Combined GPR40 and GPR119 full agonism with K-757 and K-833 results in robust glucose lowering and modest weight loss in overweight/obese subjects with T2DM
Abstract
Aims: K-757 and K-833 are novel full agonists of GPR40 and GPR119, respectively, which are nutrient receptors co-expressed on both pancreatic beta cells and gut enteroendocrine cells that signal through complementary mechanisms. We sought to assess the effects on glucose control and body weight following co-administration of K-757 and K-833.
Materials and methods: We conducted two randomized, double-blind, placebo-controlled Phase 1 studies in overweight-obese subjects with T2DM maintained on metformin to characterize the effects on secretion of gut incretin and appetite-regulating hormones, glucose control and body weight following combined therapy with K-757 and K-833. In Study 1 (28 days in duration) K-757/K-833 was titrated to 60/100 mg BID. In Study 2 (42 days in duration) K-757/K-833 was titrated to 240/200 mg QD.
Results: Twenty-five subjects were enrolled in Study 1 (12 on placebo and 13 on K-757 + K-833) and 24 in Study 2 (6 on placebo and 18 on K-757 + K-833). By design, baseline A1C was higher in Study 1 compared with Study 2. After 28 days of dosing (Study 1), the combination of K-757 + K-833 resulted in placebo-corrected LS mean reductions from baseline in 24 h-WMG, FPG, A1C and body weight of 77.3 mg/dL, 64.0 mg/dL, 0.55% and 1.61%, respectively. After 42 days of dosing (Study 2), the combination of K-757 + K-833 resulted in placebo-corrected LS mean reductions from baseline in FPG, A1C and body weight of 25.2 mg/dL, 0.26% and 4.95%, respectively.
Conclusions:…
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Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design.
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