Do GLP-1 Medications Lead to Adverse GI Events?

— By Dawn M. Sweet, Ph.D.

Gastroparesis, acute pancreatitis and ileus paralysis are among potential GLP-1 side effects now being empirically investigated.

GLP-1 RA medications have transformed the management of type 2 diabetes and weight loss. Like all medications, GLP-1 RAs do have side effects, the most common and well-known of which are vomiting, diarrhea, and vomiting. Other GI risks now being empirically investigated include gastroparesis and acute pancreatitis. Although GLP-1 RAs are considered generally to be safe, there are some lawsuits¹ related to these more adverse side effects, and in 2023 the FDA² added blocked intestines (also known as ileus paralysis, paralytic ileus or pseudo-obstruction) to the list of potential side effects.

Semaglutide Pancreatitis and GLP-1 Medications

A recently updated meta-analysis of randomized, placebo-controlled studies¹ investigated semaglutide’s connection to pancreatitis. Guidelines for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed, and the study was registered with PROSPERO. Randomized clinical trials through November 2023 that met the four eligibility criteria were included. Inclusion criteria were: (1) comparisons of the safety and efficacy of semaglutide and placebo; (2) ≥ 3 months for duration of follow-up; (3) randomized controlled trial; and (4) reporting incidence of acute pancreatitis. After inclusion criteria were applied, 21 studies that included 34,721 patients were eligible.

Seven studies assessed oral doses of semaglutide, four studies analyzed low doses (0.5 – 1mg), nine studies analyzed high doses of semaglutide (1.7 – 2.4 mg) of weekly subcutaneous injections, and one study assess two active arms, daily oral semaglutide and weekly subcutaneous semaglutide at 0.5 – 1.0 mg doses. Within this set of studies, 12 included patients with type 2 diabetes and seven counted this as an exclusion criterion; two studies included patients with and without type 2 diabetes.

Results indicate there was no increased risk of pancreatitis with semaglutide. These meta-analyses found evidence to support more common GI events such as nausea, vomiting, and diarrhea; however, the authors note that the data suggest that the association between semaglutide and acute pancreatitis is controversial. Pancreatic duct gland hyperplasia was noted as a proposed mechanism of GLP-1 RA related pancreatitis as were pancreatic duct obstruction leading to proinflammatory reactions, acinar cell hypertrophy, and pancreatic vascular injury. Increased risk of gall bladder disease was also noted as another risk in patients using semaglutide for longer periods of time. The authors further note that type 2 diabetes is itself a risk factor for acute pancreatitis, and previous studies may have been affected by insufficient statistical power, insufficient duration of follow up time, or confounding variables.

Gastroparesis and GLP-1 Medications

Gastroparesis is a known side effect of diabetes, and because semaglutide is used to treat patients with type 2 diabetes, there are concerns about semaglutide’s association with gastroparesis.^4,5 In a study led by researchers from the University of Kansas, TriNexT records were used to identify patients prescribed a GLP-1 RA to help manage obesity or diabetes between 2021 – 2022. Age, gender, race, ethnicity, the Charleston comorbidity index, BMI, and HbA1 were used as part of a propensity score match (1:1).

After propensity matching, 148,366 patients for each cohort, those prescribed a GLP-1 RA and those not prescribed a GLP-1 RA, were included in the analysis. Results suggest that patients prescribed a GLP-1 had a significantly higher incidence of gastroparesis, with 53 percent of patients in this group being diagnosed with gastroparesis (0.53 %, RR 1.66, 95% CI 1.48-1.86) compared to the non-GLP-1 group. Patients taking a GLP-1 were 66 percent more likely to be diagnosed with gastroparesis.

In another study using TriNexT records,⁶ researchers from University Hospitals in Cleveland investigated the prevalence of gastroparesis in patients with type 2 diabetes who were prescribed a GLP-1 RA or a twincretin drug between January 2021 – December 2022. The GLP-1 medications prescribed included dulaglutide, semaglutide, liraglutide, lixisenatide, exenatide, tirzepatide, or albiglutide. Exclusion criteria were bariatric surgery, fundoplication, celiac disease, IBD, GI cancers, or a history of gastroparesis. A 1:1 propensity match was again used with 336,655 patients in both the GLP-1 and non-GLP 1 groups. Results suggest that patients with type 2 diabetes who were prescribed a GLP-1 had an increased risk of gastroparesis at six, nine, 12, 18, and 24 months. At three months, the risk of gastroparesis was similar between groups; however, from six months forward the GLP-1 group was more likely to experience gastroparesis. By 18 months, the GLP-1 group was 25 percent more likely to experience gastroparesis. It should be noted that the overall incidence of gastroparesis was low, between 0.16 – .-77 percent over the two-year timeframe.

What is Ileus Paralysis?

Ileus, or lack of intestinal motility that can lead to an obstruction or buildup, was reported by 16 patients prescribed Ozempic in 2023 as noted in the FDA Adverse Reporting System (FAERS; searchable database).^1,7According to the same report¹, the FDA received over 8,500 reports of GI events related to semaglutide, 20 of which were related to ileus. Of the 20 ileus-related reports, two resulted in death. While the exact rate of ileus among GLP-1 users remains somewhat an empirical uncertainty, health care providers should monitor patients prescribed a GLP-1, particularly patients with diabetes. Despite the general safety of GLP-1 medications, obstructions in patients with diabetes was 4.5 times higher than patients taking other glucose control medications.⁸ In a study of 25,617 participants, a 3.5 increase in intestinal obstruction was observed with a GLP-1 treatment.⁹

Implications for Clinical Practice

As noted above, GLP-1 RAs have transformed the management of type 2 diabetes and obesity. GLP-1 RAs are effective at managing type 2 diabetes and facilitating weight loss, though they are not without risks. When prescribing GLP-1 RAs, health care professionals should monitor their patients for side effects and work with their patients to build a sustainable weight loss and weight management plan to minimize the use long-term use of GLP-1 RAs.

In addition to medication, health care providers should work collaboratively with patients to implement sustainable lifestyle changes that can help them achieve long-term, sustainable weight loss — even after they discontinue GLP-1 RA use. A Low Calorie Diet (LCD) or Very Low Calorie Diet (VLCD) program, which combines structured behavioral education with scientifically formulated meal replacements to meet nutritional needs, is a proven and time-tested approach. Further, combining GLP-1s with quality meal replacements helps to ensure long-term success and safety for patients — and creates a business growth opportunity for practitioners.