Patients on semaglutide who experienced constipation had greater weight loss than those without constipation, according to a real-world retrospective analysis presented at Digestive Disease Week (DDW) 2026.

“The finding surprised us,” Thomas Fredrick, MD, Mayo Clinic, Rochester, Minnesota, told Medscape Medical News. “We had expected the presence of nausea and vomiting to be more associated with weight loss, particularly in the first 3 months of treatment. However, we found that individuals who experienced constipation had significantly greater weight loss than those who did not at 3, 6, and 12 months.”

Higher Semaglutide Doses, Less T2D

Researchers conducted a retrospective review of electronic medical records from individuals at 3 academic centers who had at least one order for semaglutide 2.4 mg weekly dosing. Participants had a mean age of 53; 73% were women; 52% were White; 83% had a BMI exceeding 30; and 31% had type 2 diabetes. Eighty-seven had constipation, and 334 had no constipation.

A total of 188 participants (37%) received semaglutide without interruption for 12 months or longer, and the most common reasons for discontinuation were ineffectiveness and adverse events (AEs).

The primary outcome was total body weight loss (TBWL) at 12 months. Weight, AEs, semaglutide dosing, and additional anti-obesity medications were assessed at 3-month intervals.

The most common AEs were nausea and constipation. Among those who discontinued due to side effects, most individuals experienced nausea (57%).

An assessment of the impact of side effects on weight loss showed that nausea was not associated with 12-month weight loss (10.8% vs 10.8%). In contrast, constipation was significantly associated with weight loss at 3, 6, and 12 months. 

Participants with constipation had 14.4% TBWL compared to 10.8% in those without constipation. The difference was 6.62% vs 4.55% at 3 months, 10.7% vs 8.15% at 6 months, and 13.3% vs 10.7% at 9 months.

A subgroup analysis showed that constipation was associated with higher doses of semaglutide and lower rates of type 2 diabetes (18% vs 33%). Notably, participants experiencing constipation had greater 12-month TBWL at all semaglutide doses.

Genetic Variation Could Be Key

Although the findings are hypothesis-generating at this point, Fredrick said, clinical trials have shown GLP-1s act on the stomach to delay gastric emptying, and the authors suspect it may have a similar effect on the small intestine and colonic motility.

“GLP-1 modulates gastric motility in part through vagal innervation, and there may be a component of vagal nerve activity changes playing a role in the effect on constipation,” he suggested.

He also suspects that some degree of genetic variation alters the gastrointestinal motility changes seen after GLP-1 treatment “and individuals with these novel genetic changes have improved weight loss.”

Examples of that variation include genetic polymorphisms such as single-nucleotide polymorphisms variations in the TCF7L2 gene and variants in peptidyl-glycine alpha-amidating monooxygenase.

The analysis suggests that “searching for the novel genetic polymorphisms associated with GLP-1-induced constipation may help improve our ability to identify individuals who respond exceptionally well to medications like tirzepatide and semaglutide and those that should be steered towards other treatments,” Fredrick concluded.

Fredrick declared having no conflicts of interest. 

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.