Pancreatic enzyme replacement therapy (PERT) — commonly used to reverse the insufficient secretion of pancreatic enzymes, or pancreatic exocrine insufficiency (PEI) — showed benefit in the treatment of side effects associated with the use of GLP-1 receptor agonists (RAs) and GLP-1/GIP RAs, according to the results of a new study.
“PERT appears to be a promising adjunct therapy for managing gastrointestinal [GI] symptoms associated with GLP-1-RAs,” first author Idit Dotan, MD, of the Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, said in presenting the findings at the 19th International Conference on Advanced Technologies and Treatments for Diabetes (ATTD) 2026.
“Integrating PERT into treatment regimens may improve patient tolerance for GLP-1-RAs, supporting their long-term use in diabetes and obesity management,” she said.
The delayed gastric emptying and altered nutrition absorption occurring with treatment with GLP-1 and GLP-1/GIP RAs can result in functional PEI, or an “asynchronization between food transport and pancreatic secretions,” Dotan explained.
The resulting symptoms include diarrhea, abdominal pain, and bloating.
Integrating PERT With GLP-1 RA Treatment
To determine if PERT could therefore treat those symptoms, Dotan and her colleagues enrolled 51 patients at Beilinson Hospital, including eight (15.7%) with type 2 diabetes, 12 (23.5%) with obesity, and 31 (60.8%) with diabetes and obesity combined.
The primary indication for GLP-1 RA therapy was type 2 diabetes among 34 patients (66.7%) and obesity in 17 (33.3%).
Of the patients, among whom 33 (64.7%) were female, the mean age was 62.8, and all were treated with PERT due to gastrointestinal symptoms associated with GLP-1 RA therapy.
Participants’ mean BMI was 33.8, with 29.4% overweight and 64.7% obese.
Of note, patients had a range of comorbidities, including 90.2% with dyslipidemia, 74.5% with hypertension, 60.7% with metabolic dysfunction-associated steatotic liver disease, 49% with obstructive sleep apnea, and 35.3% with ischemic heart disease.
Most (88.2%) had diarrhea, 68.2% had flatulence, 56.9% had abdominal pain, 39.2% had bloating, and 21.6% had fecal incontinence at baseline.
As PERT is not indicated for the treatment of nausea, the study did not report on that side effect; for severe nausea, “we utilize metoclopramide or ondansetron,” noted Dotan.
PERT therapy — consisting of 300 mg pancreatin capsules containing a mixture of amylase, lipase, and protease — was administered to the patients at a mean dose of 3.33 capsules per day.
With GI effects of GLP-1 RAs commonly occurring during the up-titration phase of medication, PERT was initiated between a few weeks to several months following the prescription of GLP-1s, with “the timing and necessity of PERT tailored to the individual needs of each patient,” Dotan told Medscape Medical News.
The mean treatment duration was 8.3 months, with 40% of patients using PERT for less than 6 months, generally during the escalation phase of GLP-1 RA therapy.
The results showed that patient symptoms — graded on a scale of 1-5, representing symptom resolution (1) to severe worsening of symptoms (5) — either were resolved or substantially improved in as many as 62.7% of patients.
In addition, 31.4% had partial improvement that allowed for a dose escalation and continuation of GLP1-RA therapy.
Three patients (5.9%) experienced no symptom relief from PERT, resulting in the discontinuation of the adjunct treatment.
Notably, none of the patients had worsening of GI symptoms while receiving PERT.
Duration of PERT
With GLP-1 RA symptoms typically not returning once resolved, the duration of PERT treatment varied from one month to several months, Dotan reported.
“Patients are advised to utilize PERT only as long as necessary, and indeed, many report significant alleviation of side effects and ultimately discontinue PERT when it is no longer required,” she said.
Notable patterns observed in the study included that PERT appeared particularly beneficial for patients who consumed elevated amounts of dietary fat.
In addition, “some patients utilized higher doses during weekends and holidays, when meals tend to be larger and richer,” Dotan said.
In terms of specific GLP-1 RAs, “there was no discernible difference in the benefits of PERT across various GLP-1 receptor agonists; however, our study was not specifically designed to address this question,” she noted.
Larger, Prospective Study Needed
Acknowledging the study’s main limitation of size, Dotan said the current study nevertheless suggests the potential for important benefits of PERT in patients receiving GLP-1 RA treatment.
“Numerous studies indicate that discontinuation rates with GLP-1 and GLP/GIP RAs exceed 50% within the first year,” she said. “Therefore, it is crucial that we assist our patients in managing gastrointestinal side effects, which frequently contribute to treatment withdrawal, and PERT demonstrates promising efficacy in this regard.”
Dotan and her colleagues are currently developing a prospective study to further evaluate the effects of PERT in the treatment of GLP-1 RA-induced symptoms.
Commenting on the study, Satish K. Garg, MD, a professor of medicine and pediatrics and director of the Adult Clinic at the Barbara Davis Center for Diabetes, University of Colorado School of Medicine in Denver, noted that “it is intriguing to see a positive response to PERT therapy in this retrospective study.”
“It is hard to imagine any direct effect on exocrine functions from GLP-1 RAs,” Garg told Medscape Medical News. “However, if patients had diarrhea I wonder if [they] had also had some element of exocrine deficiency that was not evaluated.”
“A proper prospective study will be needed to evaluate role of PERT in GI symptoms from GLP-1 therapy patients with type 2 diabetes or obesity.”
Importantly, however, “anything that can help to alleviate GI adverse events would be helpful while using GLP-1s in patients with diabetes or obesity,” Garg added.
Dotan’s disclosures include consulting or other relationships with Novo Nordisk, Sanofi, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Novartis, Rafa, Bayer, Padagis, and Abbott. Garg is an investigator in ongoing SURPASS-type 1 diabetes studies, but had no relevant disclosures to report.
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