MON-112 Gelesis100 Reduces Insulin Resistance in Patients Who Are Overweight or Have Obesity with High Insulin Resistance: Results of the GLOW Study

Background: Overweight and obesity are predisposing conditions for the development of prediabetes and type 2 diabetes. Insulin resistance caused by excess adiposity is a key factor in this process. Methods: The effect of Gelesis100, a novel hydrogel, was assessed in patients who were overweight or had obesity, without antidiabetic medications, and who completed the Gelesis Loss Of Weight (GLOW; NCT02307279) study. GLOW was a multicenter, double-blind, placebo-controlled pivotal study with patients randomized to 2.25 g of Gelesis100 or placebo in capsules taken with 500 mL of water before lunch and dinner while on a hypocaloric diet (-300 kcal/day) for 24 weeks. Insulin resistance was measured by homeostasis model assessment-insulin resistance (HOMA-IR). Data were analyzed using analysis of covariance and Logit models comparing Gelesis100 to placebo arms in 2 subgroups of patients based on baseline HOMA-IR (subgroup 1, HOMA-IR ≥ 3.0, subgroup 2, HOMA-IR < 3.0). Results: The overall population included 290 patients (132 males, 158 females, 91 in subgroup 1, 199 in subgroup 2, 155 on Gelesis100, 135 on placebo), who were normoglycemic, had prediabetes, or had untreated type 2 diabetes. Statistically significant difference in reduction of HOMA-IR was observed in subgroup 1 (mean baseline HOMA-IR = 5.0) but not in subgroup 2 (mean baseline HOMA-IR = 1.8). Indeed, placebo-subtracted HOMA-IR changes (mean, SE) were -22.3 ± 9.5% (P = 0.0212) and -9.0 ± 9.5% (P = 0.3432) in subgroup 1 and subgroup 2, respectively. Furthermore, in subgroup 1, patients who lost < 5% body weight (n = 44, mean body weight loss = 1.3%) had a statistically significant placebo-subtracted HOMA-IR change of -27.6 ± 13.2% (P = 0.0435), while patients who lost ≥ 5% body weight (n = 47, mean body weight loss = 9.7%) had no statistically significant placebo-subtracted HOMA-IR change (-15.6 ± 13.6%, P = 0.2584). The effect on HOMA-IR decrease was driven by significant reduction in fasting serum insulin. Safety and tolerability of Gelesis100 demonstrated no increased risk compared to placebo. Conclusion: Treatment with Gelesis100 results in a significantly higher reduction in insulin resistance compared to placebo as assessed by HOMA-IR in patients who are overweight or have obesity with elevated baseline HOMA-IR. The results also suggest a potential weight-independent effect of Gelesis100 in the reduction of insulin resistance. If these findings are confirmed in future studies with larger subgroups, Gelesis100 could become a potential new treatment for insulin-resistant clinical conditions associated with overweight and obesity.