2025 Volume 72 Issue 3 Pages 273-283
Tirzepatide is a novel drug for the treatment of type 2 diabetes mellitus and chronic weight management, and there is an urgent need to explore its safety profile. The FDA Adverse Event Reporting System (FAERS) database provides a reliable pathway for adverse event (AE) disproportionality analysis. Data regarding AEs registered in the FAERS between Q2 2022 and Q4 2023 were collected for this study. The reporting odds ratio (ROR) method was applied to analyse the association between tirzepatide use and the risk of developing AEs. The occurrence of ≥3 AEs with an ROR value 95% confidence interval (CI) lower limit >1 was considered to indicate statistical significance. Data on 638,153 AEs were collected from the FAERS database, and tirzepatide use was implicated for 8,096 of those AEs. A total of 98 preferred terms (PTs) were detected as positive signals for tirzepatide use. Frequently observed expected AEs included injection site pain, nausea, injection site haemorrhage, diarrhoea, and vomiting. Some unexpected AEs that were frequently observed included incorrect doses, off-label use, the administration of extra doses, an inappropriate schedule of product administration, and increased blood glucose. In this study, we identified potential novel and unexpected AE signals associated with tirzepatide use. Our findings confirm the importance of real-world disproportionality analysis in identifying the safety profile of new drugs, ultimately contributing to the safe clinical application of tirzepatide.
Peptide hormones can regulate metabolism and balance sugars, lipids, and energy in the human body. In addition to the well-known peptide hormone insulin, there are also incretin hormones, with glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) being the predominant ones [1]. The function of GLP-1 is to stimulate insulin secretion, protect pancreatic β cells, and inhibit glucagon secretion, gastric emptying and feeding [2]. On the basis of this physiological mechanism, GLP-1 has become a suitable pharmacological target for glucose-lowering and weight-loss drugs. Since 2005, several GLP-1 receptor agonists (GLP-1 RAs) have been marketed for the treatment of diabetes or obesity, including exenatide, liraglutide, dulaglutide, and semaglutide. In the past, another incretin hormone, GIP, has been considered a diabetes therapeutic target with no potential due to its significantly reduced sensitivity to GIP in patients with type 2 diabetes mellitus (T2DM) [3]. In recent years, it has been reported that GIP resistance and inefficacy can be reversed by improving glycaemic control [4]. These findings suggest the possibility for the development of dual GIP and GLP-1 receptor agonists (GIP/GLP-1 RAs).
Tirzepatide, the first dual GIP/GLP-1 RA, was approved by the U.S. Food and Drug Administration (FDA) in May 2022 for the treatment of T2DM and in November 2023 for chronic weight management. In addition, relevant clinical trials are underway to assess the efficacy of tirzepatide for treating for cardiovascular disease [5]. With changes in lifestyle, the prevalence of metabolic diseases, such as diabetes, overweight or obesity, and hypertension, is increasing annually. Therefore, the status of drugs that combine glucose-lowering, weight-loss and cardiovascular protection functions is becoming increasingly important in therapeutic regimens [6]. Sales corroborate the status of this class of drugs, with $21.2 bn [7] and $5.339 bn [8] in sales in the year 2023 for semaglutide and tirzepatide, respectively, with semaglutide ranking second overall in terms of global sales. Previous preclinical and clinical trials have confirmed that tirzepatide provides better glycaemic control and weight loss effects than semaglutide does [9, 10]. Therefore, there is much room for growth in the application of tirzepatide.
As a new drug recently introduced to the market, we need to fully evaluate the safety and tolerability of tirzepatide. On the basis of premarketing clinical trial data, the overall safety and tolerability of tirzepatide are similar to those of GLP-1 RAs [11]. The most common adverse reactions (ARs) to tirzepatide are gastrointestinal-related ARs, such as nausea, diarrhoea and constipation, which are usually mild to moderate, often occur during dose escalation, do not generally result in discontinuation of the drug, and no significant hypoglycaemic reactions are observed [12, 13]. However, owing to the small sample size of clinical trials, the relatively homogeneous sample source, and the short duration of the medication regimen and observation period, certain late-onset or rare ARs or ARs occurring only in specific populations may not have been identified. Large-scale data analysis of all the AEs associated with tirzepatide use is still lacking, and it is necessary to investigate whether unknown tirzepatide ARs exist.
The FDA Adverse Event Reporting System (FAERS) is a database for postmarketing safety monitoring of drugs and therapeutic biologics that includes all AE information and medication error information. In recent years, many scholars have conducted studies on the safety evaluation of new drugs via the FAERS database and have established a set of mature methods [14]. Therefore, the aim of this study was to comprehensively mine the FAERS database for postmarketing reported AEs associated with tirzepatide use to realistically assess its safety profile.
Tirzepatide was launched in May 2022. We extracted data from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html) ranging from Q2 2022 to Q4 2023 and processed the data through MySQL software. The generic and brand names of the drug (tirzepatide, Mounjaro®, Zepbound®) were used as keywords for data mining. Duplicate reports were removed according to FDA guidelines, and only reports in which tirzepatide was considered to be the primary cause of the AE were included in our study. The AE reports retrieved from the FAERS database were coded with the preferred term (PT) from the Medical Dictionary for Regulatory Activities (MedDRA, Version 26.1). The PT has a hierarchical structure of level 4 in MedDRA and is connected to the System Organ Classification (SOC) at the highest level through a mapping relationship.
Statistical analysisDescriptive analysis was performed to summarize the clinical features, including patient age, sex, reporter type, reporting country and outcome, in all the AE reports associated with tirzepatide use that were obtained from the FAERS. Disproportional analysis was used to ascertain the correlation between tirzepatide use and the risk of developing AEs. The reporting odds ratio (ROR) is one of the most commonly used methods in disproportionate analysis, featuring simple calculations and good consistency of results. As shown in Table 1, a two-by-two contingency table was used to calculate the ROR. The criteria for positive signals in this study were as follows: (1) 95% confidence interval (CI) lower limit >1 and (2) ≥3 AEs reported. A larger ROR value indicates a stronger AR signal, meaning that the likelihood of this AR occurring is greater with tirzepatide use than with the use of other drugs.
| Algorithms | Equation | Criteria |
|---|---|---|
| ROR | ROR = 95% CI = |
lower limit of 95% CI > 1, a ≥ 3 |
a, number of reports containing both the suspect drug and the suspect adverse event; b, number of reports containing the suspect drug with other adverse drug reactions (except the event of interest); c, number of reports containing the suspect adverse event with other medications (except the drug of interest); d, number of reports containing other drugs and other adverse events. ROR, reporting odds ratio; CI, confidence interval.
From Q2 2022 to Q4 2023, the FAERS database received a total of 638,153 AE reports, and tirzepatide was the primary suspect for 8,096 AEs. The clinical characteristics of the reports associated with tirzepatide are presented in Table 2. The highest proportions were found in young (27.62%) and middle-aged (44.79%) adults, whereas a small number of nonadults (0.04%) were off-label. Moreover, there were significantly more female (73.84%) than male (18.44%) users, and the United States (96.38%) reported the most cases, among others. The proportion of consumers (94.43%) in the reporting population was greater than that of healthcare professionals, a phenomenon also observed in a pharmacovigilance study of GLP-1 RAs, which included exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide [15]. Serious outcomes, including 23 deaths, occurred in 800 patients.
| Characteristics | Category | Number of cases | Percentage (%) |
|---|---|---|---|
| Age (year) | <18 | 3 | 0.04 |
| 18–45 | 2,236 | 27.62 | |
| 45–65 | 3,626 | 44.79 | |
| 65–75 | 741 | 9.15 | |
| >75 | 199 | 2.46 | |
| Not Specified | 1,291 | 15.94 | |
| Gender | Male | 1,493 | 18.44 |
| Female | 5,978 | 73.84 | |
| Not Specified | 625 | 7.72 | |
| Reporting country | United States | 7,803 | 96.38 |
| Japan | 51 | 0.63 | |
| United Arab Emirates | 13 | 0.16 | |
| Others | 229 | 2.84 | |
| Reporter Type | Consumer | 7,645 | 94.43 |
| Other health-professional | 240 | 2.96 | |
| Physician | 130 | 1.61 | |
| Pharmacist | 68 | 0.84 | |
| Not Specified | 13 | 0.16 | |
| Serious outcomes | Hospitalization-Initial or Prolonged | 324 | 4.00 |
| Life-Threatening | 34 | 0.42 | |
| Required Intervention to Prevent Permanent Impairment/Damage | 25 | 0.31 | |
| Disability | 24 | 0.30 | |
| Death | 23 | 0.28 | |
| Other Serious | 370 | 4.57 |
In total, 98 PTs were detected as positive signals for tirzepatide-related AEs from the FAERS database, mapping to 15 SOCs. Some of the PTs can be mapped to multiple SOCs, and we only counted the primary SOCs. As shown in Fig. 1, the most frequent SOCs were “general disorders and administration site conditions,” “gastrointestinal disorders,” “metabolism and nutrition disorders,” “investigations,” and “injuries, poisoning and procedural complications.”
We described PTs that were concordant with the drug package inserts and clinical trial results as expected AEs and the discordant PTs as unexpected AEs. As shown in Table 3, of the 98 positive signals, 64 were expected AEs, and 34 were unexpected AEs. Among the expected AEs, injection site pain (n = 1,152, PT: 10022086), nausea (n = 960, PT: 10028813), injection site haemorrhage (n = 612, PT: 10022067), diarrhoea (n = 463, PT: 10012735), and vomiting (n = 403, PT: 10047700) were the most frequently reported AEs. Among the unexpected AEs, incorrect doses (n = 3,192, PT: 10064355), off-label use (n = 1,914, PT: 10053762), extra doses (n = 596, PT: 10064366), inappropriate schedules of product administration (n = 457, PT: 10081572), and increased blood glucose levels (n = 221, PT: 10005557) were the most frequently reported AEs. In addition, the PTs with the highest ROR signal strengths were incorrect doses (ROR = 47.20, PT: 10064355), extra doses (ROR = 31.18, PT: 10064366), sleep disorders due to general medical conditions (ROR = 21.84, PT: 10040986), accidental underdoses (ROR = 18.13, PT: 10074904), and intercepted product selection errors (ROR = 16.44, PT: 10041954).
| PT | n | ROR (95% CI) | Primary SOC | |
|---|---|---|---|---|
| Expected AEs | Injection site pain | 1,152 | 8.38 (7.85, 8.94) | General disorders and administration site conditions |
| Nausea | 960 | 2.48 (2.32, 2.66) | Gastrointestinal disorders | |
| Injection site haemorrhage | 612 | 13.17 (12.05, 14.39) | General disorders and administration site conditions | |
| Diarrhoea | 463 | 1.29 (1.17, 1.41) | Gastrointestinal disorders | |
| Vomiting | 403 | 1.74 (1.57, 1.92) | Gastrointestinal disorders | |
| Injection site erythema | 375 | 7.50 (6.73, 8.36) | General disorders and administration site conditions | |
| Decreased appetite | 287 | 2.31 (2.05, 2.61) | Metabolism and nutrition disorders | |
| Injection site bruising | 282 | 7.60 (6.71, 8.61) | General disorders and administration site conditions | |
| Constipation | 246 | 2.45 (2.16, 2.79) | Gastrointestinal disorders | |
| Injection site pruritus | 203 | 6.62 (5.72, 7.66) | General disorders and administration site conditions | |
| Abdominal pain upper | 168 | 1.68 (1.44, 1.96) | Gastrointestinal disorders | |
| Injection site mass | 144 | 6.48 (5.46, 7.70) | General disorders and administration site conditions | |
| Weight decreased | 143 | 1.29 (1.09, 1.53) | Investigations | |
| Eructation | 141 | 19.64 (16.28, 23.69) | Gastrointestinal disorders | |
| Injection site swelling | 135 | 3.26 (2.74, 3.88) | General disorders and administration site conditions | |
| Dyspepsia | 130 | 2.78 (2.33, 3.32) | Gastrointestinal disorders | |
| Abdominal discomfort | 123 | 1.65 (1.37, 1.97) | Gastrointestinal disorders | |
| Injection site urticaria | 108 | 7.75 (6.35, 9.47) | General disorders and administration site conditions | |
| Injection site rash | 103 | 6.08 (4.97, 7.44) | General disorders and administration site conditions | |
| Injection site injury | 102 | 31.84 (25.20, 40.24) | General disorders and administration site conditions | |
| Hunger | 97 | 21.37 (17.02, 26.84) | General disorders and administration site conditions | |
| Blood glucose decreased | 94 | 7.04 (5.69, 8.71) | Investigations | |
| Abdominal distension | 90 | 1.87 (1.52, 2.31) | Gastrointestinal disorders | |
| Dehydration | 89 | 1.40 (1.13, 1.73) | Metabolism and nutrition disorders | |
| Flatulence | 71 | 2.84 (2.24, 3.60) | Gastrointestinal disorders | |
| Pancreatitis | 65 | 4.21 (3.27, 5.41) | Gastrointestinal disorders | |
| Gastrooesophageal reflux disease | 64 | 2.69 (2.09, 3.45) | Gastrointestinal disorders | |
| Feeding disorder | 50 | 3.64 (2.74, 4.84) | Metabolism and nutrition disorders | |
| Injection site reaction | 49 | 2.12 (1.59, 2.82) | General disorders and administration site conditions | |
| Gastrointestinal disorder | 43 | 1.60 (1.18, 2.16) | Gastrointestinal disorders | |
| Hypoglycaemia | 40 | 2.59 (1.89, 3.55) | Metabolism and nutrition disorders | |
| Injection site irritation | 35 | 8.07 (5.69, 11.46) | General disorders and administration site conditions | |
| Injection site warmth | 29 | 4.13 (2.84, 6.00) | General disorders and administration site conditions | |
| Injection site discomfort | 27 | 4.04 (2.74, 5.96) | General disorders and administration site conditions | |
| Hypophagia | 23 | 1.68 (1.11, 2.55) | Metabolism and nutrition disorders | |
| Impaired gastric emptying | 21 | 7.81 (4.97, 12.26) | Gastrointestinal disorders | |
| Cholelithiasis | 18 | 1.69 (1.06, 2.69) | Hepatobiliary disorders | |
| Injection site discolouration | 16 | 2.61 (1.58, 4.29) | General disorders and administration site conditions | |
| Injection site vesicles | 15 | 4.05 (2.41, 6.82) | General disorders and administration site conditions | |
| Lipase increased | 14 | 4.21 (2.46, 7.23) | Investigations | |
| Gallbladder disorder | 14 | 2.42 (1.42, 4.13) | Hepatobiliary disorders | |
| Injection site paraesthesia | 14 | 13.32 (7.52, 23.58) | General disorders and administration site conditions | |
| Injection site induration | 13 | 2.61 (1.50, 4.54) | General disorders and administration site conditions | |
| Injection site coldness | 12 | 45.06 (21.86, 92.85) | General disorders and administration site conditions | |
| Sensitive skin | 11 | 2.31 (1.26, 4.21) | Skin and subcutaneous tissue disorders | |
| Appetite disorder | 11 | 3.25 (1.78, 5.96) | Metabolism and nutrition disorders | |
| Cholecystitis | 11 | 2.01 (1.10, 3.66) | Hepatobiliary disorders | |
| Glycosylated haemoglobin decreased | 9 | 13.10 (6.43, 26.67) | Investigations | |
| Injection site hypersensitivity | 9 | 6.29 (3.18, 12.44) | General disorders and administration site conditions | |
| Starvation | 8 | 31.69 (13.78, 72.90) | Metabolism and nutrition disorders | |
| Food aversion | 7 | 7.23 (3.32, 15.74) | Metabolism and nutrition disorders | |
| Injection site hypoaesthesia | 7 | 5.87 (2.72, 12.69) | General disorders and administration site conditions | |
| Injection site laceration | 6 | 23.76 (9.43, 59.88) | General disorders and administration site conditions | |
| Pancreatitis necrotising | 6 | 7.64 (3.29, 17.73) | Gastrointestinal disorders | |
| Allodynia | 5 | 8.48 (3.36, 21.45) | Nervous system disorders | |
| Biliary colic | 5 | 2.87 (1.17, 7.03) | Hepatobiliary disorders | |
| Injection site scar | 5 | 4.45 (1.80, 11.00) | General disorders and administration site conditions | |
| Injection site scab | 5 | 10.80 (4.21, 27.67) | General disorders and administration site conditions | |
| Vomiting projectile | 5 | 2.60 (1.07, 6.35) | Gastrointestinal disorders | |
| Application site wound | 4 | 35.63 (10.73, 118.36) | General disorders and administration site conditions | |
| Diabetic retinopathy | 4 | 7.70 (2.75, 21.62) | Eye disorders | |
| Skin sensitisation | 3 | 6.68 (2.04, 21.82) | Skin and subcutaneous tissue disorders | |
| Medullary thyroid cancer | 3 | 71.26 (14.38, 353.12) | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| Gallbladder enlargement | 3 | 4.55 (1.42, 14.62) | Hepatobiliary disorders | |
| Unexpected AEs | Incorrect dose administered | 3,192 | 47.20 (44.91, 49.62) | Injury, poisoning and procedural complications |
| Off label use | 1,914 | 4.97 (4.72, 5.24) | Injury, poisoning and procedural complications | |
| Extra dose administered | 596 | 31.18 (28.27, 34.39) | Injury, poisoning and procedural complications | |
| Inappropriate schedule of product administration | 457 | 3.05 (2.77, 3.36) | Injury, poisoning and procedural complications | |
| Blood glucose increased | 221 | 3.78 (3.30, 4.34) | Investigations | |
| Injury associated with device | 117 | 8.90 (7.33, 10.79) | General disorders and administration site conditions | |
| Accidental underdose | 113 | 18.13 (14.73, 22.30) | Injury, poisoning and procedural complications | |
| Product administered at inappropriate site | 108 | 8.88 (7.26, 10.85) | Injury, poisoning and procedural complications | |
| Overdose | 85 | 2.50 (2.01, 3.11) | Injury, poisoning and procedural complications | |
| Increased appetite | 57 | 10.29 (7.79, 13.60) | Metabolism and nutrition disorders | |
| Underdose | 47 | 1.45 (1.08, 1.93) | Injury, poisoning and procedural complications | |
| Glycosylated haemoglobin increased | 43 | 5.29 (3.88, 7.22) | Investigations | |
| Accidental overdose | 35 | 2.64 (1.88, 3.70) | Injury, poisoning and procedural complications | |
| Product prescribing error | 33 | 2.18 (1.54, 3.09) | Injury, poisoning and procedural complications | |
| Blood glucose abnormal | 28 | 4.42 (3.02, 6.49) | Investigations | |
| Sleep disorder due to general medical condition, insomnia type | 15 | 21.84 (12.25, 38.97) | Psychiatric disorders | |
| Food craving | 15 | 11.39 (6.60, 19.64) | Metabolism and nutrition disorders | |
| Diabetic ketoacidosis | 15 | 1.74 (1.04, 2.90) | Metabolism and nutrition disorders | |
| Blood glucose fluctuation | 12 | 4.11 (2.30, 7.37) | Investigations | |
| Food poisoning | 9 | 2.59 (1.33, 5.03) | Gastrointestinal disorders | |
| Glycosylated haemoglobin abnormal | 7 | 7.56 (3.47, 16.48) | Investigations | |
| Thyroid mass | 7 | 3.75 (1.75, 8.02) | Endocrine disorders | |
| Fluid intake reduced | 7 | 2.33 (1.10, 4.95) | Metabolism and nutrition disorders | |
| Lymph node pain | 5 | 5.75 (2.31, 14.30) | Blood and lymphatic system disorders | |
| Postmenopausal haemorrhage | 5 | 4.82 (1.95, 11.91) | Reproductive system and breast disorders | |
| Sleep disorder due to a general medical condition | 5 | 4.29 (1.74, 10.59) | Psychiatric disorders | |
| Counterfeit product administered | 4 | 10.56 (3.69, 30.18) | Injury, poisoning and procedural complications | |
| Pancreatic enzymes increased | 4 | 8.64 (3.06, 24.39) | Investigations | |
| Norovirus infection | 4 | 2.79 (1.03, 7.59) | Infections and infestations | |
| Intercepted product selection error | 3 | 16.44 (4.69, 57.72) | Injury, poisoning and procedural complications | |
| Gastric pH decreased | 3 | 10.69 (3.18, 35.98) | Investigations | |
| Polycystic ovaries | 3 | 6.11 (1.88, 19.86) | Reproductive system and breast disorders | |
| Thyroid hormones increased | 3 | 3.62 (1.14, 11.56) | Investigations | |
| Metabolic disorder | 3 | 3.56 (1.12, 11.36) | Metabolism and nutrition disorders |
Expected AEs: expected or previously reported adverse events, mentioned in the package insert. Unexpected AEs: unexpected or previously unreported adverse events, not mentioned in the package insert.
Among the reports related to tirzepatide use, 4,376 included the correct time of drug administration and AE occurrence. The mean onset time was 44 days, and the median onset time was 8 days (interquartile range [IQR] 2–74 days). As shown in Fig. 2, our study demonstrated that the onset time of most AEs was less than 7 days (n = 2,180, 49.82%). Owing to the short time that tirzepatide has been on the market, the longest occurrence of AEs that we observed was 223 days (n = 6, 0.14%).
Tirzepatide, a very promising drug, is expected to be prescribed at an accelerating rate after it recently gained the indication for weight management. This frenzy has caused many scholars to address safety concerns related to tirzepatide [16]. Therefore, continuous postmarketing safety monitoring is important for tirzepatide. To our knowledge, this is the first pharmacovigilance study of tirzepatide based on a real-world database (Graphical Abstract).
When analysing the population characteristics of the reports related to tirzepatide use, we found an interesting phenomenon in that the proportion of users was significantly greater in females than in males. However, the International Diabetes Federation Diabetes Atlas and the World Obesity Atlas show no significant difference in the incidence of these two diseases between men and women [17, 18]. It follows that the demographic characteristics in the FAERS database cannot be used directly in epidemiological studies. In addition, we found that more than 90% of the reporters were consumers rather than medical professionals such as physicians, pharmacists and nurses. The FAERS is a self-reporting system, and the willingness to report AEs is not universal, which may lead to differences in the characteristics of the reporting population. There were 23 reports of deaths suspected to be caused by tirzepatide use, but unfortunately, the FAERS database lacked more details to judge the association between the drug and death.
The package insert is the basis for the use of drugs and is also an important channel for users to obtain information on drug ARs. The AR information in the tirzepatide label is derived primarily from the SURPASS program [19-24]. As documented in the insert, the most common ARs reported in ≥5% of patients treated with tirzepatide are nausea, diarrhoea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. Consistent with our findings, these gastrointestinal disorders accounted for a large proportion of the expected AEs. Additionally, our study revealed that injection site reactions, e.g., injection site pain, injection site haemorrhage, injection site erythema, and injection site bruising, were reported more frequently than gastrointestinal reactions in terms of the expected AEs. The reason for this discrepancy can be that a medical professional administered the drug to the participants or gave them detailed instructions on how to use the injection pen in clinical trials, which was not the case in practice. Hence, we remind physicians and pharmacists of the need to guidance the prescriber on how to use tirzepatide, even if the label documents the use method.
In addition, we found that numerous AEs were not documented on the tirzepatide label. Among them, AEs such as incorrect dose administration, extra dose administration, intercepted product selection error, and off-label use should be noted. These AE signals suggest the irregular use of tirzepatide in the real world. In one study, Chiappini verified the misuse of semaglutide by analysing the FAERS database [25]. Semaglutide is marketed as Ozempic® for T2DM and Wegovy® for weight loss, both of which share the same active ingredient, which has led to widespread off-label use. Recently, Belgium banned the use of the diabetes drug Ozempic® for weight loss, and Germany is considering a similar action [26]. Similarly, although the ingredients are the same, tirzepatide has two trade names, and the recommended dosages for the treatment of T2DM and obesity are different, making it difficult for many patients to differentiate between them and leading to misuse. Therefore, it is advisable for manufacturers to show the indications prominently on the packaging of the drug, as well as for medical professionals to instruct patients on the proper use of the drug to avoid misuse of tirzepatide.
On the basis of the criteria for positive signals, we detected medullary thyroid carcinoma as a rare AE with the highest ROR (n = 3, ROR = 71.26), and the manufacturer also made a black box warning about this in the label. The basis for the black box warning is derived primarily from animal experiments; in rodent experiments, there is evidence of a greater incidence of thyroid C-cell tumours in response to the use of GLP-1 RAs (such as liraglutide, exenatide, and lixisenatide) [27, 28]. The results of a nested case-control analysis based on the French National Health Care Data System (SNDS) database revealed an increased risk of developing all thyroid tumours after 1–3 years of GLP-1RA use (adjusted hazard ratio [HR] 1.58, 95% CI 1.27–1.95) [29]. However, the opposite view also exists. In humans, GLP-1 receptor expression in C-cells of the normal thyroid is significantly lower or absent than GLP-1 receptor expression in rodents [30, 31], so animal experiments are not representative of humans. During its November 2023 meeting, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) concluded that the available evidence does not support a causal association between GLP-1 RAs and thyroid tumours [32]. In addition, owing to the short time on the market, only three reports of thyroid tumours have been collected from the FAERS database, and the association between tirzepatide use and the risk of developing thyroid tumours still needs to be verified with more reports. Even so, for the time being, it is necessary to warn of this risk on the tirzepatide label.
Pancreatitis is another AR highlighted in the tirzepatide instructions, and if pancreatitis is suspected, the drug should be discontinued immediately. The reason for this warning is that pancreatitis has occurred in tirzepatide-treated patients in clinical trials. However, the results of a recent meta-analysis revealed no increased risk of developing pancreatitis with tirzepatide use compared with all control treatments (RR = 1.46, 95% CI 0.59 to 3.61, p = 0.436), which included basal insulin (glargine or degludec), selective GLP-1 RAs (dulaglutide or semaglutide), and placebo [33]. Another meta-analysis revealed that the risk of developing acute pancreatitis in the different dose groups of tirzepatide did not differ from that in the placebo group, but tirzepatide significantly increased blood lipid levels, especially in the 15 mg dose group [34]. Our study confirmed a correlation between tirzepatide use and the risk of developing pancreatitis (n = 65, ROR = 4.21) but was unable to differentiate the risk of developing pancreatitis associated with the use of tirzepatide vs. the use of other drugs. Considering that the data for the meta-analysis originated from clinical trials and that our study was based on real-world data, the two studies are complementary.
After searching, we retrieved three case reports documenting tirzepatide-induced acute kidney injury [35], diabetic ketoacidosis [36] and injection site reactions [37]. Acute kidney injury is an AE documented in the package insert, but our pharmacovigilance analysis revealed that it was not a positive signal, as the ROR value was less than 1. This discrepancy could be explained by the fact that acute kidney injury is fairly common for all drugs in the FAERS database. Diabetic ketoacidosis is not an AE documented in the tirzepatide label, and it is generally accepted that among glucose-lowering drugs, the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors is more likely to induce ketoacidosis [38]. Sharma reported diabetic ketoacidosis in a female patient with type 1 diabetes mellitus (T1DM) who used tirzepatide for weight loss [36]. Tirzepatide is not approved for the treatment of T1DM, so regardless of the therapeutic purpose, patients with T1DM should use tirzepatide with caution.
Notably, one study systematically evaluated the safety profile of semaglutide on the basis of the FAERS database [39]. The difference between semaglutide and tirzepatide is whether they act on GIP receptors; they are very important drugs in the fields of weight loss and diabetes and are often compared with each other. In a study by Du et al. [39], the unexpected AEs associated with semaglutide use were ketoacidosis, chronic cholecystitis, obstructive pancreatitis, allodynia, pancreatic enlargement, breath odour, chronic pancreatitis, and polycystic ovaries. In our study, ketoacidosis and polycystic ovaries were also among the unexpected AEs associated with tirzepatide use, but chronic cholecystitis, obstructive pancreatitis, allodynia, and chronic pancreatitis were among the expected AEs associated with tirzepatide use, whereas signals of pancreatic enlargement and breath odour were not detected. Considering the potential for new AEs due to GIP receptor stimulation, another study needs to be implemented to compare the differences in safety characteristics between tirzepatide and semaglutide use.
AEs associated with GLP-1 RA use generally occur early in treatment, peak within a week, and then gradually resolve. This was confirmed by our findings that the majority of AEs occurred within 7 days (n = 2,180, 49.82%) after exposure to tirzepatide. We observed that AEs still occurred after 223 days, so a longer follow-up period is needed to observe the AEs associated with tirzepatide use in future clinical studies.
While the results thus far are intriguing, they need to be interpreted with caution. First, unlike epidemiological studies, it is not possible to estimate the incidence of each AE associated with tirzepatide use in the real world because of the lack of a base population. Second, the FAERS is a self-reported database; most of the reporters in this study are consumers, and their judgements about the association of drugs with AEs may not be as accurate as those of healthcare professionals. Third, just over a year after tirzepatide has been introduced to the market, more AEs may not have been exposed yet. Furthermore, this study did not consider the effects of confounding factors (e.g., disease itself, comorbidities, dosages, and concomitant drugs consumed) on safety signals. Finally, importantly, the ROR method has low specificity and is prone to producing false positive signals, so it does not imply that there is an inevitable causal relationship between the use of certain drugs and the development of AEs [40]. Hence, more research is needed for future work. Despite these limitations, the FAERS is still very useful for postmarketing safety surveillance of tirzepatide use, and physicians and pharmacists need to be vigilant for those potential AEs.
In this study, we systematically quantified the safety profile of tirzepatide via the FAERS database. The frequent AEs (e.g., injection site pain, nausea, injection site haemorrhage, diarrhoea, vomiting) and additional observed AEs (e.g., incorrect dose administered, off-label use, extra dose administered, inappropriate schedule of product administration) need to be monitored. Comprehensive analyses indicate that there is misuse of tirzepatide, which requires vigilance on the part of manufacturers and healthcare professionals. We hope that in the future, more clinical practitioners will provide high-value evidence on the safety profile of tirzepatide.
This study was performed via the FDA Adverse Event Reporting System (FAERS) database, which was provided by the FDA. The information, results, or interpretation of the current study do not represent any opinion of the FDA.
The authors declare that this research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.
No external funding was provided for this study.
The datasets generated and analysed for this study are available from the corresponding author upon reasonable request.
