Gastrointestinal Adverse Events Associated with GLP-1 Receptor Agonists: Causes and Mitigation - High-Quality UK SARMs | #1 SARMs Supplier

GLP-1RAs, including dual and triple receptor agonists, are a relatively new class of weight loss drugs that have become increasingly popular over the past few years. They effectively reduce body weight by acting on receptors in the body that control appetite, insulin secretion and metabolism. Since these receptors are found in different tissues across the body, these drugs have the ability to exert a wide range of effects, some beneficial, but some of which are undesirable and potentially harmful. This article will go over the gastrointestinal (GI) adverse events that have been reported in clinical studies, why they are experienced and what researchers have done to help mitigate them.

Gastrointestinal Issues

Most often, adverse events are mild to moderate, but they are sometimes severe enough to cause discontinuation of the medication. The most commonly reported adverse events involve GI issues, with up to 41.9%, 72.8% and 35% of patients taking semaglutide, tirzepatide and retatrutide, respectively, experiencing them. These occur mostly during the initiation and escalation period^1–3.

Nausea and Vomiting

GLP-1 stimulates the release of insulin, promotes satiety and slows gastric emptying. Although this is beneficial for the effectiveness of the drugs, since GLP-1Rs are present in the area postrema, the part of the brain that triggers vomiting, activation of these receptors causes nausea and vomiting in a significant number of patients.

Between 15.4 to 19.1% of people taking semaglutide experienced nausea according to a 2023 meta-study, with up to 7.5% experiencing vomiting¹. This is lower than the 24% and 13% incidence of nausea and vomiting, respectively, experienced by participants taking tirzepatide⁴. In a phase 2 trial, up to 36% of people who took retatrutide experienced nausea, while 12% experienced vomiting⁵.

Slowed Gastric Emptying and Gut Motility

The slowing of gastric emptying means that food remains in the stomach for longer, producing a prolonged feeling of fullness. This can contribute to the nausea experienced by some and also make gastroesophageal reflux disease more likely.

Gut motility is also slowed, which can lead to food remaining in the colon for much longer than normal. Water is continuously absorbed in the colon, leading to dry, hard stools that are more difficult to pass. In severe cases, gastroparesis can occur, allowing food to accumulate in the gut and leading to the formation of a bezoar.

Because food is sitting in the digestive tract for longer than usual, it is also subject to excessive bacterial fermentation, which results in the production of excess gas.

Upper abdominal pain, which tends to be associated with slowed gastric emptying and reduced gut motility, was found to have been most commonly reported by those taking liraglutide⁶.

Diarrhoea

Altered gut motility, combined with the fact that these drugs also affect the balance of electrolytes in the colon, can lead to the unpredictable movement of food through the gut and the prevention of normal fluid absorption, resulting in diarrhoea.

Similar incidences in diarrhoea have been reported in clinical trials on semaglutide, tirzepatide and retatrutide, with the percentage of incidence being around 10-20% depending on the study^1,5,7.

Pancreatitis

The release of insulin from pancreatic beta cells is thought to be overstimulated in response to these drugs in some people. This could cause swelling and obstruction of the ducts in the pancreas, leading to the development of pancreatitis. Those with type 2 diabetes or obesity are at greater risk of pancreatitis, as the free fatty acids that are produced when fat is broken down are toxic to pancreatic cells and can trigger stress and inflammation. People with obesity are also more likely to suffer from pancreatitis regardless of whether or not they take GLP-1RAs.

Despite being linked to an increased risk of pancreatitis in several studies, a meta-study on the incidence of pancreatitis in patients taking GLP-1RAs found no clear evidence to strengthen this connection⁸.

Gall Bladder Issues

The slowing of the GI tract also affects the gallbladder. The release of bile from the gallbladder becomes less frequent and bile is not emptied from the gallbladder completely. If meal portions have also been reduced as a result of taking the drug, this contributes even further to the slow release of bile. When fat tissue is being lost rapidly, more cholesterol is released into the bile, thickening it and increasing the likelihood of gallstones forming. Gallstones can sometimes cause pancreatitis when they become stuck in the common bile duct, as this is where the pancreatic duct empties out. This traps pancreatic juices in the pancreas, building up pressure and digesting the pancreas, leading to inflammation.

A meta-analysis looking at the association between GLP-1RAs and adverse events involving gallbladder or biliary disease found that there was an overall increase in the development of these diseases. This risk was higher in those taking higher doses and for longer periods⁹. There is currently no association between gall bladder issues and retatrutide, but this may be because it is still a very new drug for which we have collected relatively little data.

Other Side Effects

Some other non-GI-related adverse events include:

Anxiety and Depression: GLP-1 receptors exist in the brain and regulate the brain’s reward system. They can suppress cravings and other compulsive behaviours, but also dull the response to what was once rewarding stimuli¹⁰.
Fatigue: A calorie deficit, dehydration, fluctuations in blood sugar and metabolic changes can all contribute to fatigue.
Hair Loss: When the body loses weight rapidly, this acts as a stress signal. It allocates energy towards the functioning of vital organs and signals to hair follicles to enter a resting phase. A few months after entering this resting phase, the hairs are shed in a process called telogen effluvium¹¹. Although some people have reported hair loss, others have reported hair regrowth¹², making the connection between GLP-1RAs and hair loss a subject of continued interest.
Rash: The most common cause of rash is due to a reaction at the injection site, and this has been reported in all commercially available GLP-1RAs. Exenatide has been noted to produce reactions leading to the development of nodules, which have resulted in patients discontinuing the treatment¹³.

Mitigating Side Effects in Clinical Trials

In clinical trials, drugs are often titrated to reduce the frequency and severity of adverse events. This involves gradually increasing the dose over the course of weeks. As the body adjusts to the drug, the nausea typically improves and may resolve entirely after a few months.

Over time, the discomfort associated with delayed gastric emptying tends to subside, and the stomach adapts, to a certain degree, to the effects of the drug, meaning there is less of a delay in gastric emptying after being on the drug for some time.

Conclusion

We are still learning more about adverse events associated with GLP-1RA use. Despite the additional receptor targets of drugs such as tirzepatide and retatrutide, we consistently see the same array of side effects in these drugs. GI issues are the most commonly experienced and best understood adverse event associated with all GLP-1RAs. Although these issues are normally mild to moderate and transient, they are severe enough in some people to result in the discontinuation of treatment. To help reduce these adverse events, titration of the drug along with dietary and lifestyle changes can benefit most patients.

References

Aroda VR, Erhan U, Jelnes P, et al. Safety and tolerability of semaglutide across the SUSTAIN and PIONEER phase IIIa clinical trial programmes. Diabetes Obes Metab. 2023;25(5):1385-1397. doi:10.1111/dom.14990
Rubino DM, Pedersen SD, Connery L, et al. Gastrointestinal tolerability and weight reduction associated with tirzepatide in adults with obesity or overweight with and without type 2 diabetes in the SURMOUNT‐1 to ‐4 trials. Diabetes Obes Metab. 2025;27(4):1826-1835. doi:10.1111/dom.16176
Rosenstock J, Frias J, Jastreboff AM, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet Lond Engl. 2023;402(10401):529-544. doi:10.1016/S0140-6736(23)01053-X
Patel H, Khunti K, Rodbard HW, et al. Gastrointestinal adverse events and weight reduction in people with type 2 diabetes treated with tirzepatide in the SURPASS clinical trials. Diabetes Obes Metab. 2024;26(2):473-481. doi:10.1111/dom.15333
Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972
Liu L, Chen J, Wang L, Chen C, Chen L. Association between different GLP-1 receptor agonists and gastrointestinal adverse reactions: A real-world disproportionality study based on FDA adverse event reporting system database. Front Endocrinol. 2022;13. doi:10.3389/fendo.2022.1043789
Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-515. doi:10.1056/NEJMoa2107519
Wen J, Nadora D, Bernstein E, et al. Evaluating the Rates of Pancreatitis and Pancreatic Cancer Among GLP ‐1 Receptor Agonists: A Systematic Review and Meta‐Analysis of Randomised Controlled Trials. Endocrinol Diabetes Metab. 2025;8(5):e70113. doi:10.1002/edm2.70113
He L, Wang J, Ping F, et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022;182(5):513-519. doi:10.1001/jamainternmed.2022.0338
Kornelius E, Huang JY, Lo SC, Huang CN, Yang YS. The risk of depression, anxiety, and suicidal behavior in patients with obesity on glucagon like peptide-1 receptor agonist therapy. Sci Rep. 2024;14(1):24433. doi:10.1038/s41598-024-75965-2
Gupta AK, Teasell EM, Economopoulos V, Mirmirani P. GLP-1 therapies and hair loss: A systematic review of current evidence and implications for counseling. Sci Prog. 2026;109(2):368504261444578. doi:10.1177/00368504261444578
Alsuwailem OA, Alanazi R, Almutairi HM, et al. Hair Loss Associated With Glucagon-Like Peptide-1 (GLP-1) Receptor Agonist Use: A Systematic Review. Cureus. 2025;17(9):e92454. doi:10.7759/cureus.92454
Jones SC, Ryan DL, Pratt VSW, Niak A, Brinker AD. Injection-Site Nodules Associated With the Use of Exenatide Extended-Release Reported to the U.S. Food and Drug Administration Adverse Event Reporting System. Diabetes Spectr Publ Am Diabetes Assoc. 2015;28(4):283-288. doi:10.2337/diaspect.28.4.283

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