Gastrointestinal Symptom Events and Motility Alterations Associated With GLP-1 Receptor Agonists

Gastrointestinal symptom events (GISE) are common with glucagon-like peptide-1 receptor agonists (GLP-1RA). We aimed to determine the prevalence of GISE and clinical factors associated with GISE.

An integrated platform database was used to collect real-world data. Using a retrospective cohort study design, Kaplan-Meier analysis was used to estimate GISE-free survival over 60 months. To identify predictors of GISE, the cohort was randomly split 80/20 into training and testing sets. A LASSO-penalized Cox model was used to identify relevant associations, after which main-effect and interaction models were constructed. Gastric emptying scintigraphy (GES) of solids was extracted from electronic medical records, where available.

Among 78,277 patients, 87% reported no baseline GI symptoms. At 60 months, 53% reported at least one GISE, most commonly abdominal pain (28%) and nausea (25%). Women were at higher risk of GISE than men (Kaplan-Meier HR 1.4). In the prediction model, baseline diarrhea, constipation, abdominal pain, and nausea were associated with higher GISE risk (HRs 2.2, 2.0, 1.7, and 1.6, respectively), and male sex with lower risk (HR 0.79). Concomitant baseline use of metoclopramide (HR 1.6) was also associated with higher risk of GISE, with weaker associations for tricyclic antidepressants, GABA analogs, and opioids (HRs 1.1-1.2). Model discrimination was modest (C-index 0.64 training, 0.63 testing). Among 696 symptomatic patients clinically referred for GES after GLP-1RA initiation, 34.6% (N = 241) exhibited delayed GE. Constipation was more prevalent in those with delayed GE.

The 5-year incidence of GISE among patients initiating GLP-1RA therapy was over 50%. While the ability to predict GISE was modest, female sex, baseline GI symptoms, and concomitant medications were associated with an increased risk. Among the small, symptom-selected subgroup referred for testing, only a third had delayed GE.