Exenatide and glucagon co-infusion increases myocardial glucose uptake and improves markers of diastolic dysfunction in adults with type 2 diabetes

Abstract

Type 2 diabetes (T2D) significantly increases the risk of heart failure, a major cause of hospitalisation and increased morbidity and mortality. Dual and multi-agonist synthetic peptides at the GLP-1 and glucagon receptor are in clinical development as potential new treatments for a range of chronic metabolic conditions including T2D. Here, we aimed to explore the effects of GLP-1 and glucagon dual receptor agonism on myocardial glucose uptake (MGU) and myocardial function in T2D. Eight adults with a mean age of 52 ± 12 years and body mass index 31 ± 4 kg/m² attended three randomised infusion visits using combinations of 0.9% saline, glucagon (12.5 ng/kg/min) and exenatide:glucagon co-infusion (exenatide loading dose 50 ng/min for 30 min then 25 ng/min). MGU and myocardial function were assessed using ¹⁸F-FDG PET-MRI. MGU increased in n = 7/8 (88%) participants from a median of 9.2 × 10^-3 µmol/g/min (IQR 0.33-19 × 10^-3 µmol/g/min) with saline, to 20 × 10^-3 µmol/g/min (5.4-98 × 10^-3 µmol/g/min) with exenatide:glucagon, n = 8, z = 2.24, r = 0.79, P < 0.05. Exenatide:glucagon significantly increased the median left ventricular global peak diastolic circumferential strain rate from 0.619 1/s (0.580-0.716 1/s) to 0.686 1/s (0.644-0.737 1/s) n = 8, z = 2.37, r = 0.84, P < 0.05. Left ventricular global longitudinal contraction (as a measure global longitudinal strain) numerically increased by 0.6%, from - 16.0% with saline (-14.0-[-16.7]%) to -16.6% with exenatide:glucagon (-14.1-[-17.6]%), n = 8, z=-1.54, r=-0.54, P = 0.123. Further studies are required to explore whether GLP-1/glucagon dual receptor agonists have a role to play in reducing cardiovascular risk and attenuating heart failure related outcomes in patients with chronic metabolic conditions such as T2D.

Keywords: 18F-FDG; CMR; Cardiac MRI; Dual-agonism; GLP-1; GLP-1/glucagon; Glucagon; Myocardial glucose uptake; PET MRI.

Fig. 1

Schematic of study design. Visits 1–3 occurred in a random order as per the randomisation schedule. CMR indicates cardiac MRI; FDG, 18 F-fluorodeoxyglucose; m, minutes; PET, positron emission tomography.

Fig. 2

The effect of saline, glucagon and exenatide:glucagon co-infusion on cardiac MRI parameters. a: LV global longitudinal strain. b: LV stroke volume. c: LV ejection fraction. d: LV global peak diastolic longitudinal strain rate. e: LV global peak diastolic circumferential strain rate. f: LV global peak diastolic radial strain rate. Box and whiskers plot with data representing 25 th percentile, median and 75 th percentile. Error bars represent minimum to maximum values. LV indicates left ventricular; S, saline; G, glucagon; Ex: G, exenatide:glucagon combination. *P < 0.05.

Fig. 3

The effect of saline, glucagon and exenatide:glucagon co-infusion on myocardial glucose uptake and the ¹⁸F-FDG influx rate, Ki. a: myocardial glucose uptake. b: ¹⁸F-FDG influx rate, Ki. Box and whiskers plot with data representing 25 th percentile, median and 75 th percentile. Error bars represent minimum to maximum values. S represents saline; G, glucagon; Ex: G, exenatide:glucagon combination. *P < 0.05.

Fig. 4

The effect of saline, glucagon and exenatide:glucagon co-infusion on point of care glucose. a: point of care glucose plotted as median ± IQR. b: points of care glucose plotted as change from baseline area under the curve. S represents saline; G, glucagon; Ex: G, exenatide:glucagon combination. *P < 0.05, **P < 0.01.