Abstract
Aim
Incretin therapies, including dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), are crucial for type 2 diabetes treatment. Evidence of their association with gallbladder, biliary diseases, and liver injury remains inconsistent. This study evaluated the association between incretin therapies and hepatobiliary adverse events using the FDA’s Adverse Event Reporting System (FAERS) data.
Methods
Case reports involving incretin therapies and hepatobiliary events from January 2006 to December 2023 were extracted from FAERS. The association between these agents and hepatobiliary adverse events (hAEs) was analyzed using reporting odds ratios and empirical Bayesian geometric means. Descriptive analyses were conducted to characterize the demographic and clinical features of the hAE cases. Additionally, subgroup analyses calculated reporting odds ratios to evaluate the strength of the association between specific incretin drugs and hAEs.
Results
Among 68,351 case reports associated with incretin-based therapies, 1327 (1.941%) involved hepatobiliary adverse events. DPP-4 inhibitors demonstrated statistically significant associations with multiple hepatobiliary events, like cholelithiasis, chronic cholecystitis, and biliary diseases. In contrast, GLP-1 receptor agonists showed weaker associations, primarily linked to gallbladder and biliary disease risks. Subgroup analyses revealed stronger positive correlations with hepatobiliary events for liraglutide and semaglutide among GLP-1 agonists, and for sitagliptin, linagliptin, and vildagliptin among DPP-4 inhibitors. The pooled reporting odds ratio of 2.85 indicated a positive correlation between these drugs and studied adverse events.
Conclusions
This study found statistically significant associations between DPP-4 inhibitors and hepatobiliary adverse events like cholelithiasis and cholecystitis. GLP-1 agonists showed weaker gallbladder/biliary disorder links but higher acute cholecystitis risk. Subgroup analyses revealed varying correlations among specific drugs, potentially dose-dependent. Further large-scale studies are needed to evaluate class effect differences and elucidate mechanisms for guiding clinical use.
Introduction
The Global Burden of Disease study estimated that in 2021, there were around 529 million individuals with diabetes worldwide. After age standardization, the global age-standardized diabetes prevalence was 6.1%, with type 2 diabetes accounting for approximately 96.0% (1). Incretin-based therapies, comprising dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists combination products, have become important antihyperglycemic agents for treating type 2 diabetes. These agents effectively control blood glucose by promoting insulin secretion, inhibiting gluconeogenesis, and delaying gastric emptying in patients with type 2 diabetes (2).
With the widespread use of incretin-based therapies in the treatment of type 2 diabetes (3), their potential adverse effects on the hepatobiliary system have garnered increasing attention. A series of meta-analyses have found that GLP-1RAs are associated with an increased risk of gallstone disease and cholecystitis, among other gallbladder or biliary tract diseases (4, 5, 6, 7), and multiple real-world studies have supported these findings (8, 9, 10, 11, 12). However, for the novel GIP/GLP-1 dual receptor agonist tirzepatide and the GLP-1RA exenatide, a meta-analysis for each has suggested no significant association with the risk of gallbladder diseases (13, 14). Regarding the association between DPP-4is and the risk of gallbladder or biliary tract diseases, existing evidence is inconsistent. While one meta-analysis suggested that DPP-4is might increase the risk of cholecystitis (15), its conclusion contradicted that of a large population-based cohort study (10). Simultaneously, some research findings based on large databases support the notion that DPP-4is increases the risk of cholecystitis (8, 11, 12). Apart from gallbladder or biliary tract diseases, the potential association between DPP-4is, GLP-1RAs, and liver injury has also attracted widespread attention. One population-based cohort study found that, compared with sodium-glucose cotransporter-2 inhibitors, DPP-4is was associated with a 53% increased risk of acute liver injury (16). However, another large population-based cohort study found no cases of hospitalized acute liver failure among saxagliptin users, suggesting no association with acute liver injury (17), a conclusion that contradicted a real-world study based on the FDA Adverse Event Reporting System (FAERS) (18).
In summary, existing research findings regarding the associations between DPP-4is, GLP-1RAs, and the risk of hepatobiliary diseases are inconsistent, while evidence on the risk associated with novel GIP/GLP-1 dual receptor agonists remains limited. Thus, this study evaluates post-marketing adverse event reports submitted to FAERS to examine the association between incretins and hepatobiliary adverse events, supplementing the epidemiologic literature.
Methods
Material and methods
FAERS is an open public database for collecting post-marketing adverse event reports associated with drugs and therapeutic biological products, which are voluntarily submitted by healthcare professionals, consumers, lawyers, and pharmaceutical manufacturers. The FAERS database comprises seven datasets: demographic information, drug information, adverse event information, indications, patient outcomes, drug therapy information, and the sources of adverse event reports. Each individual case safety report (ICSR) may contain one or more drugs or adverse events, with the adverse events and indications coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology at the Preferred Term (PT) level. The FAERS data is updated quarterly, and this study covered the period from January 2006 to December 2023. We utilized Microsoft SQL Server 2019 software to manage and analyze the data. Following the FDA’s recommendation, we used the unique case identifier ‘Primaryid’ to eliminate duplicates. This was necessary because quarterly updates may contain revised versions of previously submitted reports. In such cases, only the most recent version of each report was retained (19). As this study analyzed a third-party anonymous public database approved by the Institutional Review Board (IRB), IRB approval was exempted. This report adheres to the guidelines for case series reporting.
Eligibility criteria
For the current study, we included adverse event reports that met the following criteria: (1) the indications contained PTs from the MedDRA 26.1 Standardized MedDRA Query ‘Hyperglycaemia/new onset diabetes mellitus’ narrow search; (2) the indications did not include any PTs under the System Organ Class (SOC) ‘Hepatobiliary disorders’; (3) however, the adverse events included one or more PTs under the SOC ‘Hepatobiliary disorders’; (4) the cases involved the use of either DPP-4is (including sitagliptin, vildagliptin, alogliptin, saxagliptin, and linagliptin) or GLP-1RAs (including exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide, semaglutide, and tirzepatide) as single agents, or a combination of the aforementioned GLP-1RAs and DPP-4is. Since tirzepatide activates both GLP-1 and GIP receptors, for simplicity, it was included in the GLP-1RA category for subsequent analyses in this study. As a comparator group, reports involving other antidiabetic drugs, which did not include incretin-based therapies, were used to contextualize the findings related to hepatobiliary adverse events.
Statistical analysis
Data mining (disproportionality analyses)
We calculated the reporting odds ratio (ROR) and 95% CI, as well as the empirical Bayesian geometric mean (EBGM) and its 95% CI (EB05, EB95) to evaluate the disproportionality of hepatobiliary adverse event reports associated with incretin-based therapies compared to other antidiabetic drugs within the same study scope (20). An EB05 ≥ 2.0 is a threshold commonly used by the US FDA to identify potential safety signals, suggesting that the reporting rate for the specific drug-event combination is at least twice as high as expected if they were independent (21). In this study, we adopted EB05 ≥ 2.0 and the lower limit of the ROR 95% CI (ROR_L0.05) > 1 as the criteria to define adverse events with hepatobiliary disorders highly related to incretin treatment (hAEs). Subsequent analyses focused on these hAEs. After identifying the hAEs, we recalculated the ROR and 95% CI for all these hAEs to compare the strength of the association between each drug and these hAEs, reflecting their relative risks of developing hAEs in comparison to the non-incretin-based antidiabetic drugs. For the ICSRs of these hAEs, the onset time was calculated by subtracting the therapy start time from the event onset time. All the aforementioned statistical analyses were performed using R software (version 4.2.1).
Descriptive analyses
We performed descriptive statistical analyses on all ICSRs associated with incretin-based therapies collected from 2006 to 2023, stratified by reporting year and specific drug product. The total number and annual distribution were calculated. For the case reports of hAEs, we further analyzed the patients’ baseline demographics and characteristics, including age, gender, reporting country, treatment strategy, report type, outcome, treatment duration, onset time, and case priority. Concurrently, frequency analyses were conducted for each specific hAE, calculating its incidence rate and proportion among the total hAE reports. Additionally, following the hierarchical terminology system of the MedDRA, the hAEs were categorized and analyzed across four levels: System Organ Class (SOC), High-Level Group Term (HLGT), High-Level Term (HLT), and Preferred Term (PT), aiming to explore the distribution characteristics of specific hAE types.
Results
During the period from 2006 to 2023, we identified 68,351 ICSRs associated with the use of incretin-based therapies, either as monotherapy or in combination therapy, from a total of 611,644 diabetes-related ICSRs. Among these, 1327 reports (1.941%) involved hepatobiliary adverse events (Fig. 1). The overall number of reports increased annually, peaking at 11,000 in 2023. However, the proportion of reports involving hepatobiliary adverse events reached a maximum of 5.36% in 2015 and subsequently declined. Despite the continuous rise in the total report count, the relative incidence of hepatobiliary adverse events did not exhibit a sustained upward trend.
Annual individual case safety reports and hepatobiliary adverse event profiles.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0404
Among the total of 68,351 individual case safety reports associated with incretin-based therapies, 54,953 (80.39%) were related to GLP-1RAs, and 12,694 (18.57%) were associated with DPP-4is (Fig. 2). The remaining 704 reports (1.030%) involved concomitant use of both incretin-based therapies. Of the 54,953 reports related to GLP-1RAs, 669 (1.217%) involved hepatobiliary adverse events. In contrast, among the 12,694 reports associated with DPP-4is, 572 (4.506%) involved hepatobiliary adverse events, a significantly higher proportion compared to GLP-1RAs.
Profile of hepatobiliary adverse event reports associated with incretin-based therapies formulations.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0404
The heatmap displays all potential adverse events from all groups with a lower limit of the 95% CI for ROR greater than 1, along with the EB05 values and reported case numbers (Fig. 3). As evident from the figure, DPP-4is detected the highest number of statistically significant adverse events, with 26 events simultaneously satisfying the criteria of a lower limit of the 95% CI for ROR greater than 1 and an EB05 value greater than or equal to 2. These adverse events encompassed some well-known hepatobiliary events, such as hepatitis, cholelithiasis, cholecystitis chronic, bile duct stone, bile duct cancer, and cholangiocarcinoma, with cholelithiasis being the most frequently reported event. Additionally, some previously underappreciated adverse events were identified, such as cholangitis, jaundice cholestatic, liver abscess, and hepatic cirrhosis. In contrast, the GLP-1R group did not exhibit signals for highly associated hepatobiliary diseases. However, when GLP-1R agonists were used in combination with DPP-4is, the risk signals for metastatic liver cancer, bile duct cancer, portal hypertension, and portal vein thrombosis were enhanced.
Risk association analysis of different incretin-based therapies with hepatobiliary adverse events.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0404
The baseline characteristics of hAEs patients are shown in Table 1, with a total of 921 cases included in the analysis. Among them, there were 442 cases (47.99%) in the DPP-4i group, 399 cases (43.32%) in the GLP-1R agonist group, and 80 cases (8.69%) in the combination therapy group. The age and gender distribution between the fatal and non-fatal groups was generally balanced, with the primary reporting country being the United States (72.31%).
Basic characteristics of hepatobiliary disease adverse event cases highly relevant to incretin therapy. Statistical tests were not performed on these data due to the limitations of spontaneous reporting systems and to avoid potentially misleading interpretations.
| Clinical characteristics | Total (n = 921) | Fatal (n = 127) | Non-fatal (n = 794) |
|---|---|---|---|
| Age (years) | |||
| <45 | 38 (4.13%) | 0 (0.00%) | 38 (4.79%) |
| 45-64 | 185 (20.09%) | 10 (7.87%) | 175 (22.04%) |
| ≥65 | 223 (24.21%) | 19 (14.96%) | 204 (25.69%) |
| Unknown | 475 (51.57%) | 98 (77.17%) | 377 (47.48%) |
| Gender | |||
| Female | 440 (44.77%) | 52 (40.94%) | 388 (48.87%) |
| Male | 454 (49.29%) | 75 (59.06%) | 379 (47.73%) |
| Unknown | 27 (2.93%) | 0 (0.00%) | 27 (3.40%) |
| Reporing country | |||
| US | 666 (72.31%) | 111 (87.40%) | 555 (69.90%) |
| JP | 45 (4.89%) | 2 (1.57%) | 43 (5.42%) |
| Other country | 201 (21.82%) | 14 (11.02%) | 187 (23.55%) |
| Country not specified | 9 (0.98%) | 0 (0.00%) | 9 (1.13%) |
| Treatment strategy | |||
| DPP-4i | 442 (47.99%) | 86 (67.72%) | 356 (44.84%) |
| Sitagliptin | 374 (40.61%) | 81 (63.78%) | 293 (36.90%) |
| Linagliptin | 31 (3.37%) | 1 (0.79%) | 30 (3.78%) |
| Saxagliptin | 16 (1.74%) | 3 (2.36%) | 13 (1.64%) |
| Vildagliptin | 14 (1.52%) | 1 (0.79%) | 13 (1.64%) |
| Alogliptin | 7 (0.76%) | 0 (0.00%) | 7 (0.88%) |
| GLP-1RA | 399 (43.32%) | 17 (13.39%) | 382 (48.11%) |
| Liralutide | 122 (13.25%) | 4 (3.15%) | 118 (14.86) |
| Semaglutide | 93 (10.10%) | 2 (1.57%) | 91 (11.46%) |
| Exenatide | 79 (8.58%) | 6 (4.72%) | 73 (9.19%) |
| Dulaglutide | 68 (7.38%) | 3 (2.36%) | 65 (8.19%) |
| Tirzepatide | 28 (3.04%) | 0 (0.00%) | 28 (3.53%) |
| Albiglutide | 6 (0.65%) | 1 (0.79%) | 5 (0.63%) |
| Lixisenatide | 3 (0.33%) | 1 (0.79%) | 2 (0.25%) |
| Combination | 80 (8.69%) | 24 (18.90%) | 56 (7.05%) |
| Exenatide + sitagliptin | 54 (5.86%) | 19 (14.96%) | 35 (4.41%) |
| Liraglutide + sitagliptin | 22 (2.39%) | 5 (3.94%) | 17 (2.14%) |
| Dulaglutide + sitagliptin | 1 (0.11%) | 0 (0.00%) | 1 (0.13%) |
| Other combination groups | 3 (0.33%) | 0 (0.00%) | 3 (0.38%) |
| Type of reporter | |||
| Health professional | 448 (48.64%) | 46 (36.22%) | 402 (50.63%) |
| Non-health professional | 456 (49.51%) | 76 (59.84%) | 380 (47.86%) |
| Unknown | 17 (1.85%) | 5 (3.94%) | 12 (1.51%) |
| Outcome | |||
| Death | 127 (13.79%) | 127 (100%) | 0 (0.00%) |
| Life threatning | 34 (3.69%) | 0 (0.00%) | 34 (4.28%) |
| Required intervention | 3 (0.33%) | 0 (0.00%) | 3 (0.83%) |
| Disabled | 20 (2.17%) | 0 (0.00%) | 20 (2.52%) |
| Hospitalizations | 337 (36.59%) | 0 (0.00%) | 337 (42.44%) |
| Congential anomaly | 1 (0.11%) | 0 (0.00%) | 1 (0.13%) |
| Other serious | 333 (36.16%) | 0 (0.00%) | 333 (41.94%) |
| Non-serious | 66 (7.17%) | 0 (0.00%) | 66 (8.31%) |
| Treatmen duration | |||
| ≤26 week | 173 (18.78%) | 19 (14.96%) | 154 (19.40%) |
| >26 week | 311 (33.77%) | 83 (65.35%) | 228 (28.72%) |
| Unknown | 437 (47.45) | 25 (19.69%) | 412 (51.89%) |
Figure 4 shows the four levels of SOC, HLGT, HLT, and PT corresponding to the 26 hAEs. In addition to hepatobiliary disorders, the main SOC involved in these PTs also includes neoplasms benign, malignant, and unspecified (including cysts and polyps), infections and infestations, gastrointestinal disorders, and metabolism and nutrition disorders.
Hierarchical relationship diagram of adverse events with hepatobiliary disorders highly related to incretin treatment.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0404
Among the GLP-1RAs, liraglutide and semaglutide exhibited higher RORs of 1.72 (95% CI: 1.44–2.06) and 1.90 (95% CI: 1.56–2.33), respectively, suggesting a positive association with the studied event (Fig. 5). In contrast, albiglutide showed a lower ROR of 0.27 (95% CI: 0.13–0.57). For the DPP-4is, sitagliptin, linagliptin, and vildagliptin had RORs of 11.58 (95% CI: 10.45–12.84), 4.16 (95% CI: 2.92–5.92), and 3.95 (95% CI: 2.36–6.59), respectively, indicating a significant association with the studied event. Saxagliptin and alogliptin exhibited RORs of 5.47 (95% CI: 3.33–8.98) and 8.01 (95% CI: 3.79–16.93), respectively, but their CIs were wider, suggesting a less definitive association than the previous three agents. For the three combination therapy regimens, their RORs were all much greater than one, but they also suffered from the issue of relatively wide CIs. Overall, the pooled ROR for all drugs was 2.85 (95% CI: 2.64–3.07), indicating a positive correlation between the use of these drugs and the studied adverse event.
Forest plot analysis of the risk association between different incretin therapies and adverse events with hepatobiliary disorders highly related to incretin treatment.
Citation: Endocrine Connections 13, 12; 10.1530/EC-24-0404
Discussion
This is the first study to systematically evaluate the association between DPP-4is, GLP-1RAs, and hAEs using data from the FAERS. Through analysis of a large FAERS sample, this study provides new evidence-based findings in this field. Annual safety reports showed that in 2015, the proportion of reports involving hAEs peaked at 5.35%. Analysis of 310 relevant cases from 2015 revealed that 68.7% of hAE reports were associated with sitagliptin monotherapy, potentially due to a surge in its use following the positive trial evaluating cardiovascular outcomes with sitagliptin trial results and subsequent prescriber preference (22, 23). Although the overall number of adverse event reports was lower for DPP-4is (18.57%) compared to GLP-1RAs (80.39%), the proportion involving hAEs was significantly higher with DPP-4is (4.506%) versus GLP-1 agonists (1.217%). This finding raised concerns about a link between DPP-4is and hAEs, further supported by DPP-4i cases comprising 62.6% of the hAE baseline data.
Calculating RORs and EBGM values revealed statistically significant associations between DPP-4is and multiple hAEs, including cholelithiasis, chronic cholecystitis, biliary disease, and hepatic cirrhosis. In contrast, GLP-1RAs showed weaker risk signals for cholecystitis, cholelithiasis, cholangitis, and bile duct stone, with no hepatic disease signals identified, although their acute cholecystitis risk signal exceeded that of DPP-4is. Cholelithiasis was among the most frequently reported adverse events for both drug classes. For example, in one RCT of liraglutide, the occurrence of cholelithiasis was 0.8% (event rate 0.9 per 100 patient-years) in the liraglutide group compared to 0.4% (event rate 0.5 per 100 patient-years) in the placebo group. The same trial reported an incidence of acute cholecystitis of 0.5% in the liraglutide group compared to 0.1% in the placebo group, and cholecystitis in 0.2% of liraglutide-treated patients, with no cases in the placebo group (24). Another RCT found similar cholelithiasis rates (1%) in both liraglutide and placebo groups, with an event rate of 0.7 versus 0.4 per 100 patient-years, respectively, while acute cholecystitis occurred in 1% of liraglutide patients (event rate of 0.3 per 100 patient-years) compared to less than 0.1% in the placebo group (25). While DPP-4is like sitagliptin, saxagliptin, and vildagliptin have been previously linked to hepatic injury (18), with mechanisms involving potential impacts on CD26/DPPIV activity in hepatocytes, no significant DPP-4i-hepatic injury signals emerged in this analysis (26, 27). Meantime, RCTs of alogliptin and saxagliptin showed no significant differences in hepatic abnormalities between the treatment and placebo groups, supporting a lower liver-related risk profile for DPP-4is. For instance, the proportion of patients with serum aminotransferase values three times the upper limit of normal was similar in both alogliptin and placebo groups, and the same was true in a saxagliptin trial (28, 29). Nevertheless, signals for hepatic disorders and jaundice were detected in the current analysis, warranting further population studies to assess potential class effects. Additionally, DPP-4is showed some association with increased cholangiocarcinoma and bile duct neoplasm risk, unlike GLP-1RAs, contrasting with findings by Devin Abrahami et al. who reported increased cholangiocarcinoma risk with both DPP-4is (HR: 1.77, 95% CI: 1.04–3.01) and GLP-1 agonists (HR: 1.97, 95% CI: 0.83–4.66) (8), potentially attributable to differences in study populations, sample sizes, follow-up durations, and risk assessment methods. It should be noted that diabetes itself is a risk factor for intrahepatic cholangiocarcinoma, with a 3.6-fold increased incidence reported in diabetic patients (30), necessitating consideration of the underlying disease when evaluating risks associated with these antidiabetic therapies. Combination use may also increase the risk of serious adverse events like metastatic liver cancer, cholangiocarcinoma, and portal vein thrombosis.
Subgroup analyses revealed that among GLP-1RAs, liraglutide and semaglutide showed stronger positive correlations with hAEs, possibly related to their higher approved dosages for weight loss indications, which may increase risks of gallbladder and biliary diseases, with rapid weight loss itself being a potential mechanism for increased cholelithiasis risk (31, 32). In contrast, the correlation was weaker for albiglutide. Among DPP-4is, sitagliptin, linagliptin, and vildagliptin demonstrated significant positive correlations, suggesting close associations with hAEs, while saxagliptin and alogliptin showed less pronounced correlations.
In summary, current research indicates that DPP-4is are associated with certain hAEs such as cholangiocarcinoma and hepatic disorders, while GLP-1RA are primarily linked to increased risks of gallbladder and biliary diseases. The mechanisms underlying GLP-1RA-induced gallbladder and biliary adverse events have been relatively well studied, but research on DPP-4is in this regard is lacking. This disparity in research focus may be influenced by various factors, including differences in perceived risk profiles, market presence, or reporting patterns between these drug classes across different regions. Additionally, some studies suggest no increased risk with DPP-4is, potentially further reducing vigilance. Proposed mechanisms for the increased gallbladder and biliary disease risk with GLP-1RAs include: i) stimulating biliary epithelial cell proliferation and activity (33, 34); ii) inhibiting cholecystokinin secretion and impairing gallbladder emptying (35, 36, 37); iii) prolonging gallbladder refilling time; iv) rapid weight loss increasing cholelithiasis risk (31, 32). DPP-4is may affect gallbladder motility and contractility by modulating glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide levels. Other studies show that while not impacting gallbladder emptying (15), DPP-4is alter bile acid levels and composition, with bile acids able to inhibit gallbladder contraction via receptor activation and feedback mechanisms involved in postprandial gallbladder relaxation (38, 39).
This study has some limitations. Firstly, as a spontaneous reporting system, FAERS data collection is often incomplete, lacking denominators for the total drug-exposed population. Although this study attempted to use indications of interest as background data to exclude potential confounding factors, this method is still imperfect. Secondly, due to extensive missing dosage data, accurate dose-time-response relationship models could not be established. Thirdly, while obesity increases cholelithiasis risk, FAERS only contains weight data without height information, precluding BMI calculations to assess the impact of obesity on outcomes, which may introduce indication bias. Similarly, liver disease itself may be an indication for GLP-1RAs. Although we excluded indications under the System Organ Class (SOC) ‘Hepatobiliary disorders’ in our inclusion criteria, we cannot completely rule out the possibility that liver disease might still be an underlying reason for prescribing these medications in some cases. Furthermore, limited concomitant medication data may introduce substantial error.
Conclusion
This study represents the first systematic evaluation of hepatobiliary adverse events (hAEs) associated with dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) using FDA’s Adverse Event Reporting System data. The analysis revealed statistically significant associations between DPP-4is and hAEs like cholelithiasis, cholecystitis, biliary disease, and hepatic cirrhosis. GLP-1RAs exhibited weaker signals for gallbladder/biliary disorders but a higher acute cholecystitis risk than DPP-4is. Notably, subgroup analyses indicated varying hAE correlations among specific drugs, potentially dose-dependent. Despite limitations, this study provides novel evidence on hepatobiliary risks with these antidiabetic therapies, highlighting the need for well-designed population studies to clarify potential class effects, dose responses, and underlying mechanisms. Therefore, further large-scale, prospective population studies are needed to comprehensively evaluate the hepatobiliary safety profiles of these two novel antidiabetic drug classes. Elucidating whether there are class effect differences between them, as well as potential mechanisms of action, is crucial for guiding rational clinical use.
Declaration of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Funding
This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Availability of data and materials
The datasets analyzed during the current study are available from the FDA Adverse Event Reporting System (FAERS, FAERS Quarterly Data Extract Files (fda.gov)), which is a publicly available repository. The specific data extracts used in this analysis are available from the corresponding author upon reasonable request.
Acknowledgements
We thank the study participants for their invaluable contributions to this study.
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