Methodological Approaches to Real-World Evidence Generation for Glucagon-like Peptide-1–Based Therapies: Synopsis of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have reshaped the clinical approach to managing obesity and type 2 diabetes. As approved indications have expanded, use of GLP-1RAs has increased rapidly in the United States. Although randomized trials demonstrate strong efficacy, many questions remain about their optimal use in clinical practice. Real-world data (RWD) from electronic health records, registries, insurance claims, and other sources offer a promising avenue to address these questions. However, concerns about data quality, selection bias, and incomplete ascertainment of medication use and outcomes pose significant challenges to the validity of the resulting evidence. In May 2025, the National Institute of Diabetes and Digestive and Kidney Diseases convened experts from regulatory agencies, payer organizations, and academia to explore these challenges. This second of 2 synopsis articles on the workshop summarizes the discussion around the strengths and limitations of various RWD sources and methodological approaches to strengthen causal inference and generalizability. Presenters highlighted pragmatic clinical trials and target trial emulation as strategies to generate stronger real-world evidence (RWE) that is relevant to both clinical practice and policy. The workshop underscored that careful attention to study design, data limitations, and analytic approach is essential to yield RWE that informs clinicians, patients, payers, and policymakers.