Additive effects of GLY-200 (oral pharmacologic duodenal exclusion therapy) and GLP-1R agonist in obesity management

Abstract

Type 2 diabetes and obesity impact billions of people and the global prevalence is only growing. Current treatment options, which include pharmacotherapy, e.g., GLP-1 receptor agonists (GLP-1RA) and bariatric surgical approaches have limitations. GLY-200 is an investigational clinical-stage oral non-absorbed polymeric drug designed to target proximal intestinal mucin and enhance its barrier function, emulating duodenal exclusion physiology for the treatment of diabetes and obesity. The efficacy of GLY-200 as a monotherapy and in combination with semaglutide, a leading GLP-1 receptor agonist (GLP-1RA) for obesity weight management was evaluated in diet-induced obesity (DIO) mice. Significant improvements in metabolic parameters were seen in mice treated with GLY-200 monotherapy. Moreover, an additive effect was observed when GLY-200 was combined with semaglutide, resulting in enhanced weight loss and metabolic improvements beyond those achieved with either treatment alone. GLY-200 showed promise as a weight maintenance drug, significantly blunting the weight rebound seen after GLP-1RA discontinuation. Phase 2a data from patients with type 2 diabetes (T2D) showed reductions in fasting and postprandial blood glucose, improved fasting lipid profiles, and progressive weight loss with GLY-200 treatment. These findings suggest that GLY-200, in combination with GLP-1RAs, holds promise as a novel therapeutic strategy for obesity, potentially offering a valuable approach for GLP-1RA dose reduction or weight maintenance following GLP-1RA discontinuation.

Keywords: Bariatric surgery; Combination therapy; Duodenal exclusion; GLP-1RA; GLY-200; Weight loss; Weight maintenance.

Figure 1

Impact of daily treatment with GLY-200 (20 mg/mouse, N = 8), semaglutide (sema, 6 nmol, SQ N = 8), or Saline (N = 10) as monotherapies on A) % change in body weight [gray dotted line at D14 indicates the start of semaglutide for the saline group], B–C) cumulative food intake (D14-28), D) delta fat mass, E) delta lean mass, F) oGTT, G) oGTT AUC, and H) fasting blood glucose at week 4. ∗p < 0.05, ∗∗p < 0.001, ∗∗∗p < 0.0001.

Figure 2

Impact of daily treatment GLY-200 (20 mg/mouse, N = 10) and semaglutide (sema, 6 nmol, SQ., N = 10) combination therapy or saline (N = 8) on A) % change in body weight S1, B) % change in body weight S2, C) cumulative food intake (D14-28) S1, D) cumulative food intake (D14-28) S2, E) oGTT, F) delta lean mass, G) delta fat mass, H) and fasting blood glucose at week 4. ∗p < 0.05, ∗∗p < 0.001, ∗∗∗p < 0.0001. Gray line delineates the addition of semaglutide to the group.

Figure 3

Impact of daily treatment of GLY-200 (20 mg/mouse) or saline on weight maintenance and glycemic control following sema discontinuation [day 15, delineated by gray dotted line]. A) % change in body weight, B) change in daily food intake, C) cumulative food intake D1-14, D) cumulative food intake D15-28, E) fat mass, F) lean mass, fasting blood glucose at G) week 2 and E, F, H) week 4. ∗p < 0.05, ∗∗p < 0.001, ∗∗∗p < 0.0001.