Are some GLP-1s harsher on the gut? Here’s what new research reveals

For clinicians navigating the surge in GLP-1 prescribing, GI safety remains a top practical concern, especially as these agents migrate beyond diabetes and into obesity and cardiometabolic care.

“Clinicians can be reassured that the three GLP-1-based agents studied have comparable [GI] safety profiles when used in everyday practice," lead author Wajd Alkabbani, PhD, told Healio. ^[]

In other words, pick the drug based on glycemic efficacy, weight goals, and patient preference, not on fears that one agent is uniquely harsher on the gut.

What the real-world data showed

Prior clinical trials had already suggested that dulaglutide (Trulicity), semaglutide (Ozempic/Wegovy), and tirzepatide (Zepbound) increase the risk of GI adverse events, from garden-variety nausea and constipation to more serious events such as pancreatitis and biliary disease. But head-to-head real-world comparisons remained limited.

Dr. Alkabbani’s team tapped Optum’s Clinformatics Data Mart to evaluate adults with type 2 diabetes who initiated one of the three agents between 2019 and 2024. The sample sizes were substantial:

• 65,238 matched pairs (semaglutide vs dulaglutide)

• 46,620 (tirzepatide vs semaglutide)

• 20,893 (tirzepatide vs dulaglutide)

The primary endpoint was a composite of severe GI adverse events, including gastroparesis, severe constipation, acute pancreatitis, biliary disease, and bowel obstruction.

Across these comparisons, the hazard ratios clustered closely around 1.0:

• Tirzepatide vs dulaglutide: HR = 0.96 (95% CI, 0.77–1.2)

• Semaglutide vs dulaglutide: HR = 0.96 (95% CI, 0.87–1.06)

• Tirzepatide vs semaglutide: HR = 1.07 (95% CI, 0.9–1.26)

GI risk: GLP-1s vs SGLT2 inhibitors

The sensitivity analyses comparing each GLP-1 agent with SGLT2 inhibitors told a different story. All three GLP-1s carried higher risks:

• Tirzepatide: HR = 1.53 (95% CI, 1.21–1.93)

• Semaglutide (SC): HR = 1.22 (95% CI, 1.09–1.37)

• Dulaglutide: HR = 1.36 (95% CI, 1.21–1.53)

The signal was “driven by an increase in the risk for GI motility-related outcomes,” the authors wrote.^[]

Mechanistically, GLP-1–based therapies enhance incretin hormone activity, delaying gastric emptying and slowing motility more broadly—effects that SGLT2 inhibitors do not share.

Limitations and context

As with any claims-based study, diagnostic code accuracy and underrecording of certain adverse events can limit precision. Residual confounding—BMI, for example— also can’t be fully excluded.

But the authors emphasize that population-level studies like this one are crucial for complementing clinical trials, especially as GLP-1 agents expand into broader indications, such as obesity and cardiovascular risk reduction.

What this means for clinicians

For many physicians, the practical question is whether one GLP-1 agent is safer than another from a GI standpoint. Based on this analysis, the answer appears to be no.

The GI risk appears to be a class effect rather than an agent-specific phenomenon.