Real‐world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP‐1RA‐based weight‐loss therapies

Abstract Glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have emerged as key agents for weight management, based on their marked efficacy as observed in randomized controlled trials. While still limited, real‐world studies on GLP‐1RA use in populations with obesity are increasingly available. This narrative review discusses contemporary real‐world evidence demonstrating the utilization, clinical and comparative effectiveness, and adverse effects of the currently approved GLP‐1RA‐based weight‐loss therapies, that is, liraglutide, semaglutide and tirzepatide. The observed weight reduction in clinical practice overall tends to be lower than in randomized controlled trials; however, outcomes approach those seen in trials when focusing on highly adherent patients. Real‐world studies demonstrate high discontinuation rates of GLP‐1RAs (20%–50%) within the first year, and the use of much lower doses than those evaluated in clinical trials. Evidence from observational studies within type 2 diabetes or obesity populations suggests frequent gastrointestinal disturbances in GLP‐1RA users, as also observed in trials, but no clear increase in risks of severe events like pancreatitis or pancreatic cancer, thyroid disorders, or depression and self‐harm. Further evidence is needed to understand possible real‐world associations of GLP‐1RAs with eye disease and other rare outcomes. We provide 10 areas of particular importance for further research on GLP‐1RA within the real‐world space, including improved understanding of the exact drivers of early discontinuation and suboptimal dosing, studies of the effects of stopping GLP‐1RA treatment, and investigations of clinical and cost‐effectiveness for hard clinical outcomes in real‐world settings, including not only cardio‐reno‐metabolic outcomes but also obesity‐induced diseases like neuropsychiatric disease, cancer, musculoskeletal disease, and infections. Plain Language Summary Recent advancements in weight‐loss medications have sparked a lot of interest. The so‐called GLP‐1 receptor agonist medications (GLP‐1RAs) have gained a lot of attention, because they have shown to be very effective, leading to significant weight loss in patients participating in clinical trials. GLP‐1RAs, like liraglutide, semaglutide, and tirzepatide, help manage weight by mimicking hormones that control blood sugar and appetite. However, how these medications perform in real life can be different from the controlled settings of clinical trials, in which patients are carefully selected and their treatment plans closely followed. This literature review looks at how these medications are used and their effectiveness and safety in real‐world settings. In real‐life practice, GLP‐1RAs are often less effective than in clinical trial conditions. This is usually because patients don't follow their medication plans as strictly as in trials. Real‐world data shows that many patients use lower doses and do not stick to their treatment as strictly as participants in a controlled trial might, leading to less weight loss. However, those who do follow their plans closely can achieve results similar to those in trials. A major issue with GLP‐1RAs is that many patients stop using them within the first year due to side effects or high costs of the medications, especially if not covered by insurance. Common side effects include nausea and digestive problems, which are the main reasons patients stop taking these treatments. These side effects are often manageable and decrease over time, and this reviews found no strong real‐world evidence that GLP‐1RAs cause severe side effects in many users. Despite these challenges, when GLP‐1RAs are used effectively and consistently, they show substantial benefits in weight loss, most so the newest medications semaglutide and tirzepatide. These medications are also likely to help manage and prevent weight‐related health conditions like type 2 diabetes and cardiovascular disease, but evidence for these beneficial outcomes is still scarce in real‐world settings. The review emphasizes the need for more research to understand why many patients stop using these medications and how to improve dosing. It also calls for studies on the long‐term effects of these therapies on various health outcomes, including mental health, cardiometabolic health, cancer, and rare conditions like eye diseases. Overall, while GLP‐1RAs are a valuable tool for weight management, their real‐world use requires careful consideration of individual patient factors, such as the ability to stick to treatment plans, manage side effects, and afford the medications. Further research will help make these treatments more effective for a wider range of people that need them.