Harnessing Real-World Evidence to Optimize GLP-1-Based Therapies: Insights from a NIDDK Workshop

Highlight

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for diabetes and obesity management, but key questions remain on long-term safety, effectiveness, and cost-effectiveness across diverse populations. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) convened a multidisciplinary workshop in May 2025 to discuss leveraging real-world evidence (RWE) to inform regulatory, clinical, and coverage decisions related to GLP-1RA therapies. Experts emphasized the complementary role of RWE alongside randomized controlled trials (RCTs) particularly for assessing rare adverse events, long-term outcomes, and routine clinical use, while noting persistent challenges in data quality, confounding, and equitable representation.

Background

GLP-1 receptor agonists have revolutionized Type 2 diabetes and obesity treatment over the last decade due to their dual benefits on glycemic control and weight reduction. Currently, these agents are FDA-approved for multiple indications, and their use is rapidly expanding among U.S. adults. However, despite promising clinical trial data, significant gaps remain regarding optimal treatment pathways, long-term safety profiles especially in real-world diverse populations, medication adherence, persistence, economic implications, and off-label usage patterns. As GLP-1RAs become more widely prescribed—as monotherapy or in combination—clinicians, payers, and regulators require robust evidence to guide decisions beyond the controlled environment of clinical trials.

Workshop Design and Objectives

The NIDDK organized a comprehensive 2025 workshop assembling stakeholders including academic researchers, regulatory agency officials (FDA, CMS), guideline developers, payers (private and public insurers), pharmacists, and patient representatives. The workshop sought to identify outstanding knowledge gaps in GLP-1RA use, evaluate how RWE—from electronic health records (EHR), administrative claims, registries, and other sources—can address these gaps, discuss methodological challenges in RWE generation and interpretation, and consider strategies for enhancing data quality and reducing bias.

Key Findings

Utility of Real-World Evidence: RWE offers critical insights into rare adverse events that are underpowered or missed in RCTs, such as pancreatitis, thyroid cancer risk, or cardiovascular outcomes over longer durations. It also illuminates effectiveness in heterogeneous populations including racial/ethnic minorities, pediatric patients, and those with multiple comorbidities, which are often underrepresented in trials.

Data Challenges: Workshop panelists highlighted several constraints complicating RWE use. Inconsistent and evolving insurance coverage policies lead to variable access and adherence patterns. High rates of medication discontinuation, compounded formulations, and off-label prescribing further obscure precise exposure measurement. Moreover, EHR and claims data often incompletely capture medication dosing, duration, and clinical endpoints. These limitations increase risks of confounding and misclassification bias, which can distort safety and effectiveness estimates.

Coverage and Policy Variability: Payer policies for GLP-1RAs differ markedly across Medicare, Medicaid, and private insurers, with heterogeneous criteria and copayment burdens that influence patient utilization and outcomes. This variability underscores the urgent need for rigorous cost-benefit analyses leveraging RWE to inform value-based coverage decisions that balance clinical benefit with economic sustainability.

Strategies to Improve RWE Quality: Enhancing data interoperability, integrating pharmacy dispense records with clinical and claims data, and deploying advanced analytic methods (e.g., causal inference models, propensity score adjustment) can help address confounding and improve confidence in RWE findings. The workshop emphasized importance of inclusive data sets that capture understudied populations and pediatric cohorts to ensure equitable evidence generation.

Expert Commentary

Experts noted that although RCTs remain gold standard for establishing efficacy, RWE plays an invaluable complementary role, particularly as real-world practice diverges from trial protocols. GLP-1RAs exemplify this need due to evolving indications, rapid uptake, and complex prescribing patterns. However, the challenges in RWE quality mandate cautious interpretation. There is consensus that investment in high-fidelity data infrastructure and analytic rigor is paramount to translating RWE into actionable guidance.

Guideline bodies and regulatory agencies are increasingly receptive to integrating RWE in decision-making frameworks, provided transparency in methodology and validation against experimental data. Enhanced collaboration between stakeholders will be essential to standardize data elements, share timely findings, and update coverage policies responsively.

Conclusion

The NIDDK workshop highlights that high-quality real-world evidence is critical to advancing understanding and optimizing the use of GLP-1 receptor agonists in clinical practice. Addressing data gaps, improving analytic approaches, and fostering stakeholder collaboration can substantially enhance the utility of RWE. This will support regulatory decisions, clinician guidance, and value-based coverage policies that maximize patient benefit while ensuring sustainable healthcare expenditure in the expanding landscape of GLP-1-based therapies.

Continued commitment to generating and integrating robust RWE will be essential as GLP-1RAs evolve in indications and clinical contexts, aiding the translation of promising trial findings into real-world health improvements.

Funding and Clinical Trials

The workshop was convened and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Specific clinical trials and data registries discussed are referenced in the original workshop publications.

References

1. 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 Jun 30. PMID: 42372278.
2. Nauck MA, Meier JJ. Glucagon-like peptide 1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab. 2019 Feb;30:170-183.
3. Pratley RE, Aroda VR, Lingvay I, et al. Cardiovascular outcomes with GLP-1 receptor agonists: trial evidence and real-world data. Diabetes Obes Metab. 2021 Jul;23(7):1670-1687.
4. U.S. Food and Drug Administration. Real-World Evidence. FDA.gov. 2023.
5. Maruthur NM, Tseng E, Hutfless S, et al. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2016 Jun 21;164(11):740-51.