About one-third of U.S. adults eligible per FDA labeling for GLP-1/GLP-1–GIP weight-loss drugs would have been excluded from the pivotal trials supporting these medications.

Background

GLP-1 receptor agonists (liraglutide, semaglutide) and dual GLP-1/GIP receptor agonist (tirzepatide) are approved for weight loss. Pivotal trials excluded many common medical and psychiatric conditions, yet FDA labeling does not restrict use in these groups. This study estimated how many U.S. adults meeting FDA label indications would have met trial exclusion criteria.

Patients

• Nonpregnant, nonbreastfeeding U.S. adults ≥20 years without diabetes
• BMI ≥27 kg/m² (BMI 27–29 required a weight-related comorbidity) or BMI ≥30 kg/m²
• Data source: NHANES 2013–March 2020; n=8,767 representing 110.3 million U.S. adults with overweight/obesity (mean age 49 [SD 16] years; 50% female)
• Race/ethnicity (weighted): 3.1% Asian, 12.4% Black, 10.5% Mexican American, 7.4% other Hispanic, 63.0% White

Intervention

Not applicable (cross-sectional eligibility assessment; no treatment administered).

Control

Not applicable.

Outcome

• Primary: Proportion of FDA label–eligible adults who met ≥1 trial exclusion criterion for each medication (liraglutide, semaglutide, tirzepatide).
• Secondary: Prevalence of specific exclusion criteria; subgroup differences by age, sex, race/ethnicity, and BMI; sensitivity analysis including use of medications that slow gastrointestinal motility (for tirzepatide).

Study Design

• Cross-sectional analysis of nationally representative NHANES data (2013–March 2020)
• Trial inclusion/exclusion criteria emulated from pivotal trials supporting FDA approval
• Weighted estimates; univariable logistic regression for subgroup associations; STROBE guideline followed

Level of Evidence

Level IV (cross-sectional observational study).

Follow up period

None (cross-sectional). Data spanned NHANES cycles 2013–March 2020.

Results

• Population meeting FDA label criteria:
  • Liraglutide: 88.9% (95% CI, 87.8%–90.0%) of adults with overweight/obesity
  • Semaglutide: 89.0% (95% CI, 87.9%–90.1%)
  • Tirzepatide: 90.6% (95% CI, 89.5%–91.6%)
  • Weighted counts meeting FDA indications (millions): Liraglutide 98.1 (92.7–103.5); Semaglutide 98.2 (92.8–103.6); Tirzepatide 99.9 (94.6–105.3)
• Primary outcome:
  • Liraglutide: 28.1% (95% CI, 26.4%–29.8%) would have been excluded by trial criteria
  • Semaglutide: 26.2% (95% CI, 24.6%–27.9%)
  • Tirzepatide: 33.1% (95% CI, 31.4%–34.8%)
• Secondary outcomes:
  • Most common exclusion criteria (weighted prevalence among FDA-eligible):
    • Major depressive disorder: 17.3%–17.4% (across drugs)
    • Malignant neoplasms: 7.6%
    • Liver disease (tirzepatide trials): 6.1%
    • Uncontrolled hypertension (liraglutide trials): 3.7%
    • Suicidal ideation: 3.4%
    • Kidney impairment (semaglutide/tirzepatide trials): 2.5%
    • Medications linked to weight gain: ~2%
    • Other severe psychiatric disorder: 1.9%
    • Systemic glucocorticoid therapy: 0.9%
    • Current antiobesity medication use: ≤0.6%
  • Subgroups: Adults ≥60 years were more likely to meet ≥1 exclusion criterion than younger groups; patterns across sex and race/ethnicity were reported without detailed estimates in the letter.
  • Sensitivity analysis (tirzepatide):
    • Use of medications that slow GI motility among FDA-eligible: 23.5% (95% CI, 22.3%–24.8%)
    • Including GI motility–slowing medications as an exclusion increased the excluded proportion to 43.7% (95% CI, 42.1%–45.4%)
    • Common GI motility–slowing classes: proton pump inhibitors (9.9%), calcium channel blockers (7.0%), opioids (6.6%), H2 blockers (2.5%), tricyclic antidepressants (1.3%), α2-adrenergic agonists (1.2%)
• Number needed to treat (NNT): Not applicable (no treatment or dichotomous clinical outcome measured).

Limitations

• Medical conditions were self-reported; temporality of exclusions could not always be established
• Not all trial exclusion criteria could be fully emulated in NHANES; exclusions may be underestimated
• Focus on ineligibility; some trial-eligible populations may still be underrepresented
• Findings do not address effectiveness or safety in excluded populations

Funding

Supported by NIH Medical Scientist Training Program grant T32 GM144300 (University of Pittsburgh–Carnegie Mellon University MD-PhD Program) and National Institute on Aging grant K76 AG074878. Funders had no role in study design, conduct, analysis, or publication decisions.

Citation

Bessette LG, Anderson TS. Generalizability of Clinical Trials of Novel Weight Loss Medications to the US Adult Population. JAMA Internal Medicine. 2025;185(1):108-109. Published online November 25, 2024. doi:10.1001/jamainternmed.2024.6340