FDA Advised to Update Labels on GLP-1 Weight-Loss Drugs

New findings on unstudied populations who might benefit from treatment with the glucagon-like peptide 1 (GLP-1) receptor agonists liraglutide and semaglutide and the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GLP-1/GIP) receptor agonist tirzepatide have investigators calling for updates to the drugs’ FDA-labeled indications. These updates should stress cautious use of these agents as weight-loss treatments in populations for whom their safety and efficacy have not been evaluated in clinical trials, according to the authors.

These and additional findings were published online today in JAMA Internal Medicine.¹

Liraglutide, sold as Saxenda (Novo Nordisk); semaglutide, sold as Wegovy (Novo Nordisk); and tirzepatide, sold as Zepbound (Eli Lilly) are approved for weight loss and chronic weight management by the FDA among children 12 years or older and adults classified as overweight or obese.^2-4 However, the authors of this new study note that the treatment-related outcomes of these medications have not been studied in all of the populations who ultimately receive them.¹ They highlight that although trials have excluded patients with specific chronic medical and psychiatric conditions, the FDA labeling does not restrict treatment to only those in whom they are studied. Thus, they sought a more thorough understanding of applicability to those who meet the FDA label criteria to receive these medications.

“Greater understanding of trial generalizability is needed,” they wrote.

Using National Health and Nutrition Examination Survey pooled data for 2013 through March 2020,⁵ they conducted a cross-sectional study among nonpregnant, nonbreastfeeding adult patients 20 years and older (N = 8767) with a body mass index (BMI) above 27 kg/m² by applying the trial inclusion criteria of obesity (BMI ≥ 30 kg/m²) or overweight (BMI, 27-29 kg/m²).¹ The weighted population was 110.3 (95% CI, 104.2-116.4) million, and the mean (SD) patient age was 49 (16) years. Female and male patients were equally represented (50% each), and the represented races/ethnicities were Asian (3.1%), other Hispanic (7.4%), Mexican American (10.5%), Black (12.4%), and White (63.0%).

This analysis of liraglutide, semaglutide, and tirzepatide encompassed 8767 individuals, for a weighted study population of 110.3 million adult patients 20 years and older. | Image Credit: © alones-srock.adobe.com

At 90.6% (95% CI, 89.5%-91.6%) unweighted and 99.9% (95% CI, 94.6%-105.3%) weighted, tirzepatide had the most patients meet the FDA label eligibility criteria for weight loss treatment, followed by semaglutide at 89.0%(95% CI, 87.9%-90.1%) and 98.2% (95% CI, 92.8%-103.6%), respectively, and liraglutide at 88.9% (95% CI, 87.8%-90.0%) and 98.1% (95% CI, 92.7%-103.5%). The corresponding rates of individuals who also met trial exclusion criteria were 33.1% (95% CI, 31.4%-34.8%), 26.2% (95% CI, 24.6%-27.9%), and 28.1% (95% CI,26.4%-29.8%). Older age correlated with exclusion criteria, the authors noted, with more adults who were at least 60 years having at least 1 exclusion criterion compared with younger ages (<40, 40-49, and 50-59 years).

For this analysis, the exclusion criteria were major depressive disorder, malignant neoplasms, liver disease, uncontrolled hypertension, suicidal ideation, kidney impairment, use of medications linked to weight gain, diagnosis of other severe psychiatric disorder, systemic glucocorticoid therapy, and antiobesity medication use. Drilling down, their commonality varied across the medications.

• For liraglutide, semaglutide, and tirzepatide, the top 2 most common exclusion criteria were major depressive disorder (17.4%, 17.4%, and 17.3%, respectively) and malignant neoplasms (7.6% for all)
• The third most common were uncontrolled hypertension (3.7%) for liraglutide, suicidal ideation (3.4%) for semaglutide, and liver disease (6.1%) for tirzepatide
• The least common exclusion was antiobesity medication use across all medications, at 0.6% for liraglutide and semaglutide and 0.5% for tirzepatide
• Trials of tirzepatide had the most overall exclusion criteria, at all of the exclusion criteria that were evaluated

The study authors also noted that close to a third of US adults who do not have diabetes but were eligible to receive these medications were excluded from trials of their safety and efficacy, and that this is not the only patient population who may be underrepresented.

“Furthermore, treatment decisions are multifactorial, and pharmacotherapy may not be the preferred option for many patients with overweight or obesity,” they explained. “Until there is evidence from high-quality postmarketing studies, the FDA should consider updating labeling to advise caution on generalizing the safety and effectiveness of GLP-1 and GLP-1/GIP to populations excluded from pivotal trials.”

Limitations to wider generalizability of these findings are the self-reported nature of the participants’ medical conditions and the investigators’ inability to accurately measure all exclusion criteria, which lends itself to potential for underestimation.

References

1. Bessette LG, Anderson TS. Generalizability of clinical trials of novel weight loss medications to the US adult population. JAMA Intern Med. Published online November 25, 2024. doi:10.1001/jamainternmed.2024.6340

2. FDA approves weight management drug for patients aged 12 and older. News release. FDA. December 4, 2020. Accessed November 24, 2024. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-weight-management-drug-patients-aged-12-and-older

3. FDA approves new drug treatment for chronic weight management, first since 2014. FDA. June 4, 2021. Accessed November 24, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014#:~:text=Today%2C%20the%20U.S.%20Food%20and,30%20kg/m2%20or%20greater

4. Joszt L. FDA approves diabetes drug tirzepatide for chronic weight management. AJMC^®. November 8, 2023. Accessed November 24, 2024. https://www.ajmc.com/view/fda-approves-diabetes-drug-tirzepatide-for-chronic-weight-management

5. National Health and Nutrition Examination Survey. CDC. Updated May 30, 2024. Accessed November 24, 2024. https://www.cdc.gov/nchs/nhanes/index.htm