Real-world research priorities for GLP-1 weight loss therapies in obesity treatment

As GLP-1 receptor agonists like semaglutide, liraglutide, and tirzepatide are increasingly used for weight loss, real-world evidence (RWE) is needed to understand their effectiveness, safety, cost-effectiveness, and long-term outcomes beyond clinical trials. A new 2025 review identifies ten key research priorities to guide future studies and improve real-world obesity care.

As glucagon-like peptide-1 receptor agonists (GLP-1RAs) gain wider adoption in obesity treatment, attention is shifting toward how these therapies perform in routine clinical settings. A 2025 narrative review, titled, ‘Real-world evidence on the utilization, clinical and comparative effectiveness, and adverse effects of newer GLP-1RA-based weight-loss therapies’, outlines ten areas where further RWE is needed to inform both clinical practice and health policy.

While randomized controlled trials (RCTs) have consistently shown significant weight loss benefits from GLP-1RA therapies, results in real-world settings are more variable. As the authors note,

“The observed weight reduction in clinical practice overall tends to be lower than in RCTs; however, outcomes approach those seen in trials when focusing on highly adherent patients.”

Discontinuation rates in real-world settings remain a major concern, with the study stating that discontinuation rates reach, “20–50% within the first year,” with many patients also using, “much lower doses than those evaluated in clinical trials.” Common reasons for discontinuation include gastrointestinal side effects, high costs, and potentially suboptimal patient engagement. The authors call for, “improved understanding of the exact drivers of early discontinuation and suboptimal dosing.”

To advance the evidence base, the review outlines the following ten areas where further real-world studies are needed:

1. Overall drug utilization: “There is a need for continuously updated population-based drug utilization data, including key aspects such as costs and treatment persistence.” Monitoring how treatment patterns and adherence evolve and differ from those in RCTs can help explain differences between trial and real-world outcomes.
2. Responders: Many patients discontinue early, and further research should identify, “what specific patient characteristics or subgroups drive such early discontinuation and to what extent (and for which patients) it is caused by lack of tolerability or lack of effect.”
3. Real-world effects: The authors call for further study into, “the real-world weight-lowering effect and the cardiovascular and renal benefits documented in clinical trials… not only for the use of the drugs as intended in the trials… but also for effects in groups not included in the trials and with the use of lower doses.”
4. Comparative effects: Few head-to-head comparisons have been conducted in routine care. The authors note, “Direct comparisons will be essential… as the use of active comparators will likely reduce confounding in the assessment of both the efficacy and safety of these drugs.”
5. Other effects: Beyond weight and cardio-renal outcomes, the review highlights the importance of investigating, “additional clinical effects of GLP-1RA use for weight management,” including changes in healthcare use, mental health medication use, and broader potential benefits like reduced risk of cancer or dementia.
6. Cost-effectiveness: Given the high price of these therapies, “there is a need to investigate the cost-effectiveness of these drugs regarding endpoints such as cardiovascular events and total mortality.” Although current evidence is limited, early findings, “suggest very high costs per prevented event in the total population,” highlighting the need to assess value across patient subgroups.
7. Effects of stopping: The authors stress the need to understand, “the effects of stopping GLP-1RA treatment,” particularly in patients who have achieved significant weight loss. Trial data suggest rapid weight regain, and, “a substantial part of this regain seems to be fat mass.” However, the authors note that, “the clinical relevance of this finding… is very limited,” as trial conditions do not reflect how treatment is typically discontinued. Real-world studies should explore both treatment cessation and alternatives like dose reduction or spacing.
8. Data availability: Many RWD sources lack key variables such as body weight, height, and lifestyle factors, which limits the ability to assess treatment effectiveness. “The identification of which data sources can be used to answer what research questions is central.” The authors note that most sources lack non-GLP-1RA comparators, though exceptions like Norway, which offer comparators such as naloxone/bupropion, do exist. The authors suggest high-quality sources include the UK’s Clinical Practice Research Datalink (CPRD) or Scandinavian population surveys.
9. Methodological quality: With a growing number of real-world studies, the review calls for improvements in study design and transparency. “There is an increasing need to not only summarize this literature but also to evaluate and strengthen its methodological quality.” A key concern is selection bias, particularly in studies that include only “drug survivors,” meaning patients who remain on treatment or receive high doses over time. These approaches risk overestimating treatment effects and limit the generalizability of findings.
10. Adverse events in obesity: The review warns that safety data from diabetes populations may not apply to those using GLP-1RAs for weight loss, with these users, “roughly 20–25 years younger on average.” Some adverse effects may be linked to diabetes or hyperglycemia rather than the drug itself. The authors stress, “there is a need to study the occurrence of adverse effects specifically among users of GLP-1RA for weight management and in particular the absolute risk of these effects.”

The authors emphasize that:

“Future research should focus on comparative effectiveness, long-term clinical impacts, treatment discontinuation effects and cost-effectiveness to optimize the real-world application of these therapies. Addressing these gaps will be crucial for refining clinical guidelines, ensuring equitable access and guiding future pharmacological strategies for obesity management.”