(095) Gastrointestinal Adverse Events with Glucagon-like Peptide-1 Receptor Agonist in Type 2 Diabetes: A Comprehensive Meta-analysis of Randomised Controlled Trials and Refining Signals through Pharmacovigilance Analysis.

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a growing class of glucose-lowering drugs, that have undergone major changes from short-acting to long-acting, from subcutaneous injection to oral administration. Due to differences in pharmacokinetics, efficacy, and administration routes among GLP-1 RAs, a comprehensive understanding of their gastrointestinal safety is lacking.

Objectives: This study assesses the risk of gastrointestinal adverse events (GI AEs) with various GLP-1 RAs by combining safety meta-analysis of randomized controlled trials (RCTs) and individual case safety reports (ICSRs) from the FDA Adverse Event Reporting System (FAERS).

Methods: We systematically reviewed RCTs comparing GLP-1 RAs with controls in adults with type 2 diabetes on PubMed and Embase until November 2023. The quality assessment was done using the Cochrane Risk of Bias Tool. The meta-analysis used risk ratios (RR) with 95% CIs, focusing on the risk of GI AEs as the primary outcome. In a separate FAERS retrospective pharmacovigilance study, GLP-1 RAs related GI AEs cases were explored until September 2023. Signal refinement was performed by confining the drug roles to “primary suspect” status. Furthermore, we stratified the analysis by sex and age categories. Disproportionality analysis employed reporting odds ratio (ROR) and proportional reporting ratio (PRR) with 95 % CI.

Results: The literature search identified 126 RCTs involving 95,040 patients. The GLP-1 RAs significantly increased risk of GI AEs compared to placebo (RR=2.90 (95% CI: [2.45; 3.44], p< 0.0001) as well as active treatment (RR=3.36 (95% CI: [2.80; 4.02], p< 0.0001). Furthermore, the subgroup analysis showed a significantly increased risk of GI AEs with dulaglutide (RR= 3.89 (95% CI: 3.15; 4.80)) and exenatide compared to placebo. In the FAERS, a total of 48,536 reports of GI AEs were analyzed out of 106,030 AE reports associated with GLP-1 RAs. Overall GLP-1 RAs were associated with increased risk of gastrointestinal system disorders [ROR:3.966 (3.575; 4.4) and PRR:3.919 (3.538; 4.34)] which were further attributed to dulaglutide, semaglutide and tirzepatide. These associations persisted even after refining and stratification.

Conclusions: The findings of the current study represent an important advancement in stratifying the GI AEs with GLP-1 RAs during the post-marketing period, assisting in risk evaluation and mitigation for the best possible patient health care.