GLP-1 receptor agonists have been hailed as groundbreaking in the treatment of obesity and type 2 diabetes 🩺, but as a functional medicine provider, I see them as tools rather than a cure-all. While these medications have their place, they are far from the magic bullet they are often marketed as. Understanding their potential risks and limitations is crucial for both patients and healthcare providers.

The Rise of GLP-1 Agonists 📈

In just a few years, GLP-1 agonists like semaglutide (Ozempic, Wegovy, Rybelsus), liraglutide (Saxenda, Victoza), and tirzepatide (Mounjaro, Zepbound) have surged in popularity. Social media has fueled demand, with one in eight U.S. adults reportedly having tried one of these drugs. While they can be effective in managing weight and blood sugar, they also come with side effects that should not be overlooked. ⚖️

Common Side Effects: Gastrointestinal Issues 🤢

One of the most well-documented issues with GLP-1 agonists is their impact on the gastrointestinal system. Between one-third and one-half of users report symptoms such as nausea, vomiting, diarrhea, and constipation. Among the three major medications, semaglutide tends to have the highest incidence:

• Nausea: Reported by 44.2% of semaglutide users, compared to 40.2% for liraglutide and 31% for tirzepatide.
• Diarrhea, constipation, and vomiting: Affect up to one-third of semaglutide users, with slightly lower rates for liraglutide and tirzepatide.

In the early days of widespread use, many patients ended up in the emergency room due to severe constipation or even bowel obstruction. While careful dose escalation can mitigate these effects, they remain a significant concern. 🚑

Mental Health Considerations: Depression and Suicidal Ideation 💔

A growing body of research has examined whether GLP-1 agonists may be linked to mental health concerns, particularly depression and suicidal thoughts. A study analyzing 18 years of FDA data found that semaglutide and liraglutide had disproportionately high reports of these symptoms compared to insulin and metformin. However, causality remains uncertain.

Subsequent studies have been more reassuring:

• A separate analysis of FDA reports from 2018 to 2022 found no link between GLP-1 agonists and increased suicide risk.
• A cohort study of nearly 300,000 individuals found no higher incidence of suicide among GLP-1 users compared to other medication groups.

Both the FDA and European Medicines Agency have stated that current evidence does not support a causal relationship.

That said, weight loss itself can be psychologically complex. Patients who use food as an emotional coping mechanism may struggle when that coping tool is removed. As a provider, I believe it is crucial to assess mental health history before prescribing these medications and to offer psychological support as needed. 🧠

Potential Ocular Effects: Unclear Associations 👀

Some reports suggest a link between GLP-1 agonists and vision-related issues. A review of FDA reports found an association between semaglutide and conditions like blurred vision and diabetic retinopathy. A more recent study suggested a connection to nonarteritic anterior ischemic optic neuropathy (NAION), a condition that can lead to blindness.

However, a separate large-scale cohort study found no increased risk for NAION among GLP-1 users. Most of these studies rely on observational data rather than randomized controlled trials (RCTs), making definitive conclusions difficult. From a functional medicine standpoint, I advocate for a cautious approach, ensuring regular eye exams for patients on these medications. 👁️

Pulmonary Aspiration Risk Under Sedation 🛌

In response to case reports of aspiration during surgery, the FDA recently updated its labeling for GLP-1 drugs. Because these medications slow gastric emptying, food may remain in the stomach even after fasting, increasing the risk of aspiration under anesthesia.

Current guidelines recommend:

• Evaluating dosage, symptoms, and other medical conditions before surgery.
• Considering discontinuation of the drug in high-risk cases.
• Assessing gastric emptying status on the day of the procedure.
• Implementing preoperative dietary modifications, including a possible liquid diet.

Patients should be well-informed of these risks before undergoing any procedure requiring sedation. 🛑

Rare but Serious Risks ⚠️

Although uncommon, some severe side effects have been reported:

• Thyroid Cancer: Initial rodent studies suggested a risk, but human studies have not confirmed this association.
• Pancreatitis: Both liraglutide and semaglutide have been linked to slightly increased rates of pancreatitis, bowel obstruction, and gastroparesis. However, these cases are rare (~0.2% of patients).
• Colonic Ischemia and Bowel Obstruction: Case reports have linked tirzepatide to colonic ischemia, while some patients on semaglutide have experienced severe constipation leading to obstruction.

Balancing Benefits and Risks ⚖️

The benefits of weight loss and improved blood sugar control cannot be ignored. GLP-1 agonists have been shown to lower the risk of high blood pressure, heart disease, stroke, metabolic syndrome, fatty liver disease, and even some cancers. However, the potential side effects—both common and rare—must be factored into the decision-making process.

As a functional medicine provider, I emphasize a comprehensive approach. While GLP-1 drugs may have a role in treatment, they should not replace foundational strategies such as:

• Dietary Optimization: A whole-food, nutrient-dense diet tailored to individual metabolic needs 🥗.
• Exercise and Movement: A combination of strength training, cardiovascular exercise, and daily movement 🏃‍♂️.
• Gut Health Support: Optimizing gut microbiota through probiotics, fiber, and digestive support 🦠.
• Mental Health Care: Addressing emotional eating, stress, and psychological well-being as part of a holistic plan 🧘‍♂️.

Final Thoughts 💡

GLP-1 agonists are powerful tools, but they should be used with careful consideration. Patients deserve full transparency about potential side effects and a comprehensive plan that goes beyond medication alone. Functional medicine offers a broader lens through which to address metabolic health, ensuring that interventions are sustainable and truly supportive of long-term well-being. 🌱