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. 2025 Apr 3;45(2):129-143. doi: 10.5144/0256-4947.2025.129

Gastrointestinal safety of semaglutide and tirzepatide vs. placebo in obese individuals without diabetes: a systematic review and meta analysis

Moaz Safwan a, Mariam Safwan Bourgleh a,✉, Shahad Abdullah Alotaibi b, Eman Alotaibi c, Abdulsalam Al-Ruqi a, Fathiya El Raeya a
PMCID: PMC12542916  PMID: 40189856

Abstract

INTRODUCTION:

Semaglutide and tirzepatide are newly approved glucagon-like peptide-1 receptor agonists for weight management in adults without diabetes. However, safety concerns regarding gastrointestinal (GI) adverse outcomes have been raised. This review comprehensively evaluates their GI safety profile in randomized controlled trials (RCTs).

METHODS:

Thirteen RCTs involving 26 894 obese participants without diabetes were analyzed. Pooled analysis assessed the risks for GI, biliary, hepatic, and pancreatic adverse events.

RESULTS:

Overall GI adverse events were 1.86 times higher with *both* agents (95% CI=1.56, 2.21), with tirzepatide showing a greater risk (RR 2.94, 95% CI=2.61, 3.32) than semaglutide (RR 1.68, 95% CI=1.46, 1.94). Semaglutide increased gallbladder-related disorders, particularly cholelithiasis, by over 2.6 times (95% CI=1.40, 4.82), while tirzepatide showed no significant biliary risk. Neither agent significantly increased hepatic or pancreatic adverse events.

CONCLUSION:

Compared to placebo, both Semaglutide and tirzepatide are associated with increased GI adverse outcomes, with most cases being mild. Clinicians should carefully monitor patients for potential adverse outcomes.

INTRODUCTION

Global obesity prevalence has reached epidemic proportions leading to a significant proliferation of comorbidities, including cardiovascular ailments, type 2 diabetes, osteoarthritis, cancer, gallbladder disease, hypertension, among others. The World Health Organization (WHO) estimates that globally, one in eight people are obese.1 This alarming trend has driven the need for effective treatment strategies, with pharmacological interventions gaining significant attention.2 Such pharmacological interventions are Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Glucose-dependent insulinotropic polypeptide (GIP). Earlier pharmacological attempts to control obesity proved to be mostly fruitless, inspiring the development of tirzepatide and semaglutide, two newly approved drugs that have shown enhanced efficacy in helping lose weight and improve metabolic profiles.3

Currently, semaglutide, which was originally developed for managing type 2 diabetes, is now being used to treat obesity, and has proven to be highly effective, particularly in obese patients without diabetes.4,5 The drug's advantages in weight control are attributed in its ability to delay gastric emptying, enhance satiety, and reduce appetite.6 Therefore, many studies positioned semaglutide as a prominent component of obesity pharmacotherapy.7 Semaglutide is a GLP-1 RA that has demonstrated significant efficacy in weight management.8 A previous study by Moll et al, established that although GLP-1 RAs may have some downsides, its benefits outweigh those within the first two years of treatment.9 However, the benefit-to-risk ratio is not zero, and patients are at risk of gastrointestinal (GI) complications following the use of this weight-loss drug. On the other hand, tirzepatide is a relatively new, dual-GIP and GLP-1 RA that represents an innovative approach to obesity treatment.10 This drug offers a unique mechanism of action which enhances its efficacy in weight management by simultaneously targeting two incretin receptors.10 Empirical evidence and clinical trials show that tirzepatide is superior to GLP-1 RAs in terms of inducing weight loss.11 However, tirzepatide‘s GI safety profile, especially in obese individuals without diabetes, warrants thorough investigation. As with all novel interventions, many randomized clinical control trials (RCTs) need to be carried out to determine its efficacy and safety from potential side effects of inducing weight loss. GI adverse events are a common concern with GLP-1 RAs and dual GIP agonists, affecting patient adherence and treatment outcomes. Some of these effects include nausea, abdominal pain, vomiting, constipation, diarrhea, and pancreatitis.12 Given their demonstrated efficacy in weight management, semaglutide and tirzepatide have both received FDA approval for use in adults with obesity and without diabetes. However, the GI safety profiles of these medications for these individuals are still insufficiently studied. In addition, the pressing need to tackle the growing obesity epidemic has led to their increased adoption, despite a lack of comprehensive testing in this population.13 The purpose of this meta-analysis and systematic review is to assess the Gl safety profile of tirzepatide and semaglutide among adult individuals with obesity and without diabetes. This will be achieved through meticulous synthesization of existing RCTs to offer a thorough evaluation of the prevalence and severity of GI side effects that come with tirzepatide and semaglutide treatment. Additionally, specific moderate to serious adverse events will be evaluated such as hepatic events (e.g. acute hepatitis or drug induced-hepatic injury), pancreatic events (e.g. pancreatitis), and gallbladder events (e.g. cholelithiasis, acute and chronic cholecystitis).

METHODS

Protocol registration

The study protocol was prospectively developed and registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (registration number CRD42024546933).

Search strategy

Four databases including PubMed, Embase, ClinicalTrials.gov, and Cochrane CENTRAL were comprehensively searched from inception until July 2024 in order to identify relevant reports. The search strategy followed the guidelines of Cochrane Handbook and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 checklist. Common text words and Medical Subjects Headings (MESH) terms such as Glucagon Like Peptide-1 Receptor Agonists (GLP-1 Ras), semaglutide, ozempic, wegovy, tirzepatide, mounjaro, zepbound, weight Loss, weight reduction, obesity, overweight, gastrointestinal adverse events, pancreatitis, gallbladder disease, cholecystitis and cholelithiasis were utilized during the search strategy. These terms were combined using specific operators, for instance, Semaglutide AND Weight Reduction. In addition to the database screening, reference lists of the included reports were subjected to a manual search in order to identify relevant studies not identified during the primary database screening. No language restriction was applied in our search strategy.

Eligibility criteria

The inclusion criteria were as follows: 1) RCTs that have included participants with obesity defined as BMI of 30 kg/m2 or higher, or 27 kg/m2 or higher if accompanied by one or more comorbidities, 2) evaluated the safety and efficacy of semaglutide or tirzepatide for weight reduction in the intervention arm, 3) has a control group for comparison, 4) reported at least one of the following safety outcomes: GI adverse events, hepatic adverse events, new cases of pancreatitis, gallbladder and biliary disorders. The studies were excluded if participants diagnosed with diabetes mellitus have been included, or if not available in full text (insufficient data).

Data extraction

The eligibility of the reports identified during the search strategy was assessed by two independent co-authors (MS and AA) based on the eligibility criteria. The same co-authors extracted the following variables from each included study: (1) first author and year of publication, (2) study design, (3) study location (country), (4) intervention, (5) route of administration, (6) dose, (7) control group, (8) sample size, (9) male percentage across each arm, (10) mean age, (11) mean weight, (12) mean BMI, and (13) follow-up duration. A third coauthor (MSB) reviewed the reports inclusion and data extraction processes, and resolved any disagreement between the authors through discussions.

Quality assessment

Cochrane Collaboration's risk of bias assessment tool was utilized to assess the methodological quality of the included studies. This tool critically assesses RCTs based on multiple domains including: random sequence generation, allocation concealment, blinding of participants and outcome assessors, incomplete outcome data, selective reporting, and other biases. Each domain was then evaluated as having a high, unclear, or low risk of bias. A risk of bias summary graph was made to illustrate the overall risk of bias of included studies.

Statistical analysis

Two of the included studies (O'Neil et al and Jastreboff et al)16,26 had multiple intervention groups that were combined into a single group to facilitate inclusion in the pooled analysis. The follow-up duration varied between the studies; thus, the results reported at the end of the follow-up period were used for the analysis. For each outcome, the pooled risk ratio (RR) was calculated and presented with 95% confidence intervals (CI). To further explore and compare the safety profile of each intervention, a subgroup analysis was conducted based on the medication used, including semaglutide and tirzepatide. Between-studies heterogeneity was evaluated using the I2 statistic, where a value less than 25% indicates unimportant heterogeneity that is mostly attributed to chance, 25%-75% indicates moderate heterogeneity indicating variability that may not significantly affect the results, and 75%-100% indicates considerable heterogeneity that suggests that the studies differ in major ways that could affect the reliability of the results. Results were deemed significant if the confidence interval did not include the null hypothesis (i.e., zero) and if the P value was less than.05. Sensitivity analysis was conducted only in case of significant heterogeneity identified where an influence analysis would be performed to identify each individual study influence on the overall heterogeneity allowing identifying outlier studies that influenced the overall heterogeneity to enable exploration of the potential causes of their deviation. Publication bias was assessed through visual inspection of the funnel plot and Egger's regression test for funnel plot asymmetry. The funnel plot visualizes the distribution of studies effect sizes against their standard errors, leading to intuitive to identify asymmetry that suggests publication bias. However, visual assessment is subjective and may not always be accurate. As a result, we used Egger's regression test to quantitatively evaluate the asymmetry. An asymmetrical distribution of studies in the funnel plot with an Egger's test P value of less than .05 suggested significant publication bias, whereas symmetrical distribution with an Egger's test P value greater than .05 indicated no evidence of publication bias. All statistical analyses were performed using R Studio 2023.12.0 with the meta package.14,15

RESULTS

Literature search results

The reports identification and selection process is summarized in Figure 1. In brief, 1115 reports have been initially identified through screening the four databases mentioned previously. Further, 1024 studies were retained after elimination of duplicates and underwent screening on the basis of titles and abstracts. Following this screening process, 33 studies were retained for the final full text review. The final review produced 13 RCTs that met the eligibility criteria and constituted the final analysis. Figure 1 and Supplementary Table 1 provides detailed information on the reasons for study exclusions.

Figure 1.

Figure 1.

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Study selection flow diagram (PRISMA chart). Abbreviations: RCTs: Randomized Controlled Trials; ICTRP: International Clinical Trials Registry Platform.

Characteristics of the included studies

As previously stated, thirteen RCT were eligible for inclusion. Of these, ten studies used semaglutide as the intervention,16–25 while three studies used tirzepatide.26–28 Overall, the thirteen studies ranged from 2018 to 2024, with nine being multinational,16–18,24–28 one conducted in Germany,19 one in Slovenia,20 and two in the USA.21,23 The semaglutide studies included a total of 23 106 participants, with 12 427 in the intervention group and 10 679 in the control group. Participants in these studies had an average age range of 36 to 61 years, an average body weight between 94.2 and 114.2 kg, and an average BMI of 33 to 40.1kg/m2. Notably, nine out of ten semaglutide studies administered the drug subcutaneously,16–24 except for the study by Knop et al, which used an oral administration method.25 The dosage in these studies varied, with one study using weekly doses of 0.05, 0.1, 0.2, 0.3, or 0.4 mg,16 another study using 1.0 mg weekly,20 eight studies using 2.4 mg weekly,17–19,21–24 and one study using 50 mg orally.25 In contrast, the tirzepatide studies included 3788 patients, with 2518 in intervention group and 1270 in control group. The average age of participants in these studies ranged from 44 to 49 years, with an average weight between 84.6 and 104.8 kg, and an average BMI of 30.1 to 38.2kg/m2. All three tirzepatide studies administered the drug subcutaneously; one study used doses of 5 mg, 10 mg, or 15 mg,26 while the other two studies administered 10 mg or 15 mg weekly.27,28 (Table 1) All thirteen included RCTs underwent a rigorous quality assessment to evaluate the possibility of different types of biases, such as selection, performance, detection, attrition and reporting biases. The judgments of the authors regarding the different metrics are shown in Figure 2. All RCTs were rated by the authors to be of high quality. However, the majority of the included RCTs (10 out of 13) were funded, with sponsors participating in data synthesis, analysis, and reporting. This involvement raises concerns about potential bias, as financial sponsors may influence study outcomes or interpretations. The authors identified this as a significant source of bias, categorizing it as a high risk under the other bias domain (Figure 2).

Table 1.

Baseline characteristics of the included studies.

Author (year) Study design Study location Intervention Route of administration Dose Control Sample size Mean age (SD) Mean weight (SD) Mean BMI (SD) Follow up (weeks or months)
Total Intervention M (%) Control M (%) Intervention Control Intervention Control Intervention Control
O'Neil et al, 201816 multicentre RCT Multinational Semaglutide Subcutaneous 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, and 0.4 mg weekly Liraglutide, and placebo 854 718 (35) 136 (35) 46 (12.6) 46 (13) 111.3 (23.1) 114.2 (25.4) 39.2 (7.06) 40.1 (7.2) 52 weeks
Rubino et al, 202117 multicentre RCT N/A Semaglutide Subcutaneous 2.4 mg weekly Placebo 803 535 (19.8) 268 (23.5) 47 (12) 46 (12) 96.5 (22.5) 95.4 (22.7) 34.5 (6.9) 34.1 (7.1) 68 weeks
Lincoff et al, 202318 multicentre RCT Multinational Semaglutide Subcutaneous 2.4 mg weekly Placebo 17,604 8803 (72.2) 8801 (72.5) 61.6 (8.9) 61.6 (8.8) 96.5 (17.5) 96.8 (17.8) 33.3 (5.0) 33.4 (5.0) 39.8 (9.4) months
Friedrichsen et al, 202119 RCT Germany Semaglutide Subcutaneous 2.4 mg weekly Placebo 72 36 (66.7) 36 (55.6) 40.7 (12.2) 45 (9.5) 106.2 (16.2) 104.9 (14) 34.2 (3) 34.6 (3.1) 20 weeks
Jensterle et al, 202320 RCT Slovenia Semaglutide Subcutaneous 1.0 mg weekly Placebo 19 10 (All are females) 9 (All are females) 36.5 (2.1) 36.5 (2.1) 94.2 (6.6) 100.8 (9) 33 (2.97) 37.4 (2.5) 12 weeks
Rubino et al, 202221 multicentre RCT USA Semaglutide Subcutaneous 2.4 mg weekly Liraglutide, and placebo 211 126 (19) 85 (22.4) 48 (14) 51 (12) 102.5 (25.3) 108.8 (23.1) 37 (7.4) 38.8 (6.5) 68 weeks
Wilding et al, 202122 multicentre RCT N/A Semaglutide Subcutaneous 2.4 mg weekly Placebo 1961 1306 (26.9) 655 (24) 46 (13) 47 (12) 105.4 (22.1) 105.2 (21.5) 37.8 (6.7) 38.0 (6.5) 68 weeks
Wadden et al, 202123 multicentre RCT USA Semaglutide Subcutaneous 2.4 mg weekly Placebo 611 407 (22.6) 204 (11.8) 46 (13) 46 (13) 106.9 (22.8) 103.7 (22.9) 38.1 (6.7) 37.8 (6.9) 68 weeks
Garvey et al, 202224 multicentre RCT Multinational Semaglutide Subcutaneous 2.4 mg weekly Placebo 304 152 (19.1) 152 (25.7) 47.3 (11.7) 47.4 (10.3) 105.6 (20.8) 106.5 (23.1) 38.6 (6.7) 38.5 (7.2) 104 weeks
Knop et al, 202325 multicentre RCT N/A Semaglutide Oral 50 mg daily Placebo 667 334 (26) 333 (29) 49 (13) 50 (12) 104.5 (22) 106.2 (22.3) 37.3 (6.3) 37.7 (6.8) 68 weeks
Jastreboff et a I, 202226 multicentre RCT Multinational Tirzepatide Subcutaneous 5 mg, 10mg, or 15 mg weekly Placebo 2539 1896 (32.5) 643 (22.2) 45.06 (12.46) 44.4 (12.5) 104.76 (22.37) 104.8 (21.3) 37.9 (6.78) 38.2 (6.89) 72 weeks
Aronne et al, 202427 multicentre RCT Multinational Tirzepatide Subcutaneous 10 mg or 15 mg weekly Placebo 670 335 (29.6) 335 (29.3) 49 (13) 48 (12) 84.6 (19.8) 85.8 (22.3) 30.3 (6.0) 30.7 (6.8) 52 weeks
Wadden et al, 202328 multicentre RCT Multinational Tirzepatide Subcutaneous 10 mg or 15 mg weekly Placebo 579 287 (36.9) 292 (37.3) 45.4 (12.6) 45.7 (11.8) 102.5 (22.1) 101.3 (20.7) 36.1 (6.1) 35.7 (6.4) 72 weeks
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Abbreviations: N/A: Not available, RCTs: Randomized controlled trials

Figure 2.

Figure 2.

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Risk of bias assessment summary graph (+)= low risk of bias (?)= unclear risk of bias (-)= high risk of bias.

Mild GI adverse events

All ten semaglutide RCTs [23 106 participants (n=12 427 in the intervention group and 10 679 in the control group)], as well as the three tirzepatide studies, [n=3788 participants (2518 in the intervention group and 1270 in the control group)], reported on overall GI adverse events at the end of follow-up. Among the semaglutide studies, it was observed that 30.81% (3829 out of 12 427) of the participants in the intervention group experienced GI events. In comparison, the control group reported a lower incidence of GI events, with 12.7% (1356 out of 10 679) of participants affected. The pooled analysis of these studies revealed a risk ratio of 1.68, indicating a 68% significantly higher risk of GI adverse events in the semaglutide group than the control group (RR 1.68 [95%CI] [1.46, 1.94], P<.01, I2=90%). On the other hand, concerning the tirzepatide studies, 79.8% (2010 out of 2518) of participants who received tirzepatide experienced GI adverse events. In contrast, only 25% (317 out of 1270) of the participants in the control group reported similar events. The pooled analysis indicated a risk ratio of 2.94 (RR 2.94 [95%CI] [2.61, 3.32], P<.01, I2=0%) signifying a 194% higher risk of GI adverse events associated with tirzepatide use as compared to controls. Based on these results, it can be concluded that tirzepatide significantly led to a higher incidence of GI adverse events compared to semaglutide (Figure 3).

Figure 3.

Figure 3.

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Forest plot of GI adverse events pooled risk ratio sub-grouped according to the intervention type, semaglutide and tirzepatide.

Moderate to serious GI adverse events

Hepatic adverse events

Seven semaglutide RCTs [n=5,411 participants (intervention group=3578, control group=1833)], and two tirzepatide RCTs [n=3209 participants (intervention group=2231, control group=978)], reported on the incidence of hepatic disorders and adverse events. In the semaglutide studies, 2.3% (84 out of 3578) of participants who received treatment experienced hepatic events, compared to 3.2% (59 out of 1833 participants) in the control group. In the tirzepatide studies, 0.17% (4 out of 2231 participants) in the treatment group experienced hepatic events, while none were reported in the control group (0 out of 978). The pooled analysis revealed no significant difference in the risk ratio of hepatic adverse events between the intervention and control groups for both semaglutide (RR 0.69 [95% CI] [0.44, 1.08], P=.10, I²=30%) and tirzepatide (RR 2.05 [95% CI] [0.20, 21.30], P=.55, I²=0%). (Figure 4).

Figure 4.

Figure 4.

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Forest plot of hepatic adverse events pooled risk ratio sub-grouped according to the intervention type, semaglutide and tirzepatide.

Pancreatic adverse events

The incidence of pancreatitis was reported in eight semaglutide studies [n=23,015 participants (intervention group=12381, control group=10634)] and two tirzepatide studies [n=3,118 participants (intervention group=2183, control group=935)]. In the semaglutide studies, pancreatitis was reported in 0.20% (26 out of 12 381) in the treatment group and 0.26% (28 out of 10 634) in the control group. For RCTs assessing tirzepatide, pancreatitis was reported in 0.1% (4 out of 2183) in the treatment group and 0.2% (2 out of 935) in the control group. The pooled analysis revealed no significant difference between groups for either the semaglutide (RR 0.74 [95%CI] [0.42, 1.29], P=.29, I2=0%) or tirzepatide studies (RR 1.02 [95%CI] [0.18, 5.86], P=.98, I2=0%), (Figure 5).

Figure 5.

Figure 5.

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Forest plot of pancreatitis pooled risk ratio sub-grouped according to the intervention type, semaglutide and tirzepatide.

Gall bladder adverse events

Data regarding gallbladder adverse events were extracted from eight RCTs examining semaglutide [n=23 015 participants (intervention group=12381, control group=10 634)] and two tirzepatide RCTs [n=3118 participants (intervention group=2183, control group=935)]. Among the RCTs assessing semaglutide, 337 out of 12 381 (3%) participants reported gallbladder adverse events in the treatment group compared to 238 out of 10 634 (2.2%) in the control group. In the tirzepatide studies, 24 out of 2183 (1.1%) participants reported similar events in the treatment group and 5 out of 935 (0.5%) in the control group. The pooled analysis showed a statistically significant risk ratio of 1.63 (RR 1.63 [95%CI] [1.04, 2.53], P=.03, I2=48%) in the semaglutide group compared to controls, indicating an increased risk of gallbladder adverse events by 63%. On the other hand, no statistically significant risk ratio was observed between the tirzepatide group and the control group (RR 1.67 [95%CI] [0.67, 4.20], P=.27, I2=0%). (Figure 6).

Figure 6.

Figure 6.

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Forest plot of gall bladder related adverse events pooled risk ratio sub-grouped according to the intervention type, semaglutide and tirzepatide.

Cholelithiasis

Five semaglutide studies [n=3754 participants (intervention group=2325, control group=1429)] and two tirzepatide studies [n=3118] were analyzed for cholelithiasis events.

In the semaglutide studies, 53 participants out of 2325 (2.3%) suffered from cholelithiasis in the treatment group, while 13 participants out of 1429 (0.9%) had similar events in the control group. In the tirzepatide studies, 24 out of 2183 (1.1%) cases were identified in the treatment group, and 9 out of 935 (0.9%) cases were observed in the control group. The pooled analysis revealed a statistically significant risk ratio of 2.59 (RR 2.59 [95%CI] [1.40, 4.82], P<.01, I2=0%) in the semaglutide group compared to controls. There was no statistically significant difference between the tirzepatide group and the control group for risk of cholelithiasis (RR 1.19 [95%CI] [0.55, 2.58], P=.66, I2=0%). These findings suggest that the administration of semaglutide increases the risk of cholelithiasis by 159% compared to controls, while no significant similar risk is observed with tirzepatide (Figure 7).

Figure 7.

Figure 7.

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Forest plot of cholelithiasis pooled risk ratio sub-grouped according to the intervention type, semaglutide and tirzepatide.

Publication bias

Egger's regression test was used to evaluate the presence of publication bias for all the outcomes investigated in the study, including GI, hepatic, pancreatitis, gallbladder, and cholelithiasis events. The results indicated no evidence of publication bias across all outcomes, with P values of .35, .23, .71, .16, and .72, respectively. The funnel plots for each outcome are presented in Supplementary Figure 1.

DISCUSSION

Obesity is on track to become the primary preventable risk factor of various morbidities including cardiovascular disease and cancer, so early targeted treatment and management of obesity is essential.29 To the best of our knowledge, this study is the first to evaluate the GI safety profiles of the newly approved dual GLP-1 receptor agonist semaglutide and the dual GLP-1 and GIP agonist tirzepatide among adults with obesity and without diabetes. The key findings of our analysis demonstrated firstly; administration of semaglutide or tirzepatide is significantly associated with mild GI events (nausea, vomiting, diarrhea, and constipation) than controls, with rates higher in tirzepatide than semaglutide treatment. Secondly; the treatment with tirzepatide and semaglutide was not associated with lower incidence of pancreatic and hepatic events with no significant difference in the risk between the two medications. Finally; administration of semaglutide increases the risk of gallbladder related disorders by 1.63 times and cholelithiasis by 2.59 times, while no risk was observed with tirzepatide. In the current analysis, mild GI adverse events were more likely to occur with both semaglutide and tirzepatide than controls. In line with our findings, a recent meta-analysis conducted by Tan et al reviewed four randomized controlled trials involving a total of 3613 participants. The analysis focused on the effectiveness of semaglutide for weight loss in non-diabetic obese adults and demonstrated that the risk of GI adverse events is 1.59 times higher with semaglutide treatment than controls.30 Similarly, Huang et al, demonstrated that patients with type 2 diabetes receiving semaglutide are at 2.14 times higher risk to develop GI adverse events than controls.31 When comparing the rate of mild GI adverse events associated with semaglutide and tirzepatide, our analysis demonstrated that tirzepatide was associated with a higher risk. This difference in the risk can be attributed to the higher doses of tirzepatide used (10 mg or 15 mg) compared to semaglutide (2.4 mg). Consistent with these findings, a meta analysis by Tong et al, demonstrated that patients with diabetes treated with high doses of tirzepatide (10 mg or 15 mg) had a significantly higher risk of GI adverse events than those receiving low doses (5 mg).32 The possibility of severe adverse outcomes has been linked to the use of GLP-1 receptor agonists. Prior research has shown that people with diabetes taking GLP-1 receptor agonists have a six-fold greater chance of developing pancreatitis than those on other medications.33,34 To investigate whether there is a correlation between the use of semaglutide and tirzepatide and the development of pancreatitis, we examined the reported instances of pancreatitis among the RCTs involving people with obesity who use either drug. Our analysis did not reveal any significant increase in the risk of pancreatitis with either treatment. similarly, a recent systematic review and meta-analysis by Masson et al., involving 34 721 patients with diabetes on various regimens of semaglutide found that the treatment was not related to an increased risk of pancreatitis.35 Furthermore, a meta-analysis conducted by Zeng et al, investigated the safety concerns of tirzepatide in type 2 diabetes and obesity and found that tirzepatide appeared to be safe in terms of the risk of pancreatitis.36 Various reports have suggested that semaglutide may offer an indirect hepatoprotective effect and could be a potential treatment for chronic liver diseases, including non-alcoholic steatohepatitis (NASH) and NASH-induced cirrhosis.37,38 In line with this, we observed a lower rate of hepatic adverse events with semaglutide compared to the control group (2.3% vs. 3.2%, respectively), with an overall relative risk of 0.69. These findings highlight the hepatoprotective role of semaglutide in the obese population, which may reduce the incidence and severity of NASH and its progression to cirrhosis. To date, there is limited evidence of semaglutide-associated liver injury, with only three reported cases in the literature.39–41 Importantly, the changes in liver enzymes and the degree of liver steatosis among the participants were not evaluated as outcomes in the current study, suggesting a potential area for future research. Unlike the pancreatic and liver-related events, we found that semaglutide significantly increased the risk of gallbladder disorders and cholelithiasis. Even though our study focused only on adults with obesity and without diabetes, our findings align with previous research, which reported a 1.58-fold higher risk of gallbladder disease with semaglutide compared to a control group.42 Most of the included trials in the present review showed a link between semaglutide and gallbladder disease, with a predominance of female participants. The exception was a study by Lincoff et al, which had 72.2% male participants. This study showed that those taking semaglutide had 1.21 times higher risk of gallbladder disease than controls, suggesting that the increased risk is not related to gender (Table 1). In contrast to semaglutide, our analysis did not show a significant increase in gallbladder disorders or cholelithiasis with tirzepatide use. This contrasts with a study by Zeng et al, which reported a 1.97-fold higher risk of gallbladder disease among patients with diabetes on tirzepatide, particularly with the 10 mg dose.43 The difference might be due to the fact that Zeng et al's study included patients with diabetes, who may already have a higher risk of gallbladder complications.44 Although both semaglutide and tirzepatide act on GLP-1 receptors in the central nervous system and the GI tract, tirzepatide also uniquely functions as a GIP agonist.45 This dual action has been associated with better glycemic outcomes compared to GLP-1 agonists like semaglutide.46 Notably, our results did not indicate an increased risk of serious gastrointestinal adverse events with tirzepatide, suggesting that the GIP effect may enhance efficacy without raising the risk of adverse events. The limitations of the current study include the small number of RCTs that have evaluated tirzepatide in this adult population. The effects of different treatment doses were not analyzed because only two studies have evaluated different dose regimens -one for semaglutide and one for tirzepatide. Future research should expand the scope by conducting more RCTs that directly focus on evaluating and comparing the safety profiles of the two treatments. This will provide a more comprehensive assessment of the associated gastrointestinal adverse outcomes. It is also ineresting to explore the impact of varying dosages and treatment durations on these adverse events. Additionally, future studies should include long-term follow-up to better understand the chronic effects on GI health and assess the persistence and severity of adverse outcomes to enhance the precision of safety profiles and guide clinical decision-making for individuals with obesity and without diabetes.

CONCLUSION

In summary, the majority of GI adverse events reported on semaglutide and tirzepatide treatment included nausea, constipation, diarrhea, vomiting, and abdominal pain. While these events were more frequent with tirzepatide treatment, semaglutide was significantly associated with gallbladder disease and cholelithiasis, regardless of gender. No statistically significant incidence of pancreatitis or hepatic events were observed with either treatment compared to the control. Based on these findings, it is imperative for the physicians to be concerned of the safety issues associated with the use of tirzepatide and semaglutide in clinical practice.

SUPPLEMENTS

Supplementary Table 1.

Reasons for excluding studies assessed for eligibility.

Author (year) Study title Reason for exclusion
Blundell et al, 2017 Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity Gl adverse events were not reported
Wharton et al, 2023 step 5 study Two-year effect of semaglutide 2.4 mg on control of eating in adults with overweight/obesity: STEP 5 Gl adverse events were not reported
Wharton et al, 2021 Gastrointestinal tolerability of once-weekly semaglutide 2.4 mg in adults with overweight or obesity, and the relationship between gastrointestinal adverse events and weight loss Non RCT study, Patients with type 2 DM were included
Enebo et al, 2021 Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2–4 mg for weight management: a randomised, controlled, phase 1b trial Did not meet the eligibility criteria, both arms received semaglutide
Weghuber et al, 2023 Once-Weekly Semaglutide in Adolescents with Obesity Patients with type 2 DM were included
Ghusn et al, 2022 Weight Loss Outcomes Associated With Semaglutide Treatment for Patients With Overweight or Obesity Non RCT study, Patients with type 2 DM were included
Slomski et al, 2022 Tirzepatide Trial Demonstrates Substantial Weight Loss Non RCT study
Hindson et al, 2022 Tirzepatide to treat obesity: phase III results Non RCT study
Malhotra et al, 2024 Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT-OSA phase 3 trial Gl adverse events were not reported
Hankosky et al, 2023 Tirzepatide reduces the predicted risk of developing type 2 diabetes in people with obesity or overweight: Post hoc analysis of the SURMOUNT-1 trial Gl adverse events were not reported
Kauffman et al, 2022 In overweight or obesity without diabetes, weekly semaglutide vs. daily liraglutide increased weight loss at 68 wk Non RCT study
Wilkinson et al, 2023 Effect of semaglutide 2.4 mg once weekly on 10-year type 2 diabetes risk in adults with overweight or obesity Gl adverse events were not reported
Ikushima et al, 2018 Randomized Trial Investigating the Pharmacokinetics, Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects Gl adverse events were not reported
Hjerpsted et a I, 2017 Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity Gl adverse events were not reported
Mu et al, 2024 Efficacy and safety of once weekly semaglutide 2–4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial Patients with type 2 DM were included
Kelly et a I, 2023 Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg Patients with type 2 DM were included + Gl adverse events were not reported
McGowan et al, 2023 Impact of BMI and comorbidities on efficacy of once-weekly semaglutide: Post hoc analyses of the STEP 1 randomized trial Gl adverse events were not reported
Snitker et al, 2022 Ease-of-use and acceptability of the novel semaglutide 2.4 mg single-dose pen-injector in people with overweight or obesity in the STEP 8 phase III trial Gl adverse events were not reported
Bjorner et al, 2023 The improved health utility of once-weekly subcutaneous semaglutide 2.4 mg compared with placebo in the STEP 1–4 obesity trials Patients with type 2 DM were included
Kolotkin et al, 2023 Effect of once-weekly subcutaneous semaglutide 2.4 mg on weight-and health-related quality of life in an East Asian population: Patient-reported outcomes from the STEP 6 trial Patients with type 2 DM were included
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Supplementary Figure 1.

Supplementary Figure 1.

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Funnel plots representing publication bias assessment of the study measured outcomes.

Funding Statement

None.

REFERENCES

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