Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes

Abstract

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 .

Fig. 1. Fasting and postprandial liver glycogen levels (part B).

a, Mean change from baseline to day 35 of treatment in fasting hepatic glycogen levels in the intent-to-treat population. b, Postprandial hepatic glycogen levels across 24 h at baseline and at day 35 of treatment in the intention-to-treat population. Glycogen levels evaluated using ¹³C MRS were adjusted for liver volume. Patients that could be evaluated: placebo, n = 11; liraglutide, n = 10; cotadutide, n = 9. Data in a are the mean ± s.d., with overlayed individual data points. Data in b are the mean ± s.e.m. In a, two-sided P values from the analysis of covariance (ANCOVA) model adjusting for baseline value and treatment group are shown, with no corrections for multiple comparisons. Source data

Fig. 2. HFF, hepatic fatty acid composition and body weight, and fasting and postprandial blood glucose (part B).

a, Mean change from baseline to day 35 of treatment in fasting HFF, measured using MRI–PDFF. b–d, Proportional composition of fatty acids in the liver at day 35 of treatment. e, Mean change from baseline to day 35 of treatment in body weight. f, Mean change from baseline to day 35 of treatment in fasting plasma glucose. g, Mean relative change from baseline to day 35 of treatment in postprandial plasma glucose (AUC_{0–220 min}) after the MMTT. Patients who were evaluated in a: placebo, n = 10; liraglutide, n = 7; cotadutide, n = 6. Patients who were evaluated in b–d: placebo, n = 7; liraglutide, n = 6; cotadutide, n = 5. Patients who were evaluated in e: placebo, n = 11; liraglutide, n = 10; cotadutide, n = 9. Patients who were evaluated in f and g: placebo, n = 11; liraglutide, n = 9; cotadutide, n = 9. Data in a and e are the mean ± s.d., with overlayed individual data points. Data in b–d are the mean ± s.e.m. Data in f and g are the mean and overlayed individual data points. Two-sided P values from the ANCOVA model adjusting for baseline value and treatment group are shown, with no corrections for multiple comparisons. Source data

Extended Data Fig. 1. Postprandial glycogen levels at baseline and after 28 days of treatment with cotadutide and placebo (Part A).

a, Postprandial hepatic glycogen levels at 4 hours after MMTT at baseline and at day 28 of treatment with placebo or cotadutide (part A primary endpoint); b, Hepatic glycogen levels across 24 hours at baseline and at day 28 of treatment with placebo or cotadutide. Arrows denote timings of standardized meals. Glycogen levels evaluated by ¹³C MRS were adjusted for liver volume. Evaluable patients: placebo, n = 9; cotadutide, n = 12. Data are means ± SEM. BL, baseline; MMTT, mixed-meal tolerance test; MRS, magnetic resonance spectroscopy; SEM, standard error of the mean.

Extended Data Fig. 2. Participant flow diagram (Part B).

Flow diagram depicting the number of individuals at each stage of the Part B of the study.

Extended Data Fig. 3. Hepatic fat fraction, body weight and plasma glucose (Part A).

a, Mean change from baseline to day 28 of treatment in fasting hepatic fat fraction measured by MRI-PDFF. Evaluable patients: placebo, n = 9; cotadutide, n = 10. Data are individual data points and means ± SD. * P < 0.01. b, Mean change from baseline to day 29 of treatment in body weight. Evaluable patients: placebo, n = 9; cotadutide, n = 10. Data are individual data points and means ± SD. ** P < 0.001. c, Mean change from baseline to day 28 of treatment in fasting plasma glucose. Mean change from baseline to day 28: placebo, ‒2.3 mg/dl (SD, 10.7); cotadutide, ‒44.5 mg/dl (SD, 34.5). Evaluable patients: placebo, n = 9; cotadutide, n = 10. Data are individual data points and mean (horizontal bar). Two-sided P-values from ANCOVA model adjusting for baseline value and treatment group are shown, with no corrections for multiple comparisons applied. MRI-PDFF, magnetic resonance imaging–estimated proton density fat fraction; SD, standard deviation.

Extended Data Fig. 4. Fasting and postprandial gluconeogenesis measured following ingestion of deuterated water (Part B).

Evaluable patients: placebo, n = 11; liraglutide, n = 10; cotadutide, n = 9. Data are means ± SD. SD, standard deviation. This analysis was not performed in Part A of the study.

Extended Data Fig. 5. Study design (Part A).

Study flow diagrams and assessment schedule for Part A. ²H₂O, deuterated water (administration); IP, investigational product; MMTT, mixed-meal tolerance test; MRS, magnetic resonance spectroscopy; SM, standardized meal; V, visit.

Extended Data Fig. 6. Study design (Part B).

Study flow diagrams and assessment schedule for Part B. ²H₂O, deuterated water (administration); IP, investigational product; MMTT, mixed-meal tolerance test; MRS, magnetic resonance spectroscopy; SM, standardized meal; V, visit.