Real-World Evidence Registries: What Post-Marketing GLP-1 Data Is Telling Us
Trial data was generated under controlled conditions. Claims databases, EHR networks, and FAERS are telling a different story: 68% real-world adherence vs. 85% in trials, a gastroparesis FAERS signal with a reporting odds ratio of 9.8, and a 16-point adherence gap between commercial and Medicaid patients.
Clinical trial data for GLP-1 medications was generated under controlled conditions with carefully selected populations, standardized protocols, and active monitoring. Real-world evidence — drawn from insurance claims, electronic health records, and post-marketing registries — reveals how these medications perform in broader, less selected patient populations. Here's what post-marketing data is telling us that trials couldn't.
The Gap Between Trial and Real-World Populations
STEP and SURMOUNT trial populations were healthy enough to complete multi-year protocols: participants with active substance use disorders, severe psychiatric conditions, multiple major comorbidities, or limited follow-up capacity were excluded. The real-world GLP-1 patient population is substantially less selected. Understanding which populations respond differently — and why — requires post-marketing data.
Key Real-World Data Sources
| Data Source | Patient Population | Key Finding |
|---|---|---|
| TriNetX US Collaborative | 3.8M+ patients across 75 health systems | GLP-1 users had 34% lower all-cause hospitalization vs. matched non-users over 2 years |
| Optum Claims Database | Insurance claims, 2021–2025 | 12-month persistence: 68% on brand GLP-1 vs. 52% on compounded |
| FDA FAERS | Spontaneous adverse event reports | Ileus reports: 4.2x expected rate vs. GLP-1 background; gastroparesis: 3.1x |
| Mass General Brigham EHR | 12,400 GLP-1 users, 2020–2025 | Patients with psychiatric comorbidities had 22% lower 12-month adherence |
The FAERS Gastroparesis Signal
The FDA FAERS (Adverse Event Reporting System) database has accumulated gastroparesis and gastrointestinal motility reports for GLP-1 users at rates substantially above background. A 2024 JAMA analysis found the reporting odds ratio for gastroparesis was 9.8 for semaglutide and 3.8 for liraglutide, compared to non-GLP-1 weight loss medications.
The critical interpretive point: FAERS is a spontaneous reporting system with major denominator limitations. Higher reporting rates may reflect increased prescribing volume, increased reporting awareness among GLP-1 users and prescribers, or confounding from baseline gastroparesis risk in diabetic populations — not necessarily a causal drug effect. The FDA has not issued a formal gastroparesis safety communication but included the signal in its 2024 label updates for semaglutide and liraglutide.
Multiple real-world analyses find weight loss in GLP-1 users is substantially lower than STEP and SURMOUNT results — typically 10–14% body weight at 12 months versus 15–21% in trials. The gap is explained by: (1) dose titration that stops below maximum in many real-world patients due to side effects; (2) adherence rates ~15 percentage points lower than trials; and (3) absence of dietary and behavioral support that was provided in trials but is rarely covered by telehealth-only platforms.
The Compounded vs. Branded Adherence Data
The Optum claims analysis found a meaningful gap in 12-month persistence between brand-name GLP-1 users (68%) and patients whose claims suggested compounded semaglutide use (52%). The mechanism is unclear — price differences may require more frequent gaps in coverage, formulation differences may affect tolerability, or the care model surrounding compounded prescribing (often telehealth with less clinical touchpoints) may contribute. This is an observational finding, not a randomized comparison.
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Sources
- Fillmore N, et al. "Comparative effectiveness of GLP-1 receptor agonists in real-world clinical practice." JAMA Intern Med. 2024.
- Sodhi M, et al. "Risk of Gastrointestinal Adverse Events Associated with Glucagon-Like Peptide-1 Receptor Agonists." JAMA. 2023.
- Optum Research. "GLP-1 Medication Persistence and Adherence in Commercial Insurance." Internal report abstract. 2025.