Letter: From Safety to Precision—Optimising the Use of GLP‐1 Receptor Agonists in Gastroenterology

The therapeutic landscape for glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is rapidly expanding within gastroenterology, paralleling the epidemics of obesity, metabolic disease, and resulting in chronic disease sequelae. Pomenti et al. have provided a timely narrative overview of GLP-1 RA use with a focus on obesity-related gastrointestinal outcomes in individuals with steatotic liver disease, irritable bowel syndrome, and obesity-associated cancers 1. Distinct from the secondary effects of improved metabolic control on these disease outcomes, preliminary data on potential primary anti-inflammatory effects of GLP-1 RAs in the setting of inflammatory bowel disease (IBD) are cited. Complementing this perspective, a systematic review in the same issue synthesises evidence on the effectiveness, safety, and metabolic effects of these therapies in IBD, a population excluded from the GLP-1 RA pivotal trials 2. Collectively, these data reflect a maturation of the field, from initial concerns regarding gastrointestinal tolerability to growing reassurance, thereby establishing a scholarly framework for evidence-based integration of GLP-1-based therapies into clinical care. While achieving consistent reductions in body weight and improvements of metabolic parameters, the most common gastrointestinal adverse effects of GLP-1 RA therapy including diarrhoea, abdominal pain and nausea appear similar in IBD and non-IBD cohorts, without an increased rate of disease flare or need for treatment escalation. In addition, several large registries report associations with improved IBD-related outcomes, including fewer hospitalisations and reduced corticosteroid exposure, although these observations are inherently limited by confounding and indication bias 3-5. The hepatology literature provides efficacy data for GLP-1 RAs for metabolic dysfunction-associated steatohepatitis with robust primary end points including resolution of steatohepatitis without worsening of liver fibrosis and reduction in liver fibrosis without worsening of steatohepatitis. In contrast, GLP-1 RAs are not prescribed specifically for IBD. Hence, IBD-specific outcomes are obtained using proxies from administrative and pharmaceutical databases, with inconsistent and inadequate capture of objective markers of disease activity, namely inflammatory biomarkers, endoscopy or histology. Moreover, body mass index or total body weight changes are used as the primary metric of adiposity, overlooking heterogeneity in visceral fat distribution and metabolic phenotypes that may be more relevant to IBD biology and treatment response. Thus, current data remain insufficient to identify which patients with IBD may benefit from GLP-1-based therapies, through what mechanisms, and at what point in the disease course. The next phase of research should focus on prospective, IBD-specific study designs that integrate metabolic and inflammatory endpoints. GLP-1-based therapies may be best evaluated as adjunctive metabolic modulators rather than primary anti-inflammatory therapies. Integrating GLP-1-based interventions into prospective IBD trials may help identify subgroups in whom metabolic-immune interactions are clinically relevant. Such efforts will require harmonised inflammatory endpoints, robust metabolic phenotyping including measurement of visceral adiposity, and careful attention to timing of drug exposures and disease outcomes to avoid overinterpretation of indirect effects. Overall, while available data on the use of GLP-1 RAs in gastroenterology are reassuring, progress in this field will depend on prospective studies that clarify patient selection, pathophysiologic mechanisms, and meaningful outcome measurement. Joëlle St-Pierre: conceptualization, writing – original draft, supervision. Brooke Maracle: writing – review and editing, conceptualization. Cynthia H. Seow: conceptualization, writing – review and editing, supervision. The authors have nothing to report. J.S.-P. Advisory boards for Pfizer, Abbvie, Eli Lilly, and Pendopharm, and speaker for Takeda and Pfizer. B.M. None. C.H.S. Advisory Boards for Janssen, Abbvie, Takeda, Lilly, Ferring, Merck, Pfizer, Sandoz, Pharmascience, Fresenius Kabi, Amgen, Celltrion, Sanofi, GSK. Speaker for Janssen, Abbvie, Takeda, Lilly, Ferring, Shire, Pfizer, Pharmascience, Fresenius Kabi, Organon. The authors declare no conflicts of interest. This article is linked to Pomenti et al. paper. To view this article, visit https://doi.org/10.1111/apt.70450. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.