Large study quantifies gut motility risk from GLP-1 drugs, including tirzepatide
A 313,342-pair cohort study found GLP-1 based therapies, including tirzepatide, carried a modestly higher rate of severe gut motility events than SGLT-2 inhibitors, with absolute risk at 1% or less per year.
Adults with type 2 diabetes who started a GLP-1 based therapy had higher rates of severe gastrointestinal motility problems than those who started an SGLT-2 inhibitor, according to a cohort study published June 4, 2026 in the journal Diabetes, Obesity and Metabolism [1]. The absolute risk was low: 1% or less per year, the authors reported [1].
The study used two de-identified US commercial healthcare databases to identify adults with type 2 diabetes who had no prior history of major gastrointestinal conditions and who newly started one of two drug classes [1]. One group began GLP-1 based therapies — GLP-1 receptor agonists or tirzepatide — and the other began SGLT-2 inhibitors, a different class of diabetes drugs used as the active comparison [1]. After matching by propensity score, the analysis included 313,342 pairs of patients. Their mean age was 60 years, 45% were female, and they were followed while on treatment for a median of 5.2 months [1].
The main outcome was a composite of three serious events: severe constipation, gastroparesis and gastrointestinal obstruction. Incidence rates for the composite were 1.02 per 100 person-years among GLP-1 based therapy initiators versus 0.75 per 100 person-years among SGLT-2 inhibitor initiators [1]. That is a rate difference of 0.27 per 100 person-years, with a hazard ratio of 1.37 and a 95% confidence interval of 1.30 to 1.45 [1]. The risk was higher for the composite outcome and for each of its three individual components, the authors wrote [1].
The authors reported that the relative increase was consistent across subgroups defined by which GLP-1 based therapy agent was used, as well as by age, sex, body mass index, frailty level, diabetes severity and opioid use [1]. In their conclusion, they wrote that the absolute risk of motility-related gastrointestinal adverse events was 1% or less, but was higher among GLP-1 based therapy initiators compared with SGLT-2 inhibitor initiators, and that the findings "can inform the risk benefit assessment by clinicians before initiating these treatments" [1].
Because the study compared two active drug classes rather than a drug against a placebo, the 0.75-per-100-person-year rate in the SGLT-2 inhibitor group reflects that serious motility events also occur in people taking other diabetes medications [1].
Why it matters for patients
Severe constipation, gastroparesis and intestinal obstruction are the kinds of events that can lead to emergency care, procedures or hospitalization, and they are already listed among the gastrointestinal concerns associated with this drug class. This study puts a number on how much more often they occurred in people starting GLP-1 based therapies, including tirzepatide, than in people starting a different diabetes drug [1].
The practical scale is important in both directions. The relative increase was 37% — a meaningful difference between the two groups. But the absolute numbers were small: roughly one event per 100 people treated for a year in the GLP-1 group, compared with about 0.75 per 100 in the comparison group [1]. In other words, most patients in both groups did not experience any of the three events during the follow-up period.
The study enrolled only adults with type 2 diabetes, and only those without a prior history of major gastrointestinal conditions [1]. Risks for people taking these drugs for weight loss without diabetes, or for people who already have a gastrointestinal condition, have not been reported in this analysis. The median follow-up of 5.2 months also means the study does not answer how risk may change with longer treatment. Whether the risk varies by dose, whether it differs among individual drugs, or whether these events resolve after treatment changes has not been disclosed in the published report [1].
What happens next
The paper's data cannot be shared by the authors because of data use agreements with the database providers; other researchers can access the databases by obtaining their own agreements or licenses [1]. The published article notes that its peer review history is available, and it includes supporting tables on the outcome definitions and on healthcare use in the 180 days after treatment initiation [1]. No regulatory action or label change tied to this analysis has been reported [1].
Sources
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