According to the International Diabetes Federation, the global population with diabetes reached 537 million by 2021, with 90% of cases attributed to type 2 diabetes (T2DM) (Ahmad et al., 2022). In 2021, diabetes was responsible for 6.7 million deaths, and it is projected that by 2045, the number of individuals with diabetes will increase to 783 million, highlighting the growing global burden of T2DM over the coming decades (Sun et al., 2022). Early diagnosis and effective treatment strategies are crucial for mitigating the risks of microvascular and macrovascular complications, as well as reducing mortality associated with T2DM.

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have gained attention not only for their role in glycemic control in T2DM but also for their potential in weight management. Increasing evidence indicates that GLP-1RAs can significantly reduce body weight, particularly in overweight or obese patients with T2DM. Semaglutide, in particular, has demonstrated superior efficacy in weight reduction across several clinical trials, driving increased interest and investment in this therapeutic area (Pagidipati, 2024). In 2021, the U.S. Food and Drug Administration (FDA) approved semaglutide for obesity management, marking a new milestone in the application of GLP-1RAs for weight loss (Jordan et al., 2024). Similarly, tirzepatide, a novel dual agonist targeting both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors, has emerged as a potent therapeutic option, demonstrating remarkable efficacy in glycemic control and weight reduction in T2DM patients (Frías et al., 2021). Its unique dual mechanism enhances incretin effects, offering superior outcomes compared to traditional GLP-1RAs in recent trials, though its gastrointestinal tolerability profile warrants further scrutiny. This dual functionality makes GLP-1RAs an ideal therapeutic option for patients with T2DM and coexisting obesity. However, despite their notable efficacy, gastrointestinal side effects remain a significant limitation in their clinical use.

Gastrointestinal adverse events, such as nausea, vomiting, constipation, diarrhea, and dyspepsia, are the most common side effects associated with GLP-1RA therapy. These effects are closely related to the activation of GLP-1 receptors in both central and peripheral pathways, often leading to reduced treatment adherence or even discontinuation, which can compromise therapeutic outcomes (Tobaiqy, 2024). Although numerous studies have evaluated the efficacy of GLP-1RAs, there remains a lack of comparative data on the gastrointestinal risk profiles of different GLP-1RAs. Some studies have utilized traditional meta-analyses to assess the adverse effects of individual GLP-1RAs. However, conventional meta-analyses are typically limited to pairwise comparisons and are unable to simultaneously evaluate multiple GLP-1RAs, which restricts their clinical applicability.

Bayesian network meta-analysis offers a solution to this limitation by enabling the simultaneous comparison of multiple treatment options, providing a more precise evaluation of the differences between drugs (Wang et al., 2024). Additionally, this method allows for the integration of indirect evidence, thus offering a more comprehensive basis for clinical decision-making. To date, no network meta-analysis has systematically compared the gastrointestinal adverse events associated with different GLP-1RAs. Therefore, this study aims to evaluate the relative risks of gastrointestinal side effects associated with various GLP-1RAs in patients with T2DM through a Bayesian network meta-analysis, providing clinicians with robust evidence to inform treatment decisions.

This study was designed and conducted according to the registration requirements of the PROSPERO database (CRD42024592308) and aims to systematically evaluate the gastrointestinal adverse effects of different GLP-1 receptor agonists (GLP-1RAs) in patients with type 2 diabetes mellitus (T2DM). The study was approved by the Ethics Committee of Guangzhou Eighth People’s Hospital of Panyu District, ensuring that all procedures were performed in accordance with the ethical standards outlined by the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Our study spearheads a systematic assessment of gastrointestinal adverse event risks for GLP-1 receptor agonists and multi-target agonists in type 2 diabetes patients, addressing a critical gap in comparative safety data via Bayesian network meta-analysis. A total of 45 randomized controlled trials (RCTs) were included, involving 27,729 patients. The overall incidence of gastrointestinal adverse events was 11.66%, with nausea (21.49%) being the most frequently reported adverse event and reduced appetite (5.49%) the least frequent. While the overall incidence was lower than previously reported rates of 30%–50% (Jones et al., 2018), this discrepancy may be attributable to the subjective nature of symptom assessment in the included studies, as many lacked objective quantitative methods (Kong et al., 1998). Additionally, heterogeneity in study design and individual patient differences may have influenced the reported incidence rates, underscoring the need for further investigation into the evaluation of gastrointestinal adverse events in different patient populations.

The mechanisms underlying GLP-1RA-induced gastrointestinal adverse events are not yet fully understood. GLP-1RAs primarily influence gastrointestinal function by inhibiting gastric emptying and activating central GLP-1 receptors. As demonstrated in this study, short-acting GLP-1RAs, such as lixisenatide, were associated with a significantly higher risk of nausea and vomiting compared to long-acting and ultra-long-acting GLP-1RAs, such as dulaglutide and semaglutide. This finding aligns with previous studies, suggesting that short-acting agents may more readily cross the blood-brain barrier, thereby activating central GLP-1 receptors and exacerbating symptoms such as nausea and anorexia (Levin et al., 2017). Moreover, the faster metabolic rate of short-acting GLP-1RAs may induce abrupt changes in gastrointestinal function, further supporting the higher incidence of nausea and vomiting with these agents. A key finding of this study is the increased incidence of diarrhea with long-acting and ultra-long-acting GLP-1RAs, particularly semaglutide which a recent meta-analysis similarly found to have a higher diarrhea risk compared to lixisenatide, liraglutide, and exenatide, though lower than tirzepatide (risk ratios 1.66–1.80 vs. 1.81–2.18 relative to placebo) (Karagiannis et al., 2024). For exenatide, our analysis primarily reflects the short-acting formulation (Byetta^®, dosed twice daily), which likely contributes to its higher vomiting risk due to frequent dosing and greater fluctuations in plasma concentrations. In contrast, the long-acting formulation (Bydureon^®, dosed once weekly) utilizes a sustained-release microsphere technology, potentially reducing vomiting risk by stabilizing plasma levels, though this distinction was not separately analyzed in our meta-analysis. Diarrhea is believed to result from the effect of GLP-1RAs on intestinal motility, mediated through the vagus nerve. This effect is likely driven by the prolonged circulating half-lives of long-acting and ultra-long-acting GLP-1RAs, such as semaglutide (via fatty acid acylation) and dulaglutide (via Fc fragment fusion), which maintain sustained GLP-1 receptor stimulation and enhance intestinal motility, thereby increasing diarrhea risk. In contrast, short-acting GLP-1RAs, such as lixisenatide, require more frequent dosing due to shorter half-lives, resulting in intermittent receptor stimulation that may reduce the risk of diarrhea. This observation is corroborated by previous findings (Baraboi et al., 2011). Therefore, for patients with preexisting gastrointestinal conditions or poor gastrointestinal tolerance, short-acting GLP-1RAs may be preferable due to their intermittent receptor stimulation, potentially lowering diarrhea risk.

Tirzepatide, a dual agonist of both GLP-1 and GIP receptors, warrants special consideration in this analysis. Tirzepatide is a pivotal therapeutic option for type 2 diabetes management, chronic weight management in adults with obesity or overweight with weight-related comorbidities, and treatment of moderate to severe obstructive sleep apnea in obese adults, leveraging its dual GLP-1 and GIP receptor agonism to achieve superior glycemic control and weight reduction. It received U.S. Food and Drug Administration (FDA) approval in May 2022 for type 2 diabetes, November 2023 for chronic weight management, and December 2024 for obstructive sleep apnea, marking it as the first approved therapy for this indication. A recent meta-analysis confirms its efficacy in reducing HbA1c and body weight, though its gastrointestinal adverse event risk necessitates careful patient monitoring (Liu et al., 2025). Semaglutide and liraglutide exhibited higher rates of decreased appetite in our analysis, primarily driven by central nervous system-mediated satiety regulation, delayed gastric emptying, and modulation of appetite-regulating hormones such as ghrelin (Gupta and Sharma, 2025; Naveed et al., 2025). These mechanisms, rather than weight loss itself, are the primary contributors to appetite suppression, with weight loss as a consequence. Notably, weight loss further reinforces appetite reduction through decreased ghrelin levels, establishing a bidirectional feedback loop that enhances therapeutic outcomes (Blundell et al., 2017). The role of GIP receptor agonism in tirzepatide’s gastrointestinal profile remains debated. While earlier evidence suggested GIP agonism may exacerbate GI adverse events (Min and Bain, 2021), recent preclinical and clinical studies indicate it may reduce nausea and vomiting, though its effect on diarrhea is less pronounced. In animal models, GIP receptor agonists significantly attenuated GLP-1R agonist-induced nausea and emesis while maintaining glycemic and weight loss benefits (Borner et al., 2021). A clinical study further supports that co-administration of GIP receptor agonists with GLP-1RAs reduces nausea and vomiting incidence, potentially via neuronal interactions in the hypothalamus and brainstem, though diarrhea rates remain comparable (Knop et al., 2024). These findings suggest tirzepatide’s dual agonism may contribute to its favorable GI profile in some patients, warranting further investigation to reconcile these conflicting perspectives. Our findings that tirzepatide has the highest risk of nausea and diarrhea, dulaglutide and lixisenatide the lowest, and exenatide the highest vomiting risk with dulaglutide showing a lower risk, are consistent with a recent meta-analysis reporting higher diarrhea risk for tirzepatide (risk ratio 1.81–2.18) than semaglutide (1.66–1.80) versus placebo, as well as trial data showing elevated nausea with tirzepatide and higher vomiting with exenatide’s short-acting formulation (Karagiannis et al., 2024).

Effective management of gastrointestinal adverse events associated with GLP-1 receptor agonists and multi-target agonists is critical to optimize their therapeutic application in type 2 diabetes management. Gradual dose escalation can significantly mitigate the frequency and severity of symptoms such as nausea and diarrhea, as it allows patients to adapt to therapy over time (Huang et al., 2025; Rodriguez et al., 2025). This approach facilitates physiological adaptation to GLP-1 and GIP receptor stimulation, enabling patients to develop tolerance to gastrointestinal symptoms over weeks to months, thereby reducing their intensity. Patient education emphasizing the transient nature of these side effects, particularly for high-risk agents like tirzepatide and semaglutide, can enhance adherence by setting realistic expectations. Dietary modifications, such as adjusting meal timing or composition, may further alleviate discomfort during the initial treatment phase. For patients with persistent or intolerable symptoms, switching to agents with lower gastrointestinal risk profiles, such as dulaglutide, which demonstrated reduced nausea incidence in our analysis, represents a viable strategy. Emerging evidence suggests that dual GLP-1/GIP agonists like tirzepatide may offer a more favorable gastrointestinal profile in some patients, potentially improving adherence (Kim et al., 2025). Clinicians must also remain vigilant for rare but serious complications, such as bowel obstruction, particularly in patients with preexisting motility disorders, although these risks may be overstated when comorbidities are considered (Jones and Cappola, 2025; Kałas et al., 2025; Gmehlin et al., 2025). Additionally, addressing the psychological impact of these adverse events is essential, as GLP-1RAs may influence emotional regulation, necessitating a holistic approach to patient care (Lu et al., 2025). Regular follow-up and supportive care are recommended to monitor and manage ongoing symptoms effectively (Narayan et al., 2025).

It should be noted that this study did not conduct subgroup analyses based on dosage and administration routes, which may limit the comprehensive assessment of GLP-1RA safety. The variability in trial durations, ranging from 3 to 12 weeks across the included studies, and differences in the number of titration steps for each drug may further influence the reported incidence of gastrointestinal adverse events, particularly for agents like tirzepatide, where nausea risk escalates with higher doses (e.g., OR = 4.36, 95% CI: 3.42–5.61 at 10 mg) (Liu et al., 2025). Previous studies have shown that the incidence of gastrointestinal adverse events varies depending on GLP-1RA dosage, particularly at higher doses, where nausea and vomiting are more prevalent. Additionally, baseline characteristics of patients, such as age, BMI, and renal function, may significantly impact the occurrence of GLP-1RA-induced adverse events. Other factors, including drop-out rates due to GI AEs, use of anti-emetics or other rescue therapies, specific dosing regimens (e.g., semaglutide’s approved doses of 0.5–1.0 mg for T2D vs. 2.4 mg for weight management), number of titration steps, route of administration (subcutaneous vs. oral), and pharmacokinetic properties (e.g., absorption rates, peak-to-trough ratios, and compound half-lives), were not analyzed in this study. These factors may significantly influence GI AE incidence, as higher doses, oral administration, or rapid absorption may exacerbate nausea and vomiting, while gradual titration can mitigate such effects. Sex distribution was not analyzed in our study, which is a limitation given evidence that females may be more susceptible to nausea and vomiting induced by GLP-1RAs, potentially due to hormonal influences or differences in gastric emptying rates. These factors were not explored in detail in this study. A potential limitation of this study is the variability in adverse event classification across different trials. Terms such as nausea, loss of appetite, and feeling full or bloated may overlap in some studies, and vomiting could be confounded with dyspepsia or gastroesophageal reflux disease (GERD). This variability could affect the comparability of AE incidences between different GLP-1RAs. However, our network meta-analysis included a large number of studies (n = 45), and the inconsistency testing using node-splitting analysis showed no significant differences between direct and indirect evidence (P > 0.05), suggesting that the data are consistent and reliable for the purposes of this analysis. Nonetheless, future studies with standardized AE reporting, such as using the Medical Dictionary for Regulatory Activities (MedDRA), would be beneficial to confirm our findings and enhance comparability across trials. Thus, further large-scale prospective studies are necessary to elucidate the risk of gastrointestinal adverse events in different patient populations, particularly with respect to personalized treatment strategies for high-risk groups, including sex-specific analyses to address potential differences in nausea and vomiting susceptibility.

The findings of this study hold important implications for clinical practice. Although GLP-1RAs are widely utilized for glycemic control and weight management in T2DM, gastrointestinal adverse events remain a significant barrier to patient adherence. Clinicians should carefully consider individual patient characteristics, especially in those with preexisting gastrointestinal conditions, when selecting GLP-1RAs and adjusting dosages. Future research should also investigate strategies to minimize GLP-1RA-induced gastrointestinal adverse events, potentially through drug design innovations or combination therapies, to enhance patient tolerance and adherence.

This study highlights the varying risks of gastrointestinal adverse events associated with GLP-1 receptor agonists, with nausea being most common and reduced appetite least frequent. Short-acting GLP-1RAs carried a higher risk of nausea and vomiting, while long-acting agents were linked to increased diarrhea. Tirzepatide showed the highest overall risk. These findings emphasize the importance of individualized treatment approaches to optimize both efficacy and tolerability.