Tirzepatide is a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor dual agonist (Frias et al., 2018). This dual-pathway intervention enhances efficacy through synergistic responses generated by complementary mechanisms, resulting in significant weight loss, improved glycemic control, and lipid reduction, which contribute to disease management and its progression delay (Samms et al., 2020). In May 2022, the U.S. Food and Drug Administration (FDA) approved tirzepatide for type 2 diabetes (Mullard, 2022). Additionally, due to its weight-reducing effects, tirzepatide was approved in November 2023 for chronic weight management in obese or overweight adults with at least one weight-related condition, such as hypertension, type 2 diabetes, or hyperlipidemia. Owing to its metabolic effects, tirzepatide has a broad range of applications, including obstructive sleep apnea (Malhotra et al., 2024) and metabolic dysfunction-associated steatohepatitis with liver fibrosis (Loomba et al., 2024).

Given the remarkable efficacy and widespread use of tirzepatide in diabetes mellitus and weight control, understanding its potential for adverse drug events (ADEs) is crucial. In the SURPASS-1 to −5 trials (N = 6263), nausea (12%–24%), diarrhea (12%–22%), and vomiting (2%–13%) were the most common gastrointestinal ADEs associated with tirzepatide (Patel et al., 2024). The SURMOUNT-4 randomized clinical trial similarly identified mild to moderate gastrointestinal events as the most common adverse reactions (nausea [35.5%], diarrhea [21.1%], constipation [20.7%], and vomiting [16.3%]) (Aronne et al., 2024). Network meta-analyses underscore the need for safety concerns regarding drug use, particularly gastrointestinal events (Yao et al., 2024). A systematic review and meta-analysis of tirzepatide’s safety in patients with type 2 diabetes mellitus and obesity indicate that tirzepatide appears to be safe concerning pancreatitis risk (Zeng et al., 2023). However, the increased risk of gallbladder or biliary tract disease observed in clinical trials warrants further attention from physicians in clinical practice (Zeng et al., 2023). Information on tirzepatide’s efficacy and safety has been primarily documented through case reports, clinical trials, and meta-analyses. However, these studies often target specific populations or include relatively limited sample sizes and selection criteria, resulting in a lack of comprehensive safety data from large samples and real-world cohorts.

The FDA Adverse Event Reporting System (FAERS) database is an invaluable resource for post-marketing surveillance and early detection of drug safety issues. Regularly updated and publicly available for download on the FDA website, it contains authentic adverse event reports from various sources, including healthcare professionals, consumers, and manufacturers’ records. This study aims to assess tirzepatide’s safety through post-marketing surveillance and provide a comprehensive and valuable reference for its real-world safety.

In this study, we conducted a quantitative assessment of tirzepatide’s safety through a comprehensive analysis of real-world data from the FAERS database. This evaluation was performed from both an overall population perspective and a sex-specific perspective, aiming to balance the drug’s benefits and risks and provide informed guidance for clinical decision-making.

Tirzepatide-related ADEs were more frequently observed in females (68.8%) compared to males (19%). This discrepancy may be attributed to the drug’s relatively short market presence and the limited availability of data that require further observation over time. Additionally, the primary reporters of these ADEs were consumers, and social factors may contribute to females being more proactive in reporting adverse reactions (Lee et al., 2023). The epidemiologic characteristics of the obese population also support these findings (Jaacks et al., 2019; NCD Risk Factor, 2024). ADEs were more prevalent in individuals aged 18-65 who received tirzepatide. Unfortunately, over 90% of the reports lacked detailed information on patients’ weight and outcomes. The U.S was the predominant reporting country (98.9%), likely because it was the first to authorize the drug for marketing. The annual analysis report shows more than half of the ADEs were reported in the first quarter of 2024 than in the entire year of 2023. These results underscore the widespread clinical use and efficacy of tirzepatide and highlight the importance of enhancing the detection of tirzepatide-related ADEs.

The three most common SOCs identified in our study with tirzepatide were injury, poisoning and procedural complications, general disorders and administration site conditions, and gastrointestinal disorders. Injury, poisoning, and procedural complications were not mentioned in the drug labeling, but the other two were consistent with the documented safety information. The results of the disproportionality analysis showed four significant signals at the SOC level, some of which were explicitly mentioned in the drug labeling, validating the reliability of our findings. The most common ADEs reflected reporter concerns about drug use. Incorrect dose administered, injection site pain, off-label use, and nausea were the top four PTs with the highest percentage of tirzepatide for both males and females. Notably, incorrect dose administered and off-label use were unexpected PTs, emphasizing the importance of standardizing medication use and increasing restrictions on prescriptions by healthcare professionals. Headache (n = 511, 0.91%) is a common nervous system disorder among females. Many clinical studies have reported adverse effects of headaches (Frias et al., 2018; Rosenstock et al., 2021; Garvey et al., 2023), but the relationship with sex is unknown. Further studies on the relationship between tirzepatide and headaches may be needed.

The signals with strongest signal values included injection site coldness, injection site injury, accidental underdose, extra dose administered, injection site laceration, and starvation ketoacidosis. The SURPASS trial indicated a higher incidence of injection site responses than placebo, which were mild to moderate (Rosenstock et al., 2021; Dahl et al., 2022). Injection reactions to tirzepatide are also mentioned in the drug label but not in detail. Our data provides a detailed list of the number of cases and signal values of injection ADEs associated with tirzepatide, aiding doctors in detecting these ADEs. Notably, starvation ketoacidosis exhibited a strong correlation, with a significant signal strength of ROR 45.56 (19.26-107.75), PRR 45.56, IC 34.01, EBGM 5.09. There are two known cases of tirzepatide-induced ketoacidosis (Mercer et al., 2023; Iqbal et al., 2024). Both cases were female non-diabetic obese patients, with starvation ketoacidosis being the likely mechanism. Ketoacidosis is serious, and physicians should be aware of this complication and alert for early symptoms.

Gastrointestinal events were the most common treatment-emergent ADEs in several clinical trials, and most were mild to moderate in intensity (Frias et al., 2018; Ludvik et al., 2021; Rosenstock et al., 2021). Through a real-world analysis of tirzepatide, we identified several significant gastrointestinal ADEs, including nausea (n = 4358, ROR 5.20, PRR 4.97, IC 2.27, EBGM 4.82), constipation (n = 1215, ROR 4.48, PRR 4.43, IC 2.11, EBGM 4.32), eructation (n = 716, ROR 43.63, PRR 43.25, IC 32.71, EBGM 5.03), dyspepsia (n = 559, ROR 5.12, PRR 5.09, IC 2.30, EBGM 4.93), flatulence (n = 380, ROR 6.00, PRR 5.98, IC 2.53, EBGM 5.76), and pancreatitis (n = 307, ROR 7.18, PRR 7.16, IC 2.77, EBGM 6.84), consistent with previous clinical studies and drug labeling. A randomized, parallel-group, multicenter, phase 3 trial found that tirzepatide caused pancreatitis (5 mg n = 3, 10 mg n = 2, 15 mg n = 1) in patients with type 2 diabetes mellitus (Del Prato et al., 2021), and another double-blind, randomized, multicenter, phase 3 trial found that tirzepatide also caused pancreatitis (15 mg n = 2) in obese patients with type 2 diabetes mellitus (Garvey et al., 2023). It is important to note that clinical trials of overweight or obesity and obstructive sleep apnea and obesity also found adverse event reports of pancreatitis (Kadowaki et al., 2022; Wadden et al., 2023; Malhotra et al., 2024). These studies were constrained by relatively limited sample sizes and specific selection criteria. Based on our findings, vigilance regarding the association between tirzepatide and pancreatitis is needed, which may require further experimental verification. We recommend observing patients for nausea, vomiting, and abdominal pain during dosing, monitoring amylase and lipase levels in the patient’s blood and urine for early recognition, and conducting abdominal computed tomography scans if necessary.

We also identified unexpected signals, such as impaired gastric emptying (n = 181, ROR 16.60, PRR 16.57, IC 3.89, EBGM 14.81), abnormal gastrointestinal sounds (n = 37, ROR 5.28, PRR 5.27, IC 2.35, EBGM 5.11), and projectile vomiting (n = 22, ROR 8.09, PRR 8.09, IC 2.94, EBGM 7.67). Hypoglycemia is a low blood sugar condition that occurs during medication and can lead to discomfort and even life-threatening situations. Fortunately, fewer severe hypoglycemic events have been reported in prior clinical studies, but a higher incidence was observed in patients receiving background sulfonylurea and glinides. Therefore, regular monitoring of blood glucose during the use of hypoglycemic drugs is recommended to help prevent hypoglycemia.

For ADEs of special interest, both medullary thyroid cancer (n = 7, ROR 17.19, PRR 17.19, IC 15.3, EBGM 3.94) and follicular thyroid cancer (n = 3, ROR 16.27, PRR 16.27, IC 14.57, EBGM 3.87) had higher EBGM values. Based on the results of a rat study, a black box warning was issued in the United States in the prescribing information for tirzepatide, alerting patients to the risk of thyroid C-cell tumors and recommending further evaluation in patients with significantly elevated calcitonin levels or those found to have thyroid nodules. Our study identified diabetic retinopathy (n = 15, ROR 5.45, PRR 5.45, IC 2.40, EBGM 5.27) and retinopathy (n = 12, ROR 3.63, PRR 3.63, IC 1.83, EBGM 3.56). Although one study showed that tirzepatide did not affect the risk of diabetic retinopathy in patients with type 2 diabetes mellitus, however, there is still a need for large-scale randomized controlled trials are needed to assess the long-term safety of tirzepatide with respect to the risk of diabetic retinopathy (Popovic et al., 2024).

A Korean study on antidiabetic drugs revealed significant sex differences, with females reporting more ADEs than males (Joung et al., 2020). Our study similarly found significant sex differences in the reported baseline profiles, prompting a further comparison of ADEs between sexes. For males, the top three case-number significant PTs were incorrect dose administered, injection site pain, and nausea, whereas for females, they were incorrect dose administered, injection site pain, and off-label use. Interestingly, unique ADEs in males were more frequently related to gastrointestinal disorders, while in females, they were associated with general disorders and administration site conditions. Males are often linked with unhealthy lifestyles, such as poor diet, stress, physical inactivity, smoking, and excessive alcohol consumption, leading to a higher prevalence of non-malignant upper gastrointestinal diseases (Bai et al., 2024). In contrast, females may experience more distress from externally visible drug ADEs due to higher societal expectations and internalized pressures regarding appearance, making them more likely to report such ADEs (Lee et al., 2023). Skin hypersensitivity, an allergic manifestation due to an excessive immune response to external stimuli, can occur in both sexes (Demoly et al., 2014). Our study found that injection site erythema, bruising, pruritus, and mass can occur in both male and female; however, injection site rashes and urticaria were more common in women. The treatment of cutaneous hypersensitivity reactions depends on the severity, necessitating early intervention and management to prevent more serious systemic reactions. It is important to consider that the number and specificity of AE reports depend largely on individual reporting habits. We can only estimate the signal by its intensity and frequency. These results should not be overly relied upon to draw definitive conclusions about the causal relationship between drugs and adverse events. Therefore, it is not feasible to infer a causal relationship between medications and ADEs in male and female patients based solely on these data.

Our study analyzed the temporal relationship between drug administration and ADE onset time. The results showed that tirzepatide-related ADEs occurred predominantly within the first month (55.24%), and the Weibull distribution test indicated that the probability of ADEs decreased over time in the general population and in most subgroups. Tirzepatide is primarily used in patients with type 2 diabetes and obesity, necessitating long-term use, and these findings support the drug’s long-term safety. Crucially, we conducted a comprehensive study of the specific onset time in each organ system following tirzepatide administration. While most SOCs manifested within the first month of medication use, our results indicated that the median time to onset of hepatobiliary disorders was 35.5 days (IQR 4.75–154 days). This suggests the need for a follow-up program for early detection of hepatobiliary disease. Furthermore, SOCs with the longest time to onset were neoplasms benign, malignant, and unspecified (including cysts and polyps), suggesting that semiannual surveillance and follow-up may be warranted. Therefore, early detection and follow-up requirements for adverse reactions should vary depending on the affected systems. To investigate the effect of sex on the type of ADE, we performed a sex-based subgroup analysis, which suggested that the time to onset of ADEs associated with tirzepatide might not affected by sex. This underscores the importance of a uniform follow-up cycle for both men and women in monitoring ADEs.

While one study has already analyzed tirzepatide real-world data using the FAERS database (Liu, 2024), the significant increase in spontaneously reported ADEs for tirzepatide prompted us to comprehensively document and evaluate the drug’s safety for post-marketing use based on the largest sample of real-world data to date. However, several limitations remain. First, FAERS is inherently limited by underreporting, incomplete reporting, and selective reporting. Of the 37,827 reports we collected, the majority (93.3%) did not include outcome information, making more detailed analysis difficult. Second, the lack of detailed clinical information on patients, such as comorbidities, severity of underlying disease, and concomitant medications, limited our ability to control for confounding variables, which may have influenced the study results. Third, disproportionality analyses were limited to assessing signal strength and establishing statistical associations, which, despite our explanation in the Discussion section, did not provide sufficient evidence to establish a causal relationship between substance use and ADE. Lastly, the low reporting rate of TTOs (3.6%) represents a significant limitation of our analysis, and thus, these results require careful interpretation. Given these shortcomings, along with other potential confounders and biases, it is important to consider these limitations when interpreting our findings.

Our study conducted a comprehensive and systematic pharmacovigilance analysis using the FAERS database to identify ADEs associated with tirzepatide. “injury, poisoning and procedural complications,” “general disorders and administration site conditions,” “gastrointestinal disorders,” and “metabolism and nutrition disorders” were the significant system organ classes with adverse events. Attention should also be directed towards unexpected signals, including “starvation ketoacidosis,” “medullary thyroid cancer,” and “follicular thyroid cancer”. We differentiated between sex-specific types of ADEs and examined the onset timing of these events. Given the inherent limitations of the FAERS database, potential confounders, and biases, our findings should be interpreted with caution. Further prospective clinical studies are necessary to confirm and enhance our understanding of the association between tirzepatide and these ADEs.