Diabetes, obesity & metabolism · 2025
Combined agonism of nutrient receptors GPR40 and GPR119 with K-757 and K-833 results in weight loss and blood pressure reductions in obese subjects without type 2 diabetes mellitus.
СтатьяРандомизированное исследованиеКлиническое исследование I фазыКлиническое исследование II фазыНазвание и аннотация: Перевод пока не подготовлен
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Crutchlow Michael, Liu Jiajun, Romero Christopher, Watkins Elaine, Zhang Harry, Arreglado Anna, Vance Annemarie, Boisvert Daniel, Terracina Giuseppe, Chan Bryan, Consolati Matt J, Poterewicz Gregory, Talaty Jennifer E, Lauring Brett
Аннотация
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 beyond glucose control of co-agonism with K-757 and K-833.
MATERIALS AND METHODS: A Phase 1 study of the combination of K-757 and K-833 was conducted in overweight-obese participants to identify dose regimens causing maximal secretion of multiple gut hormones. Subsequently, a randomised, double-blind, parallel arm and 13-week Phase 2a study was conducted to assess the effects of K-757 alone and in combination with K-833, in comparison to placebo (n = 155 [51-52/arm]).
RESULTS: Co-administration of K-757 120 mg twice daily (BID) and K-833 100 mg BID resulted in elevations of circulating glucagon-like peptide 1 (3.44×), active glucagon-like peptide 1 (5.06×), peptide YY (8.63×), glucagon dependent insulinotropic peptide (1.65×), cholecystokinin (3.06×) and oxyntomodulin (5.66×) relative to placebo. In Phase 2a, placebo-adjusted weight loss with the K-757 + K-833 combination and K-757 alone was -2.78% (p < 0.001) and -1.42% (p = 0.0756), respectively. Though blood pressure, an exploratory endpoint, was not elevated at baseline, placebo-adjusted reductions were observed with the combination (-6.9/-5.4 mmHg) and K-757 alone (-5.3/-3.2 mmHg). Gastrointestinal adverse events (AEs) and discontinuation due to AEs were more common in the active treatment arms. The combination and K-757 alone were otherwise well tolerated.
CONCLUSIONS: K-757, alone and in combination with K-833, elicited robust elevations in circulating concentrations of multiple satiety peptides, which elicited some weight loss and blood pressure reductions that suggest potential for metabolic benefit independent of weight loss.
MATERIALS AND METHODS: A Phase 1 study of the combination of K-757 and K-833 was conducted in overweight-obese participants to identify dose regimens causing maximal secretion of multiple gut hormones. Subsequently, a randomised, double-blind, parallel arm and 13-week Phase 2a study was conducted to assess the effects of K-757 alone and in combination with K-833, in comparison to placebo (n = 155 [51-52/arm]).
RESULTS: Co-administration of K-757 120 mg twice daily (BID) and K-833 100 mg BID resulted in elevations of circulating glucagon-like peptide 1 (3.44×), active glucagon-like peptide 1 (5.06×), peptide YY (8.63×), glucagon dependent insulinotropic peptide (1.65×), cholecystokinin (3.06×) and oxyntomodulin (5.66×) relative to placebo. In Phase 2a, placebo-adjusted weight loss with the K-757 + K-833 combination and K-757 alone was -2.78% (p < 0.001) and -1.42% (p = 0.0756), respectively. Though blood pressure, an exploratory endpoint, was not elevated at baseline, placebo-adjusted reductions were observed with the combination (-6.9/-5.4 mmHg) and K-757 alone (-5.3/-3.2 mmHg). Gastrointestinal adverse events (AEs) and discontinuation due to AEs were more common in the active treatment arms. The combination and K-757 alone were otherwise well tolerated.
CONCLUSIONS: K-757, alone and in combination with K-833, elicited robust elevations in circulating concentrations of multiple satiety peptides, which elicited some weight loss and blood pressure reductions that suggest potential for metabolic benefit independent of weight loss.