GLP-1 agonist, DM and GI safety - Real World Data

GLP-1 receptor agonists are a class of medications commonly used for the treatment of type 2 diabetes mellitus (DM) and, more recently, for obesity management. These drugs work by mimicking the action of the hormone glucagon-like peptide-1 (GLP-1), which helps regulate blood sugar levels by enhancing insulin secretion, suppressing glucagon release, slowing gastric emptying, and promoting satiety.

### Gastrointestinal (GI) Safety of GLP-1 Agonists in Type 2 Diabetes

A recent large real-world study published in *Annals of Internal Medicine* focused on the gastrointestinal (GI) safety of three GLP-1 receptor agonists—**dulaglutide**, **semaglutide**, and **tirzepatide**—in adults with type 2 diabetes. The study analyzed data from over 130,000 matched patient pairs using Optum’s Clinformatics database, comparing these drugs head-to-head and against a different class of diabetes medications, **SGLT2 inhibitors**.

#### Key Findings:

1. **Similar GI Safety Profiles Among GLP-1 Agonists**:

• When dulaglutide, semaglutide, and tirzepatide were compared directly, they showed **no significant differences** in the risk of serious GI events.
• Hazard ratios (HR) for severe GI events were:
• **Tirzepatide vs. Dulaglutide**: HR 0.96
• **Semaglutide vs. Dulaglutide**: HR 0.96
• **Tirzepatide vs. Semaglutide**: HR 1.07
• These findings suggest that all three drugs carry **comparable levels of GI risk** when used in routine clinical practice.

2. **Higher GI Risk Compared to SGLT2 Inhibitors**:

• When each GLP-1 agonist was compared to SGLT2 inhibitors, all three showed a **higher risk of GI adverse events**:
• **Tirzepatide**: HR 1.53
• **Dulaglutide**: HR 1.36
• **Semaglutide**: HR 1.22
• The increased risk was primarily attributed to **GI motility-related issues**, such as delayed gastric emptying. This effect is a known physiological consequence of GLP-1 and GIP hormone stimulation.

3. **Types of Serious GI Events Studied**:

• The study assessed a composite of serious GI events, including:
• Bowel obstruction
• Gastroparesis (delayed stomach emptying)
• Pancreatitis
• Biliary disease
• Severe constipation
• Despite these risks, the differences within the GLP-1 class were minimal, reassuring clinicians about the safety of these treatments.

#### Clinical Implications:

• **GLP-1 Agonists in Routine Practice**:
• Clinicians can feel confident that dulaglutide, semaglutide, and tirzepatide have **similar GI safety profiles** and can be used interchangeably based on patient-specific factors such as efficacy, weight loss benefits, and tolerability.
• **Comparison to SGLT2 Inhibitors**:
• While GLP-1 agonists are associated with higher GI risks than SGLT2 inhibitors, these risks are generally manageable and expected due to the mechanism of action of GLP-1 receptor agonists.
• **Monitoring and Counseling**:
• Patients on GLP-1 agonists should be counseled about potential GI side effects, including nausea, vomiting, and constipation, which are common but often transient.
• Clinicians should monitor for more serious GI events, especially in patients with pre-existing GI conditions like gastroparesis.

#### Limitations of the Study:

• The study relied on diagnostic codes from electronic health records, which may lead to **underreporting or misclassification** of GI events.
• Uncontrolled confounding factors could influence the results, and the data may not fully capture all real-world adverse events.
• The findings primarily apply to patients with type 2 diabetes and may not fully extend to individuals using these drugs for obesity treatment without diabetes.

### Conclusion:

GLP-1 receptor agonists (dulaglutide, semaglutide, tirzepatide) are effective treatments for type 2 diabetes and obesity, with **similar GI safety profiles** within the class. However, they carry a **higher risk of GI adverse events** compared to SGLT2 inhibitors, driven mainly by delayed gastric emptying. Clinicians should consider these risks when prescribing GLP-1 agonists and provide appropriate monitoring and patient education. Ongoing studies and post-marketing surveillance are essential as these drugs are increasingly used in broader populations, including non-diabetic individuals for obesity management.