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Obesity has reached epidemic proportions globally, posing a significant public health burden. Its impact on patients’ guts and livers is self-evident. Weight is known to be an influencer of many digestive diseases including non-alcoholic fatty liver disease (NAFLD), gastroesophageal reflex disease (GERD), and inflammatory bowel disease (IBD). Biomedical literature suggests there’s a link between type 2 diabetes (T2D) and gastrointestinal cancers. Anti-obesity medications have been prescribed to help manage glycemic levels and weight. While the benefits of these medications have significantly changed the treatment landscape for obesity, what do we know about its effects on digestive diseases?  

Current Landscape of Anti-Obesity Medications
Several classes of anti-obesity medications are currently available, each with distinct mechanisms of action, briefly:  

• Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the actions of the gut hormone, GLP-1, that has roles in satiety, gastric emptying, and increases insulin secretionthatproduces a full feeling.This class of drugs has been commonly associated with gastrointestinal issues, including nausea, vomiting, diarrhea, constipation, and dyspepsia, among others.  
• Lipase inhibitors prevent pancreatic lipase from synthesizing lipids, which reduce fat absorption from the diet. Like the adverse effects of GLP-1 RAs, lipase inhibitors have also been associated with oily spotting, fecal incontinence, and even elevated blood pressure.  
• Combination therapies like a sympathomimetic and topiramate or an opioid receptor antagonist with a norepinephrine and dopamine reuptake inhibitor, is thought to have effects on the central nervous system with effects on appetite and reward pathways. Some adverse effects from these therapies also include nausea, constipation, headache, and vomiting.  

Unfortunately,someanti-obesity medications are helpful for some patients with digestive diseases, but also can cause adverse effects that cause digestive diseases. At the Digestive Disease Week 2024, here’s a few presentations exploring the potential impact of anti-obesity medication on digestive diseases. 

IBD, Obesity, and a GLP-1 RA
The efficacy and safety of a GLP-1 RA on weight management were evaluated in patients with IBD and obesity. In this retrospective, patients who identified in a muti-institutional database were included if they were diagnosed with IBD and obesity receiving the GLP-1 RA greater than three months. Patients with type 2 diabetes were excluded from this study. The primary outcome evaluated mean total body weight (TBW) from baseline, at six months and 15 months, compared to control patients without IBD with obesity who were prescribed the GLP-1 RA greater than three months, based on one-to-one propensity score matching (PSM) for demographics, smoking status, and mean BMI. In this study, 128 patients were included in this study. Similar reduction in TBW was observed between the two cohorts, regardless of IBD status. The study also concluded that this GLP-1 RA was not associated with increased presentation of IBD. 

Incidence of Hepatocellular, Biliary, and Pancreatic Cancers and GLP-1 RA
A retrospective cohort study investigated the incidence of hepatobiliary, pancreatic, or color rectal cancer in patients with T2D taking GLP-1RA in adult patients across 80 hospitals in the US between January 1, 2010, and October 31, 2023. In this study, researchers identified 15,706 patients with T2D on a GLP-1RA, which were age, demographic, comorbidities, and medication matched to patients who were not on a GLP-1 RA. In patients with T2D without GLP-1 RA treatment, the study found a higher incidence of hepatocellular(HR: 1.52; 95% CI: 1.03, 2.20), biliary (HR: 1.44; 95% CI: 1.03, 2.02), and pancreatic cancers (HR: 1.50; 95% CI: 1.07, 2.09) although not statistically significant, respectively. Additionally, there was a decrease in all-cause mortality rate among patients with T2D using a GLP-1 RA compared to patients who did not receive a GLP-1 RA (HR: 0.59; 95% CI: 0.054, 0.63).  

Incidence of Digestive Diseases With GLP-1 RA Use
In a large, five-year, retrospective study aimed to characterize the long-term effects of GLP-1 RAs on gastrointestinal and hepatobiliary diseases. Six cohorts were developed using PSM comparing injectable forms of GLP-1 RAs, such as semaglutide, liraglutide, dulaglutide, exenatide, and lixisenatide and oral semaglutide to controls. Investigators found a trend toward cholecystitis and gastroparesis with oral semaglutide compared to controls, although not statistically significant. However, injectable semaglutide was associated with statistically significant incidence of cholecystitis, pancreatitis, gastroparesis, and GERD, compared to controls. On top of that, there was also a trend towards an increased incidence of pancreatic cancer in this cohort. 

Collectively, these findings are both promising because of the positive effects on weight-associated digestive diseases and are causes of concern for some patients and healthcare professionals alike for others. But additional research is needed to confirm the results of this study to learn more about the long-term effects of anti-obesity medications on digestive diseases, including gastrointestinal cancers. These studies further highlight the need for individualized patient care using a collaborative approach to account for patient specifics and preferences, comorbidities, and drug interactions.  

Check out these and other presentations at this year’s Digestive Disease Week meeting taking place online and in-person from May 18 – 21, 2024 in Washington, D.C. 

References 
Desai A, Khataniar H, Hashash JG, et al. Efficacy and Safety of Semaglutide in Patients With Inflammatory Bowel Disease and Obesity. Poster presented at: Digestive Disease Week; May 18-21, 2024; Washington D.C. Presentation Number Tu1887 

Nieto LM, Navaez S, Palacio Argueta P, et al., Glucagon Like Peptide-1 Receptor Agonist Use is Associated With Lower Incidence of Hepatobiliary or Pancreatic Cancer in Patients with Type 2 Diabetes: A Multi-center Cohort Study Across the United States. Poster presented at: Digestive Disease Week; May 18-21, 2024; Washington D.C. Poster Number TU1944 

Niu C, Zhang J, Bhatta P, et al,.Exploring Gastrointestinal and Hepatobiliary Adverse Events in GLP-1 Receptor Agonists Therapy: A Large Cohort Retrospective Study. Oral presentation at: Digestive Disease Week; May 18-21, 2024; Washington D.C. Presentation Number 1181