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 (SI). 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. SI, insulin secretion, glucose rate of appearance (Ra), metabolomics, and faecal microbiota were analysed. Results: ForePass improved SI 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 Ra 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.