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Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) such as liraglutide, semaglutide, and tirzepatide, are being increasingly used to promote weight loss in individuals with obesity. To clarify the balance between the therapeutic benefits and the risks of these agents, Wissam Ghusn, MD, of Boston Medical Center in Massachusetts, and Maria D. Hurtado, MD, PhD, of the Mayo Clinic in Jacksonville, Florida, undertook a comprehensive clinical review.

As they explained in , the analysis drew on published data from inception to December 2023 from systematic reviews, meta-analyses, randomized controlled trials, and cohort studies. Examining a cohort of more than 8,000 GLP-1 RA–treated patients in the three main trials alone and more in other studies, the researchers reported that while these agents can effectively help to manage obesity, they are associated with gastrointestinal (GI) side effects and rare but serious adverse events.

Ghusn elaborated on the findings in the following interview.

What was the impetus for the review?

Ghusn: The review is timely owing to the increasing adoption of GLP-1 RAs in both diabetes treatment and weight loss therapy, necessitating a better understanding of their efficacy and emergent risks.

Additionally, new agents such as tirzepatide have gained approval, expanding their clinical use and raising safety concerns as they transition from diabetes management to widespread obesity treatment.

Were the risks of GLP-1 RAs apparent from the outset of their use in diabetes treatment?

Ghusn: No. While nausea, vomiting, and GI symptoms were expected early on, other risks such as gallbladder issues, delayed gastric emptying, and increased surgical risks (like aspiration under anesthesia) only became more apparent after broader clinical use for weight loss.

Which GLP-1 RA appeared most effective for weight loss, and is it known why that would be the case mechanistically?

Ghusn: Tirzepatide demonstrated the most significant weight loss effects. Mechanistically, it works through dual receptor agonism -- stimulating both GLP-1 receptors and GIP, or glucose-dependent insulinotropic polypeptide, receptors -- resulting in enhanced appetite suppression and improved metabolic outcomes compared with other GLP-1 RAs.

Which of all the emergent adverse effects was the most concerning, and did the results surprise you?

Ghusn: While Gl side effects were expected, the severity and clinical implications of these issues, again, such as aspiration risks during surgery, were unexpected.

Were any patient subgroups at greater risk than others?

Ghusn: Individuals with preexisting GI conditions or gallbladder issues were at a higher risk for adverse effects.

Do the associated risks outweigh the benefits for obesity treatment?

Ghusn: For most individuals with obesity, the benefits of GLP-1 RAs, including substantial weight loss and improved cardiometabolic health, outweigh the risks, though careful patient selection and monitoring are essential to minimize adverse events.

Did you find any affective changes such as improved mood with these agents?

Ghusn: Some studies reported improved mood, reduced anxiety, and better overall mental health in patients taking GLP-1 RAs. The improvements may stem from both accelerated weight loss and better mobility.

What does the future of GLP-1 RA therapy look like, and what further research is needed?

Ghusn: The future involves tailoring therapy to specific patient populations, refining dosing strategies, and improving guidelines for surgical management in view of risks such as aspiration from delayed gastric emptying. Additionally, research into combination therapies with other agents may further enhance outcomes.

Further longitudinal studies are warranted to comprehensively assess the long-term safety profile and perioperative risks associated with GLP-1 RAs, particularly as their use extends from diabetes management to obesity treatment.

Additionally, ongoing research efforts are focused on identifying molecular and clinical biomarkers to predict individual responsiveness to GLP-1 RAs, with promising developments emerging from investigations conducted in the [Andres] Acosta lab at Mayo Clinic in Rochester, Minnesota.

What is your main takeaway message for healthcare professionals treating persons with obesity?

Ghusn: GLP-1 RAs represent a promising therapeutic option for weight loss and metabolic management, but clinicians must carefully monitor for side effects, particularly GI risks, and ensure appropriate patient selection for optimal results.

Read the study here and expert commentary about it here.

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