A recent publication in JAMA Internal Medicine suggests that the FDA should update the labels of glucagon-like peptide 1 (GLP-1) receptor agonists and dual GLP-1/GIP receptor agonists used for weight loss. The recommendation stems from findings that the safety and efficacy of these drugs may not be generalizable to all populations currently receiving them.
The analysis focused on liraglutide (Saxenda, Novo Nordisk), semaglutide (Wegovy, Novo Nordisk), and tirzepatide (Zepbound, Eli Lilly), all FDA-approved for weight loss in adults and children over 12 with overweight or obesity. The study authors emphasize that clinical trials for these medications often exclude patients with specific chronic medical and psychiatric conditions, yet the FDA labeling does not restrict treatment to only those included in the trials.
Applicability to Real-World Populations
To assess the applicability of these drugs to a broader population, researchers analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2013 through March 2020. The cross-sectional study included 8767 nonpregnant, nonbreastfeeding adults aged 20 years and older with a BMI above 27 kg/m². The weighted population represented 110.3 million adults.
The study found that while a high percentage of individuals met the FDA label eligibility criteria for weight loss treatment with tirzepatide (99.9%), semaglutide (98.2%), and liraglutide (98.1%), a significant proportion also met trial exclusion criteria (33.1%, 26.2%, and 28.1%, respectively). Older adults were more likely to have at least one exclusion criterion compared to younger adults.
Common Exclusion Criteria
The most common exclusion criteria across all three medications were major depressive disorder (17.3%-17.4%) and malignant neoplasms (7.6%). Other notable exclusion criteria included uncontrolled hypertension, suicidal ideation, and liver disease. The researchers also pointed out that nearly one-third of US adults without diabetes who were otherwise eligible for these medications were excluded from the original safety and efficacy trials.
Call for Updated Labeling
The authors urge caution in generalizing the safety and effectiveness of GLP-1 and GLP-1/GIP receptor agonists to populations excluded from pivotal trials until high-quality postmarketing studies provide further evidence. They suggest that the FDA should consider updating the labeling to reflect this concern.
Study Limitations
The study acknowledges limitations, including the self-reported nature of medical conditions and the inability to accurately measure all exclusion criteria, which may lead to underestimation. Despite these limitations, the findings highlight the importance of considering trial generalizability when prescribing these medications.
