Large cohort quantifies the motility risk for GLP-1 drugs including tirzepatide

A new cohort study published June 4, 2026 in Diabetes, Obesity and Metabolism puts a number on one of the most-discussed safety questions about GLP-1 medications: how often they lead to serious gut motility problems. Among 313,342 matched pairs of patients, rates of a combined outcome of severe constipation, gastroparesis and gastrointestinal obstruction were 1.02 per 100 person-years for people starting GLP-1-based therapies versus 0.75 per 100 person-years for people starting SGLT2 inhibitors ^[1].

That works out to a rate difference of 0.27 events per 100 person-years and a hazard ratio of 1.37 (95% confidence interval 1.30 to 1.45) ^[1]. In plain terms, the relative risk was about 37% higher, but the absolute risk in both groups was small — the authors describe it as 1% or less ^[1].

What the study did

Researchers from the University of Waterloo, Brigham and Women's Hospital, Harvard Medical School, Massachusetts General Hospital and UCLA used two de-identified US commercial healthcare databases: Optum's Clinformatics Data Mart and MarketScan Commercial Claims and Encounters ^[1]. They identified adults with type 2 diabetes who had no prior history of major gastrointestinal conditions and who newly started either a GLP-1-based therapy — GLP-1 receptor agonists or tirzepatide, the molecule in Mounjaro and Zepbound — or an SGLT2 inhibitor ^[1].

The design is what epidemiologists call a new-user, active-comparator study, with propensity score matching to balance the two groups on measured characteristics. Using SGLT2 inhibitors as the comparison group, rather than people on no diabetes drug, is meant to reduce the chance that sicker patients end up concentrated in one arm. The matched population had a mean age of 60 years and was 45% female, and patients were followed while on treatment for a median of 5.2 months ^[1].

The increased risk showed up not just for the combined outcome but for each individual component — severe constipation, gastroparesis and gastrointestinal obstruction ^[1].

Consistent across agents and patient groups

One of the more practical findings is how stable the relative increase was. The authors report that the elevated risk was consistent across subgroups defined by which GLP-1-based agent was used — including tirzepatide — as well as by age, sex, BMI, frailty level, diabetes severity and opioid use ^[1].

That matters because opioids, frailty and longstanding diabetes are all independently linked to slowed gut motility, and because tirzepatide's dual GIP/GLP-1 mechanism has raised questions about whether its gastrointestinal profile differs from semaglutide's. In this analysis, the relative signal did not appear to vary meaningfully by those factors ^[1].

The published abstract does not break out separate event rates for individual drugs such as semaglutide versus tirzepatide, so agent-by-agent absolute numbers are not available from the material reviewed here ^[1].

Why it matters for patients

Gastrointestinal side effects are the most common reason people stop GLP-1 medications, and stories about gastroparesis have circulated widely. This study gives a size to the risk rather than leaving it as an open-ended worry: in a large, matched population, roughly 1 in 100 people per year of treatment had one of these severe motility events, compared with about 0.75 in 100 on a different diabetes drug ^[1].

The authors frame the finding as information for shared decision-making, writing that the results "can inform the risk benefit assessment by clinicians before initiating these treatments" ^[1].

Several limits are worth keeping in mind. The study enrolled adults with type 2 diabetes, not people taking these drugs solely for weight management, so it does not directly describe Wegovy or Zepbound users without diabetes ^[1]. Follow-up on treatment was a median of 5.2 months, which says little about risk over years ^[1]. And because the data come from insurance claims, events are identified from diagnosis codes; the authors ran sensitivity analyses that removed specific codes, including the code for drug-induced constipation ^[1].

What happens next

The paper appears in Volume 28, Issue 8, pages 7494–7504, and its peer review history is publicly posted ^[1]. Whether regulators or label committees act on the findings is not addressed in the study and is not yet known.

Among disclosures, one author reports consultancy for Novo Nordisk and service on data monitoring committees for the SOUL and FLOW trials; the corresponding author reports institutional research grants from Boehringer Ingelheim, AstraZeneca and Bayer unrelated to this work, consulting for IQVIA and royalties from UpToDate ^[1].