Real-world Challenges and Predictors of Success in Glucagon-like Peptide-1 Receptor Agonist Therapy

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have revolutionized the management of type 2 diabetes mellitus (T2DM) and obesity, demonstrating robust efficacy in landmark trials for glycemic control, weight reduction, and cardiovascular protection. However, real-world discontinuation rates exceed trial-reported rates, highlighting a gap between clinical efficacy and practical outcomes.

This review synthesizes evidence from 2018 to 2024, including trial data, population studies, and registry analyses, to identify and contextualize major real-world barriers. High rates of gastrointestinal side effects, substantial out-of-pocket costs, and patient aversion to injectable formulations often result in 1-year discontinuation rates ranging from 27 to 41%. These challenges are compounded by heterogeneity in patient response, with predictors of successful long-term use including higher baseline HbA1c, elevated body mass index (BMI), absence of severe gastrointestinal disorders, and robust early response to therapy.

A proposed clinical scoring model is presented to improve patient selection and predict adherence, while digital health tools and emerging combination therapies offer additional avenues to enhance persistence and outcomes. Despite promising advances such as dual- and triple-incretin agents and oral GLP-1 RA formulations, cost and access remain major hurdles.

Key factors, including baseline HbA1c >8.0%, BMI >30 kg/m², absence of severe gastrointestinal (GI) disorders, and prior adherence success, correlate strongly with higher persistence. Real-world data reveal that discontinuation rates for GLP-1 receptor agonists remain high, with 1-year discontinuation ranging from approximately 28% to around 41%, depending on the patient population and indication. Discontinuation is more common among patients using GLP-1 RAs for obesity without diabetes, reaching rates above 50% in some cohorts. The primary reasons for stopping therapy include gastrointestinal side effects, reported in over 25% of discontinuations, high medication costs, and issues with insurance coverage or medication access. Persistence is generally higher among patients with T2DM, those with higher baseline BMI, and those who experience greater early weight loss or favorable tolerability, while frequent adverse effects and logistical barriers contribute to poorer long-term adherence. Although emerging clinical tools and digital health interventions are proposed to help address these barriers, further prospective data are needed to quantify their impact on persistence at scale.

Bridging trial evidence with real-world practice requires proactive candidate profiling and side-effect management. Combining predictive scoring, artificial intelligence (AI)-supported adherence tools, and emerging dual-incretin agents may transform GLP-1 RA therapy from short-term use to durable metabolic benefit.