FDA Database Reveals Which GLP-1 Drugs Have the Most Stomach and Gut Side Effects

What the researchers found

From 2007-2023, 187,757 adverse events were reported with GLP-1 RAs in the US, including 16,568 GI-related events. Semaglutide was significantly associated with nausea, vomiting, and delayed gastric emptying. Exenatide was associated with pancreatitis and a significantly elevated death risk (ROR: 4.50).

Dulaglutide and liraglutide were associated with fewer significant GI adverse events compared to semaglutide and exenatide. Semaglutide had the broadest range of notable GI adverse effects among all GLP-1 RAs analyzed.

Why it matters

With millions of people now taking GLP-1 drugs, understanding the comparative GI safety profile of different drugs in this class is crucial for prescribing decisions. This real-world data from nearly 188,000 adverse events provides a practical guide: patients prone to nausea may do better on dulaglutide or liraglutide than semaglutide, and the exenatide pancreatitis signal reinforces the need for monitoring.

How the study worked

Retrospective pharmacovigilance study using the US FDA FAERS database from 2007-2023. The researchers collected demographic, treatment indication, and adverse event data for all GLP-1 RA medications. Analysis used reporting odds ratios, proportional reporting ratios, Bayesian confidence propagation neural networks, and multivariate logistic regression to identify significant safety signals.

What this study cannot tell us

FAERS data relies on voluntary reporting, which introduces reporting bias — more popular drugs (like semaglutide) may have more reports simply due to higher usage. The data cannot establish causation, only statistical associations. Reporting rates may not reflect true incidence rates. The exenatide death signal needs careful interpretation given that it was an earlier drug used in a potentially sicker population. Confounders like concomitant medications and comorbidities are difficult to control in FAERS analyses.

How to read the evidence

This is a pharmacovigilance analysis of the FAERS database, which provides real-world safety signals but cannot establish causation due to voluntary reporting, lack of denominator data, and potential confounding. It complements but does not replace clinical trial safety data.

When this study was published

Published in 2024 using data through 2023, this is a current analysis capturing the recent surge in GLP-1 RA use and the expanding patient population taking these medications.

The bigger picture

As GLP-1 RA prescriptions surge worldwide, real-world pharmacovigilance data becomes essential for understanding safety profiles that clinical trials — with their selected populations and limited follow-up — may not fully capture. This study provides the largest systematic comparison of GI safety across GLP-1 drugs, directly informing the drug selection process that millions of patients and clinicians face.

Questions still open

• Is semaglutide's higher GI adverse event profile due to the drug itself or its much larger patient population?
• Would dose titration protocols reduce the GI side effect differences between GLP-1 drugs?
• Should the exenatide death signal change prescribing patterns, or does it reflect historical use in higher-risk patients?

Common questions

Read the original research

Gastrointestinal Safety Assessment of GLP-1 Receptor Agonists in the US: A Real-World Adverse Events Analysis from the FAERS Database.

Diagnostics (Basel, Switzerland), 14(24)

Citation

Osei, Samuel Prince; Akomaning, Edwin; Florut, Teodora Francesca; Sodhi, Mohit; Lacy, Brian E; Aldhaleei, Wafa A; Bhagavathula, Akshaya Srikanth. (2024). Gastrointestinal Safety Assessment of GLP-1 Receptor Agonists in the US: A Real-World Adverse Events Analysis from the FAERS Database.. Diagnostics (Basel, Switzerland), 14(24). https://doi.org/10.3390/diagnostics14242829