Vagal activity-related events and glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) carry side-effects such as dizziness and nausea related to increased vagal tone. This study investigated associations between GLP-1 RA use and the risk of vagal activity-related (VAR) events.

Using the Danish health registers, patients with type 2 diabetes mellitus (T2DM) first-time initiated on GLP-1 RAs (exposure) or sodium-glucose cotransporter-2 inhibitors (SGLT-2i) (active control) were identified between January 2010 and October 2022. Standardized 1-year absolute risks of VAR events (syncope, fractures, bradyarrhythmia, or cardiac device implantation) were computed to compare risk associated with GLP-1 RA and SGLT-2i initiation. Complementary analyses in patients treated for obesity were performed as well. During the study period, 50 076 and 73 138 patients with T2DM were initiated on GLP-1 RA [47% women, median age: 59 years (interquartile range {IQR}: 50–68)] or SGLT-2i [39% women, median age: 64 years (IQR: 55–72)]. Comorbidity was equally prevalent. The standardized 1-year absolute risk of syncope was 0.58% [95% confidence interval (CI): 0.51–0.66%] among patients initiated on GLP-1 RA and comparable to patients initiated on SGLT-2i [0.56% (95% CI: 0.50–0.62%)]. One-year risks of fractures, bradyarrhythmia, and cardiac device implantation were equally low and with corresponding standardized risk ratios of 0.90 (95% CI: 0.79–1.01), 0.97 (95% CI: 0.67–1.28), and 0.86 (95% CI: 0.62–1.10), respectively. No associations were found in the group treated for obesity either.

In nationwide cohorts of patients treated for T2DM or obesity, initiation of GLP-1 RA was not associated with an elevated risk of VAR events. Despite a proposed argumentation of vagal activity, GLP-1 RA use was not associated with an increased risk in real-life users.