GLP-1 agonists and gastroparesis: what is the connection?

Glucagon-like peptide-1 (GLP-1) receptor agonists are increasingly utilized in the management of type 2 diabetes and obesity due to their beneficial effects on glycemic control and weight loss. However, one of the notable adverse effects associated with these agents is gastroparesis, a condition characterized by delayed gastric emptying. The mechanisms by which GLP-1 agonists induce gastroparesis involve both central and peripheral pathways that affect gastric motility.

GLP-1 acts as an enterogastrone, which is a type of hormone that slows gastric motility. This effect is mediated through the activation of GLP-1 receptors located on vagal afferents, which are responsible for transmitting signals from the gastrointestinal tract to the brain (Wilson, 2023). Studies have demonstrated that GLP-1 receptor agonists, such as exenatide and liraglutide, significantly delay gastric emptying. For instance, a randomized controlled trial indicated that liraglutide led to a significant delay in gastric emptying, with a marked reduction in the rate of gastric emptying observed in patients with type 2 diabetes (Ghazanfar, 2024). Furthermore, research has shown that exenatide inhibits small intestinal motility and reduces glucose absorption by decreasing the flow and transit time of intestinal contents (Thazhath et al., 2015; Beti et al., 2019).

The physiological basis for the delayed gastric emptying induced by GLP-1 agonists can be attributed to their effects on gastric contractility. These agents inhibit the motility of the stomach antrum and duodenum, as well as pyloric contractions, which collectively contribute to slowed gastric emptying (Kalas et al., 2021; Parkman, 2024). Additionally, GLP-1 receptor agonists can cross the blood-brain barrier and exert effects centrally, particularly in areas of the brain that regulate appetite and gastrointestinal motility, such as the dorsal motor nucleus of the vagus nerve (Kalas et al., 2023; Secher et al., 2014). This central action may further exacerbate the delay in gastric emptying, leading to symptoms associated with gastroparesis.

Clinical observations have corroborated the association between GLP-1 receptor agonists and gastroparesis. Reports indicate that patients on these medications often experience gastrointestinal side effects, including nausea, vomiting, and abdominal discomfort, which are consistent with delayed gastric emptying (Mahase, 2023; Smits et al., 2016). Moreover, the presence of particulate gastric contents in patients treated with GLP-1 receptor agonists has been documented, highlighting the impact of these drugs on gastric motility (Wilson, 2023).

In summary, GLP-1 receptor agonists cause gastroparesis primarily through their inhibitory effects on gastric motility mediated by both peripheral and central mechanisms. The resultant delay in gastric emptying can lead to significant gastrointestinal symptoms, complicating the management of patients with diabetes and obesity.