$ 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.