Constipation is one of the most common gastrointestinal (GI) adverse effects associated with GLP-1s. Although typically characterized as mild-to-moderate, constipation remains a frequent contributor to treatment discontinuation and impaired adherence.

John Wiley & Sons, Inc. recently convened an expert panel to discuss strategies for managing constipation in patients taking these medications. Moderator Chee Khoo, MBBS, associate professor at Western Sydney University, Australia, noted that with the rapid expansion of GLP-1s, including dual and triple agonists, clinicians can expect to see an increase in GI adverse events.

“It’s important to get a handle on how to manage them today,” he said.

Mechanisms of Constipation

Panelist Juris J. Meier, MD, professor at Augusta-Kranken-Anstalt gGmbH Bochum Center, Bochum, Germany, reviewed the mechanisms underlying GLP-1-induced constipation. He noted that although the pathophysiology is multifactorial, the “most prominent effect is marked delayed gastric emptying.”

Constipation often occurs during initiation and dose escalation. Meier noted that delayed gastric emptying induced by GLP-1s is subject to rapid tachyphylaxis, which may explain why short-acting agents such as exenatide and lixisenatide tend to produce more pronounced gastric slowing than longer-acting agents. A 2022 meta-analysis found that liraglutide and semaglutide were associated with comparatively lower constipation rates.

“Inhibiting gastric emptying and reducing intestinal motility increases fluid absorption into the colon,” Meier explained. “GLP-1s can reach the central nervous system, and the activation of these receptors in the brain stem can alter gut-brain reflexes and slow motility. There’s also an impact on the fluid dynamics in the GI tract; in particular, the decreased gastric and interstitial secretion can reduce the stool water content. And of course, there is also the interaction with the comorbidities like diabetes, which further compound constipation risk.”

Identify the Pattern

“It’s hard to predict which patients will develop GI problems, or which particular GI problem,” Meier told Medscape Medical News. Some patients experience diarrhea, others constipation, and some develop alternating patterns resembling irritable bowel syndrome (IBS).

The clinician’s role, “is to assess the pathways and symptoms of constipation to guide effective treatment strategies.”

He described three constipation patterns physicians should identify at the outset: slow-transit constipation, most commonly associated with GLP-1s and characterized by an increase in infrequent bowel movements; normal-transit constipation, typically related to inadequate hydration or dietary fiber intake; and IBS-type constipation, characterized by alternating bowel patterns and symptoms such as bloating.

Taking a Constipation History

Panelist Diana Isaacs, PharmD, director of Education and Training in Diabetes Technology at Endocrinology and Metabolism Institute, Cleveland Clinic, Cleveland, emphasized the importance of taking a thorough constipation history.

“You need to work up potential causes other than GLP-1 drugs to make sure there’s no obstruction or to evaluate the person’s medication list to see if there are any other drugs we may want to adjust because they’re contributing to constipation,” she said.

Medications that can induce constipation include anticholinergics, calcium channel blockers, chemotherapy agents, diuretics, iron, narcotics/opioids, bile acid sequestrants, and ondansetron.

“Diabetes itself can lead to constipation because of autonomic neuropathy,” Meier added. “This might be aggravated by GLP-1-based therapies.”

Laxative Options

Because many laxatives are available over-the-counter, proactive patient education is essential. As such, Isaacs distinguished between five different categories of laxatives.

Bulk-forming agents either trap water in the intestine and soften stool (eg, psyllium and methylcellulose, both of which are soluble fiber) or increase stool bulk (eg, polycarbophil, which is soluble). This class of laxatives “could be an effective strategy for someone whose appetite is really decreased,” Issacs said, while cautioning that adequate hydration is critical to prevent bloating or obstruction when taking insoluble fiber.

Osmotic agents (eg, macrogol, magnesium oxide, and lactulose) draw water into the intestines to soften stool and improve transit. Isaacs warned that magnesium should be used cautiously in settings of renal insufficiency and pregnancy, and that lactulose has been associated with electrolyte abnormalities.

Stimulant laxatives (eg, bisacodyl and senna) increase motility by stimulating intestinal muscles and increase water content in stool, and are typically used short term. Side effects can include cramping and abdominal discomfort.

Stool softeners (eg, docusate) reduce surface tension of the oil-water interface in stool but generally have effectiveness and are often combined with other laxatives.

Adopting Proactive Strategies

For medications known to cause constipation, such as opioids, a proactive approach of initiating laxative prophylaxis is recommended. However, with GLP-1s, both panelists advocated a reactive approach.

“Diarrhea is more common with GLP-1s, and sometimes diarrhea and constipation alternate,” Issacs told Medscape Medical News. “The last thing you want to do is make the diarrhea worse.”

She advised initiating a laxative if the patient develops symptoms. Initial management should focus on lifestyle modifications including increased water intake, achieving 150 minutes of moderate-intensity activity weekly, and minimizing sedentary time. Dietary fiber intake should also be assessed, with recommendations that adults consume 20-30 g daily. Patients should be encouraged to attempt defecation after waking and/or within 2 hours after meals, when colonic motility is highest.

“Defecation posture should be modified to a squat-like position, or using a squat-assist device,” Isaacs added.

Foods with prebiotics and probiotics should be also incorporated into the diet.

“Prebiotics and probiotics play complementary roles in supporting gut health by modulating the composition and function of the gut microbiota, enhancing barrier integrity, and regulating immune responses,” Isaacs said.

Prebiotics are nondigestible dietary components selectively utilized by beneficial gut bacteria, which strengthen the intestinal barrier and regulate GI stool frequency and consistency. Examples include chicory root, onions, garlic, bananas, and whole grains.

Probiotics, on the other hand, are live microorganisms (most commonly Lactobacillus, Bifidobacterium, and Saccharomyces strains). When administered in adequate amounts, they restore microbial balance, inhibiting pathogen colonization, enhancing gut barrier function, and modulating local and systemic immunity. Examples of probiotic-containing foods include yogurt, kefir, and sauerkraut.

If symptoms persist, Isaacs recommends osmotic laxatives as first-line pharmacologic therapy, adding a stimulant agent for rapid relief when necessary. Management should be individualized based on tolerance and response.

She emphasized the value of multidisciplinary collaboration. Primary care physicians, endocrinologists, pharmacists, and gastroenterologists can all play a crucial role in monitoring and managing incretin-induced constipation, “ensuring effective treatment and patient adherence.”

Khoo received lecture honoraria from Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Sanofi, Amgen, and AstraZeneca. Meier reported receiving lecture honoraria and consulting fees from AstraZeneca, Eli Lilly, Merck Sharp and Dohme (MSD), Novo Nordisk, and Sanofi, and reimbursement of congress participation fees and travel expenses from MSD, Novo Nordisk, and Sanofi. Isaacs reported being a speaker or consultant for Novo Nordisk, Eli Lilly, Sanofi, Dexcom, Abbott, and Medtronic.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books, as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).