Roughly one year after their introduction, Wegovy (semaglutide) and Zepbound (tirzepatide) continue to shake up the obesity treatment landscape in the United States. Uptake for these two glucagon-like peptide receptor agonists (GLP-1 RAs) has surpassed expectations and is driving demand for Saxenda (liraglutide), an older GLP-1 also indicated for weight loss, along with off-label use of Ozempic (semaglutide) and Mounjaro (tirzepatide), two GLP-1 formulations indicated for treating diabetes. The reason for this is clear: a large body of clinical evidence shows the drugs can help patients lose 15% to 25% additional weight when used alongside evidence-based lifestyle interventions (counseling, diet, and exercise). These effects are greater than those seen with older weight loss medications (typically ~5% total weight loss) and close to typical weight loss seen with bariatric surgery.

The uptake of GLP-1 RAs for weight loss has also resulted in new patient safety concerns. Evidence from clinical trials shows that serious reactions to GLP-1 RAs are rare; however, with hundreds of thousands of patients using the drugs, serious side effects will occur and result in significant morbidity. Also, some side effects may be too rare to detect, or attribute to the drugs, even in clinical trials enrolling thousands of patients. Recently, anecdotal accounts and raw event incidence reports prompted FDA to review a potential association between GLP-1 RAs and suicidal ideation. While the review has so far found no conclusive evidence of association, reports circulating without the proper contextual information may fuel disinformation and discourage patients who would benefit from GLP-1 RA therapy. Another source of concern are adverse events (AEs) resulting from people using the medications in unsafe ways. In January, FDA issued a warning to the general public after receiving reports of events in compounding pharmacies.  

Prescribers will play a critical role in minimizing the downsides of GLP-1 RA therapy by considering AE risk into patient selection, providing updated information to discuss risks and benefits with patients, and proactively monitoring for and addressing potential side effects. To help prescribers, ECRI’s Clinical Evidence Assessment service recently published a special report on clinical best practices for managing obesity and overweight with GLP-1 receptor agonists. On patient safety and AE monitoring, we reviewed evidence from 2 systematic reviews and 6 real-world studies each including 500 or more patients, along with recommendations from 5 evidence-based clinical guidelines and 4 expert consensus documents. Our key findings include:

• Data from clinical trials and real-world studies confirm that serious AEs (i.e., requiring hospitalization or resulting in disability) related to GLP-1RAs are uncommon (5% to 10% in clinical trials and <5% in real-world studies). However, over half of patients experience mild and typically transient side effects, most commonly vomiting, nausea, constipation, and diarrhea.
• Use of GLP-1 RA is definitely associated with increased risks of biliary disease, pancreatitis, bowel obstruction, and gastroparesis; therefore, a high suspicion index is warranted in GLP-1 users with relevant signs or symptoms. However, prescribers can reassure patients that the overall absolute risk is very low: in the order of 1 or 2 for every 100 individuals taking the drug for 1 year.
• The association between GLP-1 RAs and two other serious risks, thyroid cancer and suicidal ideation, remains unclear; however, practice recommendations are likely to change as new evidence is reviewed.
• Long-term data on patients taking GLP-1 RAs for weight loss are limited; however, data on patients with diabetes provide assurance that serious AEs are likely to remain uncommon in the long term.
• Whether GLP-1 RAs may worsen symptoms of common gastrointestinal conditions (e.g., inflammatory bowel disease, irritable bowel syndrome, gastroesophageal reflux) is unclear, but interaction is likely because of GLP-1’s pleiotropic effect on gastrointestinal functions. While GLP-1 RAs are not contraindicated for many of these conditions, practical precautions such as avoiding GLP-1 RA initiation during inflammatory bowel disease exacerbation may reduce the risk of AEs.
• The potential effect of GLP-1 RAs in patients with heart failure is also unclear. While weight loss is likely to benefit these patients, GLP-1 also modulates heart function. A 2023 systematic review concluded that GLP-1 RA use in patients with heart failure and reduced ejection fraction warrants caution due to potential risk of worsening heart failure events and arrhythmias.
  

ECRI members may access this report in its entirety here. Non-members may register to receive a copy of the report.