GIP receptor agonist cut gut side effects of GLP-1 therapy in early Lilly trial
An early-stage trial found a GIP receptor agonist eased gut side effects during fast liraglutide escalation, a signal that has not been tested in patients.
A single dose of an experimental long-acting GIP receptor agonist, LY3537021, reduced gastrointestinal side effects in healthy volunteers who were quickly escalated onto the GLP-1 drug liraglutide, according to a Phase 1 trial published August 27, 2024, in the journal Diabetes, Obesity and Metabolism [1].
The randomized, placebo-controlled crossover study (NCT05444569) was run at one center in Singapore and enrolled healthy adults aged 21 to 60 with a body weight of at least 55 kg and a body mass index between 23 and 40 [1]. Participants, investigators and clinic staff were blinded to whether a person received LY or placebo; liraglutide was given open label [1].
Each participant went through two treatment periods separated by an 8-week washout. On day 1 they received a single subcutaneous 25 mg dose of LY or a matching volume of placebo. Starting on day 2, everyone received daily liraglutide: 0.6 mg on day 2, escalating to 2.4 mg by day 5, then 2.4 mg daily through day 9 [1]. LY has a half-life of roughly 11 to 14 days, so one injection stays in the body for weeks [1].
Pretreatment with LY cut the total number of gastrointestinal treatment-emergent adverse events during the liraglutide ramp-up from 75 to 41, and reduced reflux events from 14 to 5 [1]. The trial counted nausea, vomiting, constipation, diarrhea, abdominal discomfort, abdominal distension, decreased appetite, early satiety, dyspepsia, belching, flatulence and gastroesophageal reflux, among other events [1].
Why GIP is being studied this way
Tirzepatide (Mounjaro, Zepbound) activates both GIP and GLP-1 receptors and has produced greater reductions in HbA1c and body weight than placebo or selective GLP-1 receptor agonists [1]. The mechanisms behind GLP-1 receptor agonism's effects on blood sugar and weight are well understood; what GIP receptor activation contributes is less clear [1].
The authors point out that both the benefits and the nausea-type side effects of GLP-1 drugs are tied to signaling in regions of the hindbrain that also express GIP receptors, which could mean overlapping control of nausea and vomiting. In animal experiments, GIP receptor agonism reduced gastrointestinal side effects caused by chemotherapy drugs or by GLP-1 receptor agonism [1]. The trial was designed to test whether the same holds in people [1].
Several limits matter. This was a small, exploratory Phase 1 study in healthy volunteers, not in people with diabetes or obesity, and the statistical analyses were labeled exploratory with a significance threshold of P < .05 [1]. The liraglutide schedule used here reached 2.4 mg daily within four days, much faster than the gradual escalation used in routine care. Participants received liraglutide, a selective GLP-1 receptor agonist, not semaglutide or tirzepatide; whether the same effect would appear with those drugs, with slower dose increases, or in patients has not been reported. LY3537021 is investigational, and no approval, later-stage trial or timeline has been disclosed.
Why it matters for patients
Gastrointestinal side effects are a common reason people stop or reduce GLP-1 medications. The paper states that GLP-1 receptor agonist use brings "gastrointestinal tolerability challenges, including nausea and emesis, that potentially limit efficacy and compliance" [1].
If GIP receptor activity can blunt those symptoms, it could eventually shape how combination treatments are designed. For now, that remains a hypothesis tested only in 32 healthy volunteers under an unusually fast dosing schedule [1]. Nothing in this study changes the labels, dosing or side-effect guidance for any approved GLP-1 or GIP/GLP-1 medication, and the experimental drug was not tested as a treatment for side effects in people already taking these medicines.
The practical takeaway for patients is limited: existing nausea and vomiting with semaglutide, tirzepatide or liraglutide is not addressed by this finding, and no approved product works this way today.
What happens next
No follow-up study, such as a trial in people with type 2 diabetes or obesity, has been reported. Whether LY3537021 or a similar compound will be developed further, and on what schedule, has not been disclosed.
Sources
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