GLP-1 Labels Don’t Reflect Trial Exclusions

About a third of people eligible for glucagon-like peptide 1 receptor agonist (GLP-1 RA) medications for weight loss via the products’ labels would have been excluded from the clinical trials that supported their safety and effectiveness, thereby creating the potential for harm, new research suggests. 

About a quarter of those with obesity but not diabetes who were eligible for GLP-1 RA treatment reported using medications that may slow gastrointestinal motility, increasing the risk for adverse events when combined with the GLP-1 RA. Other trial exclusion criteria not listed in the labels include major depressive disorder, malignant neoplasms, liver disease (with tirzepatide only), and uncontrolled hypertension.

“Clinicians considering prescribing these medications in unstudied populations should screen for depression, liver function, and concomitant use of medications that delay gastric emptying before initiating treatment,” write Lily G. Bessette, MS, and Timothy S. Anderson, MD, both of the University of Pittsburgh, Pennsylvania, in a letter published on November 25 in JAMA Internal Medicine.

Asked for comment, a Novo Nordisk representative sent Medscape Medical News the following statement: “Novo Nordisk welcomes independent research investigating the safety, efficacy, and clinical utility of our products. We support our products being prescribed to patients who meet the indicated criteria and only promote the US Food and Drug Administration [FDA]-approved indications of our medicines for appropriate patients. We encourage patients to speak with their health care provider about the right treatment option for them.”

Eli Lilly did not respond to a request for comment. 

Bessette and Anderson examined pooled data from the National Health and Nutrition Examination Survey from 2013 to March 2020, for a total of 8767 nonpregnant adults aged ≥ 20 years with a body mass index (BMI) of 27 kg/m² or greater and excluded those with diabetes. They applied inclusion criteria of trials defining FDA label indications for liraglutide, semaglutide, and tirzepatide for weight loss, including BMI ≥ 30 kg/m² or BMI 27-29 kg/m² with a weight-related comorbidity. 

For each medication, they calculated the proportion who met the FDA label indication but who also met criteria that would have excluded them from the trials. 

Overall, the proportions meeting FDA label criteria for liraglutide, semaglutide, and tirzepatide were 88.9%, 89.0%, and 90.6%, respectively. However, of those eligible, 28.1%, 26.2%, and 33.1%, respectively, met trial exclusion criteria for those three medications. Adults aged ≥ 60 years were even more likely than younger adults to meet exclusion criteria. 

The most common exclusion criteria were major depressive disorder, malignant neoplasms, liver disease (only for tirzepatide), and uncontrolled hypertension. In a sensitivity analysis, 23.5% of people meeting FDA indications for tirzepatide reported using medications that may slow gastrointestinal motility. 

Bessette and Anderson also advise, “Until there is evidence from high-quality post-marketing studies, the FDA should consider updating labeling to advise caution on generalizing the safety and effectiveness of GLP-1 and GLP-1/[glucose-dependent insulinotropic polypeptide] to populations excluded from pivotal trials.” 

The FDA also didn’t respond to queries for comment by press time. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X @MiriamETucker.