GLP-1 Research: What Real-World Evidence Reveals

GLP-1 receptor agonists (GLP-1RAs) have rapidly reshaped how clinicians approach obesity and type 2 diabetes management — but how much do we actually know about how these medications perform outside of controlled clinical trials? A landmark workshop synopsis published in the Annals of Internal Medicine in June 2026 suggests that significant knowledge gaps remain, and that real-world evidence (RWE) will be essential to closing them. Convened by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in May 2025, the expert panel brought together representatives from regulatory agencies, guideline committees, payers, and academia to tackle some of the most pressing unanswered questions surrounding GLP-1RA use in routine clinical care (Arterburn et al., 2026).

What This Study Found

The NIDDK workshop synopsis, authored by Arterburn, Curtis, Toh, and colleagues, identified a broad set of knowledge gaps that randomized controlled trials (RCTs) alone cannot adequately address. According to the researchers, real-world data sources — including electronic health records (EHRs), insurance claims databases, and patient registries — hold significant promise for complementing traditional trial evidence. Specifically, the study suggests that RWE can capture rare adverse events, long-term outcomes, and treatment effectiveness across the diverse patient populations seen in everyday clinical practice.

However, the workshop also highlighted that leveraging RWE for GLP-1RAs is not straightforward. Researchers found that several unique challenges complicate data interpretation, including:

• High discontinuation rates: Many patients stop GLP-1RA therapy before completing a full course, making it difficult to assess true long-term effectiveness.
• Medication shortages and compounded formulations: Widespread supply disruptions have led to increased use of compounded GLP-1 preparations, creating inconsistencies in what patients are actually receiving and making medication use difficult to track in databases.
• Off-label prescribing: GLP-1RAs are increasingly prescribed for indications beyond their current approvals, which complicates outcome tracking and safety surveillance.
• Inconsistent insurance coverage: Coverage policies vary significantly across Medicare, Medicaid, and private payers, and have changed over time — factors that introduce confounding variables into real-world datasets.
• Underrepresented populations: The study suggests that pediatric patients and individuals from underserved communities remain poorly captured in existing real-world datasets, limiting the generalizability of findings to these groups.

The researchers also emphasized that data reliability, residual confounding, and incomplete outcome capture remain persistent methodological challenges that must be addressed through rigorous analytic strategies.

Clinical Significance

The clinical implications of this workshop are substantial. GLP-1RAs — a class that includes well-known agents such as semaglutide and tirzepatide — have demonstrated efficacy for weight management and glycemic control in RCTs. Yet, as the study suggests, trial populations are rarely representative of the full spectrum of patients who receive these medications in real-world settings. Individuals with multiple comorbidities, those on complex medication regimens, older adults, and patients from racial and ethnic minority groups are often underrepresented or excluded from pivotal trials.

This is where RWE becomes critically important. Researchers found that robust real-world data infrastructure could help clinicians and regulators better understand optimal treatment pathways — including questions such as: Who benefits most from GLP-1RA therapy? How long should treatment continue? What happens when patients discontinue? Are there long-term safety signals that only emerge after years of use?

The workshop concluded that answering these questions requires sustained investment in high-quality data systems and advanced analytic methods designed to reduce bias. Without this infrastructure, the study suggests, both clinical decision-making and regulatory oversight will remain constrained by evidence that does not fully reflect the complexity of real-world GLP-1RA use.

Current Access and Compliance Context

One of the more striking findings from this workshop synopsis is the degree to which access to GLP-1RAs remains inconsistent across payer types and over time. The researchers found that coverage decisions across Medicare, Medicaid, and private insurance plans are heterogeneous — meaning that a patient's ability to obtain and sustain GLP-1RA therapy may depend heavily on their insurance status and the year in which they seek treatment.

This variability has real consequences for adherence. The study suggests that high out-of-pocket costs and coverage gaps contribute meaningfully to the high discontinuation rates observed in real-world populations. From a public health standpoint, this is significant: if patients are stopping therapy prematurely due to financial barriers rather than clinical outcomes, the effectiveness data captured in real-world datasets may underestimate the true potential of these medications.

Compounding this issue, the workshop highlighted the growing role of compounded GLP-1 formulations — unregulated preparations produced by specialty pharmacies during periods of shortage. Because these formulations are not consistently captured in pharmacy claims or EHR data, they represent a significant blind spot in real-world surveillance. The researchers suggest that strategies to improve medication tracking, particularly for compounded products, will be essential for generating reliable safety and effectiveness data going forward.

The workshop also noted that the economic impact of GLP-1RAs at a population level remains incompletely understood. Rigorous cost-benefit analyses, informed by RWE, will be necessary to support value-based coverage policies that balance medication costs against long-term health outcomes such as reduced cardiovascular events, hospitalizations, and diabetes complications.

What Patients Should Know

For individuals currently using or considering GLP-1 receptor agonist therapy, this research underscores several important points. First, while GLP-1RAs have demonstrated meaningful benefits in clinical trials, the long-term picture — including rare side effects, outcomes after stopping treatment, and effectiveness for specific subgroups — is still being actively studied. The study suggests that patients should not interpret the current evidence base as complete or final.

Second, access barriers are real and well-documented. If cost, coverage, or medication availability is affecting your ability to adhere to a prescribed regimen, this is a clinically relevant concern that warrants an open conversation with your healthcare provider. Abrupt discontinuation of GLP-1RA therapy may have implications for weight regain and metabolic health that should be managed with medical guidance.

Third, patients should be cautious about compounded GLP-1 formulations. The workshop synopsis highlights that these preparations are not subject to the same regulatory oversight as FDA-approved medications, and their safety and potency cannot be guaranteed in the same way.

Finally, this research reinforces the value of working with a qualified, knowledgeable healthcare provider who can help you navigate treatment decisions based on your individual health profile, goals, and the most current evidence available.

Conclusion

The NIDDK workshop synopsis published by Arterburn and colleagues in the Annals of Internal Medicine represents an important call to action for the research, regulatory, and clinical communities. The study suggests that while GLP-1 receptor agonists have undeniably transformed the treatment landscape for obesity and diabetes, we are still in the early stages of understanding their full impact in real-world populations. Closing the evidence gaps will require sustained investment in data infrastructure, rigorous analytic methods, and a commitment to capturing the experiences of underserved and understudied patient groups.

If you are seeking guidance on peptide-based therapies from a qualified medical professional, we encourage you to connect with a vetted provider through the Peptide Association's clinician directory. Visit peptideassociation.org/find-a-doctor to find a knowledgeable healthcare provider near you.

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Medical Disclaimer: This article is intended for educational and informational purposes only and does not constitute medical advice. The content presented here is based on a published research synopsis and is not a substitute for professional medical consultation, diagnosis, or treatment. Always consult a qualified healthcare provider regarding any medical condition or before starting, changing, or discontinuing any treatment.

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Citation (AMA format): Arterburn D, Curtis LH, Toh S, et al. Leveraging Real-World Evidence to Inform Regulatory, Clinical, and Coverage Decisions Related to Glucagon-Like Peptide-1-Based Therapies: Synopsis of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. Ann Intern Med. 2026. doi:10.7326/ANNALS-25-05468. PMID: 42372278.