GLP-1 and GIP can deliver complementary pharmacology when combined. CT-868 (CT) is a biased dual GLP-1 and GIP receptor modulator that exhibits no arrestin coupling or receptor internalization at either receptor. Its effects on insulin (INS) secretion via graded glucose infusion (GGI), glucose (GLUC) homeostasis in response to a mixed meal tolerance test (MMTT), gastric emptying (GE), and food intake (FI) were investigated in a randomized, double-blind crossover study in 20 overweight and obese adults with T2D split into 2 groups: CT vs placebo (PL), n=7 and CT vs PL vs liraglutide (LI), n = 13, the latter as a fixed 3rd period. Mean age and BMI were 52.2 years and 32.7 kg/m2 with 55% males. Treatments were administered for 4 days to minimize weight loss with 14 days washout between periods. GGI data showed robust INS secretion for CT-868 vs PL [change in ISR/GLUC at GIRmax (pmol/kg/min): CT 1.1 (0.1), PL 0.1 (0.2), LI 1.0 (0.3)]. MMTT based GLUC iAUC0-240 was significantly reduced for CT vs PL [72(46) vs 392(48)mmol/L*min] and numerically lower vs. LI [187(55) mmol/L*min] accompanied by significantly decreased INS iAUC0-240 vs both PL and LI: CT 1178(846), PL 5833(873), LI 4613(1253) mU/L*min. As both CT and LI had similar delayed GE vs PL, the reduced GLUC and INS excursion seen with CT suggests improved INS sensitivity or enhanced INS independent GLUC disposal. CT demonstrated minimal suppression of glucagon during MMTT vs LI that showed glucagon lowering. FI was lower for CT vs PL accompanied by reduction in hunger and appetite as assessed by VAS. There were no significant body weight changes in any treatment period. GI side effects were mostly mild and transient. This data supports a robust weight-independent effect of CT-868 (vs unbiased liraglutide) on glucose disposal with minimal suppression of glucagon. Further delineation of CT-868's longer term effects in overweight and obese patients with both T2D and T1D is underway.


M.Chakravarthy: Employee; Carmot Therapeutics, Inc. M.Hernandez: None. M.Elliott: Employee; Carmot Therapeutics, Inc. A.Macias: None. S.K.Hansen: Board Member; Carmot Therapeutics, Inc. M.Hompesch: Board Member; ProSciento, Consultant; Wiley-Blackwell, Employee; ProSciento, Stock/Shareholder; ProSciento.

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