Aim – GLP-1 and glucagon dual receptor agonists are in clinical development for a range of metabolic conditions including type 2 diabetes and obesity. The cardiovascular actions at these receptors are well studied, however less is known about their combination. The aim was to explore the acute haemodynamic effects of dual agonism at the GLP-1 and glucagon receptor. Methods – Healthy male participants attended randomised, saline-controlled intravenous infusion studies using glucagon [low] (25 ng/kg/min), glucagon [high] (50 ng/kg/min), exenatide (loading dose 50 ng/min for 30 minutes then 25 ng/min) and exenatide:glucagon co-infusion for 120 minutes in Part A (glucagon dose-comparison study) and 60 minutes in Part B (dual-agonism study). Results – In Part A (n=7, median age 21 (IQR 21-32) years), glucagon [high] increased heart rate by 11 bpm (95% CI 4-17 bpm, p<0.01). In Part B (n=12, 24 (22-26) years), exenatide increased heart rate by 4 bpm (95% CI 2-6 bpm, p<0.001). Glucagon [low] increased heart rate by 4 bpm (95% CI 1-7 bpm, p<0.001). Co-infusion of glucagon [low] and exenatide increased heart rate by 7 bpm (95% CI 4-9 bpm, p<0.001) and the rate pressure product by 793 mmHg*bpm (95% CI 460-1127 mmHg*bpm, p<0.001). There were no differences in cardiac output, blood pressure, or heart rate variability. Conclusion – In healthy males, exenatide and glucagon co-infusion acutely increases the rate pressure product, an indirect measure of cardiac work. This increase is driven by an increase in heart rate, rather than any change in systolic blood pressure.

Aims Corticosteroids are the treatment of choice for many inflammatory diseases, but often lead to adverse effects, including hyperglycemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, a novel oral, non-steroidal, selective glucocorticoid receptor modulator, versus prednisolone in 46 patients with type 2 diabetes mellitus. Methods In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (Cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (Cohort 2); or placebo and prednisolone 5 mg daily (Cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycemic control was assessed after a standardized meal and with continuous glucose monitoring. Results A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions post-meal in Cohort 1 (glucose AUC0-4h -4.54%; 95% CI: -8.88, -0.01; p=0.049), but not in Cohort 2 (-5.77%; 95% CI: -20.92, 12.29; p=0.435). In Cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to Day 4 in insulin and glucagon secretion post-meal (p<0.001 and p=0.005, respectively), and change from baseline to Day 4 in GLP-1 response (p=0.022). Significant differences between AZD9567 and prednisolone for 24-hour glucose control were observed for both Cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; p<0.001), and Cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; p<0.001). Conclusions AZD9567 significantly reduced treatment-induced hyperglycemia compared with prednisolone.