Evidence that GIP receptor agonism eases GLP-1 gut side effects

A small clinical trial suggests that a drug targeting the GIP receptor alone may ease the stomach problems that often come with GLP-1 medicines like liraglutide. The study, led by researchers including Filip K. Knop and published August 27, 2024, in Diabetes, Obesity and Metabolism, tested whether adding a long-acting, selective GIP receptor agonist could reduce gastrointestinal side effects during a fast liraglutide dose increase ^[1].

The trial enrolled 32 healthy adults in a crossover design at one site in Singapore ^[1]. Each participant received either a single injection of the experimental GIP drug, called LY3537021, or a placebo, followed by liraglutide dosed once daily and escalated quickly from 0.6 mg up to 2.4 mg over five days, then held at 2.4 mg through day nine ^[1]. After an eight-week break, each person crossed over to the other treatment, so every participant experienced both conditions ^[1].

The results showed a clear difference. When participants got the GIP drug before liraglutide, they had a total of 41 gastrointestinal treatment-emergent adverse events across the group, compared with 75 such events when they got a placebo before liraglutide ^[1]. Gastroesophageal reflux events dropped from 14 with placebo to 5 with the GIP drug ^[1]. The study tracked a list of GI symptoms including nausea, vomiting, abdominal discomfort, bloating, constipation, diarrhea, decreased appetite, early fullness, belching, flatulence, and reflux, using standard medical terminology ^[1].

The researchers designed the study to test a specific idea: that GIP receptor agonism, on its own, could offset the nausea and vomiting that limit how well people tolerate GLP-1 drugs like liraglutide, Ozempic, Wegovy, and Rybelsus ^[1]. Liraglutide is a GLP-1 receptor agonist marketed for diabetes and weight management, distinct from newer combination drugs like tirzepatide (Mounjaro, Zepbound), which activates both GIP and GLP-1 receptors ^[1]. Earlier animal studies had already hinted that GIP receptor agonism could reduce GI side effects caused by chemotherapy drugs or by GLP-1 agonism itself, and this human trial was designed to see if that held true in people ^[1]. The paper notes that GLP-1 and GIP receptors are both found in brain regions tied to nausea and vomiting, which may help explain why combining the two signals could calm stomach symptoms rather than worsen them ^[1].

Why it matters for patients

Nausea, vomiting, and other GI side effects are among the most common reasons people cut back or stop taking GLP-1 medicines. This early study suggests that GIP receptor activity, separate from its role in blood sugar control, might help make GLP-1 therapy more tolerable during dose increases, when side effects are often worst ^[1]. That could matter for anyone who has had to slow down or pause a dose escalation because of stomach upset.

However, this was a small, short study in 32 healthy volunteers, not people with diabetes or obesity, and it used liraglutide rather than the semaglutide or tirzepatide products most commonly prescribed today ^[1]. The GIP drug tested, LY3537021, is not an approved medicine and was given alone, not as part of an approved combination ^[1]. The authors describe the statistical analysis as exploratory, meaning the findings point to a promising signal but are not yet the kind of large, confirmatory evidence regulators or doctors would rely on for treatment decisions ^[1].

What happens next

The paper does not describe specific follow-up trials or dates for testing this GIP-alone approach in larger or more diverse populations. It is not yet known whether these results will be confirmed in people who actually take GLP-1 drugs for diabetes or weight loss, or whether a standalone GIP agonist like LY3537021 will move forward in development ^[1].