Key takeaways:
- Prevalence of constipation exceeded 30% among users of GLP-1s and other obesity medications compared with nonusers.
- However, 1-year incidence of new-onset constipation among GLP-1 users was less than 4%.
Although nearly a third of individuals with obesity who use GLP-1 receptor agonists experience constipation, the risk for developing constipation among new users appears “quite low,” according to researchers.
“Constipation is one of the most commonly discussed gastrointestinal side effects of GLP-1 receptor agonists, and it is often cited as a reason patients stop therapy,” Kyle Staller, MD, MPH, gastroenterologist and director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital, told Healio.
Staller and colleagues sought to understand whether GLP-1 use increases the risk for new-onset constipation, as well as the burden and prevalence of constipation among those currently treated.
“Patients with obesity and type 2 diabetes often have multiple risk factors for constipation, independent of GLP-1 therapy,” Staller said.
Researchers used data from NIH’s All of Us Research Program to conduct a cross-sectional analysis of constipation prevalence among GLP-1 users, including individuals with preexisting constipation before starting GLP-1s, and a longitudinal analysis of new-onset constipation within the first year of medication use.
The cross-sectional analysis included individuals with obesity taking GLP-1s (n = 11,656), bupropion-naltrexone (Contrave, Currax Pharmaceuticals; n = 917) or phentermine-topiramate (Qsymia, Vivus; n = 728), as well as 91,305 nonusers.
Constipation prevalence among GLP-1 users (31.6%) was similar to that among bupropion-naltrexone (30.1%) and phentermine-topiramate (30.4%) users, and significantly higher than prevalence among individuals taking no medications (26.8%; P < .001).
For the longitudinal analysis, researchers created propensity-score matched pairs of nonusers and users of GLP-1s (n = 8,188), bupropion-naltrexone (n = 495) and phentermine-topiramate (n = 368) by age, race, gender, socioeconomic status, Charlson Comorbidity Index and other factors.
Most GLP-1 users were on semaglutide (n = 6,080), followed by liraglutide (n = 3,126) and tirzepatide (n = 940).
Constipation incidence among GLP-1 users in the first year was 3.34 per 100 person-years, which appeared comparable across individual medications: 2.9 per 100 person-years with semaglutide, 4.16 with liraglutide and 1.81 with tirzepatide. Constipation developed a mean 141 days from the start of GLP-1 use.
Incidence of constipation with bupropion-naltrexone was 3.73 per 100 person-years and 4.32 with phentermine topiramate.
“The most intriguing finding was the contrast between high prevalence and low incidence,” Staller said. “Seeing that nearly one-third of GLP-1 users had constipation at some point could easily reinforce the perception that these medications commonly cause constipation.”
Additional analysis of GLP-1 users showed those who developed constipation were younger (54.9 vs. 56.6 years; P < .05) and had a higher Charlson Comorbidity Index (4.5 vs. 3.9; P < .001) than users who did not develop constipation.
“Patients who developed constipation after starting GLP-1s had a greater comorbidity burden,” Staller said.
“That suggests that vulnerability to constipation may not be driven by medication exposure alone, but by the broader clinical context in which these medications are prescribed.”
In the study, GLP-1 users appeared to have higher risk for developing constipation than nonusers (HR = 1.49; 95% CI, 1.23-1.8), according to Cox regression models. Phentermine-topiramate (HR = 1.68; 95% CI, 0.73-3.89) and bupropion-naltrexone (HR = 2; 95% CI, 0.9-4.45) were not linked to higher risk for constipation.
“GLP-1 use was associated with a statistically significant increased risk of new constipation compared with matched nonusers,” Staller said. “The signal is real, but the absolute risk was low. That nuance is important.
“These findings suggest clinicians should not dismiss constipation as a possible adverse effect, but concerns about de novo constipation generally should not be a major deterrent to starting GLP-1 therapy when otherwise clinically appropriate,” he added.
According to Staller, future research should evaluate symptom severity longitudinally and prospectively assess bowel symptoms using standardized measures before and after GLP-1 initiation.
“Our study could identify documented constipation severe enough to appear in the medical record, but it could not capture milder symptoms, over-the-counter self-treatment or worsening of preexisting constipation,” he said.
Also of note was that that the longitudinal analysis excluded patients with constipation prior to taking a GLP-1, whereas in real-world practice, many patients already have constipation when these medications are started.
“A future study should intentionally enroll those patients and track whether symptoms worsen after initiation, dose escalation or switching between agents,” he said.
For more information:
Kyle Staller, MD, MPH, is director of the Gastrointestinal Motility Laboratory at Massachusetts General Hospital and associateprofessor at Harvard Medical School. He can be reached at gastroenterology@healio.com.
Perspective
In this study, researchers performed an analysis based on the medical records of 111,545 patients diagnosed with obesity. Specifically, they studied whether exposure to GLP-1 medications is associated with development of constipation.
In a separate analysis, they also evaluated incidence of new-onset constipation during 1 year of treatment. Paradoxically, the risk for new-onset constipation was lower among GLP-1 users.
However, Staller and colleagues showed that less than 4% of patients developed new-onset constipation if they did not have constipation before starting GLP-1 medications. Therefore, before starting a GLP-1 agent, patients should be advised that constipation may be aggravated and should be proactively treated.
One study limitation is that the analysis appraised the incidence of constipation at 1 year after GLP-1 exposure. Since GLP-1 discontinuation rates may approach 30% to 40% at 6 months, it is unknown whether constipation was more frequent or led to discontinuation in the first 6 months.
Additional research should assess whether constipation is associated with slow colonic transit with GLP-1 medications.
Reference:
Van Laren J, et al. Diabetes Obes Metab. 2026;doi.org/10.1111/dom.70579.
Michael Camilleri, MD, DSc
Disclosures: Camilleri reports an advisory role for Eli Lilly & Co. and research funding from NIH.
Sources/Disclosures
Source:
Chang M, et al. Clin Gastroenterol Hepatol. 2026;doi:10.1016/j.cgh.2026.05.018.
Disclosures:
Staller reports consulting roles with AbbVie, Ardelyx, Atmo Biosciences, Ferring Pharmaceuticals, Gemelli Biotech, Laborie Medical Technologies, Mindset Health, Salix Pharmaceuticals and Takeda Pharmaceuticals, and research support from Ardelyx and Ironwood Pharmaceuticals. The other authors report no relevant financial disclosures.
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