Increased Risk of Gastroparesis Associated with GLP-1RA Use in Type 2 Diabetes Patients

A new study uncovered an association between glucagon-like peptide-1 receptor agonist (GLP-1RAs) use and an increased risk of gastroparesis (GP) among patients with Type 2 diabetes. The research, “Gastroparesis (GP) Risk in Patients with Type 2 Diabetes (T2D) Prescribed GLP-1 Receptor Agonists,” was recently presented during the Digestive Disease Week Conference.

“Diabetes Mellitus (DM) is a global health concern, affecting approximately 10.5% of adults worldwide, with projections indicating an increase to over 12% by 2045” notes study author Samita Garg, MD, Department of Gastroenterology, Hepatology & Nutrition, Cleveland Clinic. In the U.S. alone, an estimated 11.3% of the population, equivalent to around 38.4 million individuals, are affected by DM, primarily Type 2 diabetes. Certain demographic groups, such as Native Americans, African Americans, Hispanics, and Asian Americans, experience a higher prevalence of T2D.

Approximately 40% of U.S. adults are classified as obese and 70% as overweight or obese. “There is a well-known association between obesity and diabetes — 90% of patients with Type 2 diabetes are overweight or obese. Therefore, management of both is crucial for treatment and improved outcomes.”

GLP-1RAs and, more recently, Twin-Cretins (GLP+GIP) are often used in patients with diabetes and with or without obesity. The use of these agents is increasing based on recommendations from the American Diabetes Association and the European Association for the Study of Diabetes.

However, the relationship between GLP-1RAs and new-onset gastroparesis has not been evaluated. Dr. Garg and colleagues initiated the current study to better understand the risk of new-onset GP among patients with Type 2 diabetes who received these drugs.

Research overview

Using TriNetX, a multi-institutional database of approximately 88 million patients, the researchers examined the risk of a new GP diagnosis among adult patients with Type 2 diabetes who were prescribed GLP-1RAs (dulaglutide, semaglutide, liraglutide, lixisenatide, exenatide, tirzepatide or albiglutide) between January 2021 and December 2022.

This cohort was compared with Type 2 diabetes patients who had never received GLP-1RAs. Exclusion criteria included a history of bariatric surgery, fundoplication, celiac disease, inflammatory bowel disease or GI cancers as well as a history of GP prior to GLP-1RA prescription.

Researchers performed 1:1 propensity score matching for demographics, HbA1c, BMI, motility disorders, neurological disorders, pro-kinetic medications as well as other conditions and medications to ensure the patient cohorts were balanced.

Among the study population, 336,655 patients with Type 2 diabetes received GLP-1RAs and 2,203,082 patients did not undergo treatment with GLP-1RAs. After propensity score matching, there were 336,655 in each cohort. When discussing patient demographics, Dr. Garg noted patients were predominantly female and white; however, minorities represented almost 30% of the cohort.

“As expected, patients with Type 2 diabetes who were prescribed GLP analogs had higher BMI and poor glucose control,” report Dr. Garg and team. “Patients with Type 2 diabetes who received GLP-1RAs had an increased risk of gastroparesis diagnosis at six, nine, 12, 18 and 24 months. The odds ratio for GP diagnosis significantly increased after six months through 24 months after controlling for different risk factors.”

What comes next?

Based on their findings, the researchers recommend long-term monitoring and further research in patients with Type 2 diabetes who receive GLP analogs. According to Dr. Garg, this involves prospective clinical trials following patients over a longer period of time.

“It would also be valuable to look at additional GI side effects,” she says. “While our study focused on gastroparesis, there are other potential side effects associated with these drugs, such as gastroesophageal reflux disease, biliary disease, ileus and pancreatitis, that warrant further study.”

Balancing risks against benefits

"When it comes to clinical care of these patients today, it really depends on the overall presentation and risk factors of the individual patient,” Dr. Garg advises. “Is there an underlying GI disorder? What are the GI symptoms after starting a GLP? Are they worsening? How was the dose escalated?”

Collaboration between various disciplines, particularly endocrinology and gastroenterology, is important for effective management of these patients, according to Dr. Garg, who recommends a multidisciplinary approach even before the initiation of GLP-1RAs. “Working with GI colleagues could help optimize GI symptoms before treatment begins,” she says. “When the medication is initially prescribed, starting low and going slow can also help your patients better tolerate any GI symptoms associated with GLP-1RAs.”

A better understanding of the side effects is key when prescribing any medication, and it is equally important to raise patient awareness. This study can be used to do both, notes Dr. Garg. “Providers must be vigilant to minimize and treat any GI symptoms that arise,” she concludes. “And by educating patients on both the benefits and risks, we can help them become more alert and attuned to their GI symptoms even before they start this medication.”