Dipeptidyl peptidase 4 (DPP-4) inhibitors are widely used for patients with type 2 diabetes due to their favorable therapeutic profile and low risk of hypoglycemia. Glucagon-like peptide 1 (GLP-1) receptor agonists were reported to be associated with increased risk of gallbladder or biliary diseases, which might be attributable to the effects of GLP-1 (1). DPP-4 inhibitors are known to increase the levels of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). However, the association between gallbladder- or biliary-related events and DPP-4 inhibitors remains unclear.
We did a pharmacovigilance study in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, a large pharmacovigilance database of spontaneous reports of adverse events in real-world settings. Cases of gallbladder- or biliary-related events with DPP-4 inhibitors were identified from the first quarter of 2013 to the fourth quarter of 2021. Gallbladder- or biliary-related events were identified using preferred terms according to MedDRA version 22.0. Duplicate reporting was determined based on the similarity of the patient, adverse event, and reported drug information in the reports. Disproportionality analysis was used to detect the signals according to proportional reporting ratios and 95% CI. Other noninsulin and nonincretin antidiabetes drugs were used as controls. Sensitivity analysis was conducted by including only sodium-glucose cotransporter 2 (SGLT2) inhibitors as controls. We also analyzed the reports of GLP-1 receptor agonists with similar methods. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC) and R 4.2.0.
Among the about 11 million adverse event cases available in the FAERS database, 163,454 were related to noninsulin and nonincretin glucose-lowering drugs and 24,601 were related to DPP-4 inhibitors. We identified 520 cases of gallbladder or biliary diseases that listed DPP-4 inhibitors as “primary suspect” drugs, and 56.7% were men. The median age of patients was 69.5 years (interquartile range [IQR] 61.0–79.0), and the median weight was 87.1 kg (IQR 72.1–103.4). Among the 520 cases identified, 351 had at least one serious outcome and 173 reported the death. Most cases of gallbladder- or biliary-related events with DPP-4 inhibitors involved sitagliptin (416 [80%]), while 59 (11%) involved linagliptin, 24 (5%) involved saxagliptin, 17 (3%) involved alogliptin, and 4 (1%) involved vildagliptin. Sitagliptin accounted for 62% (15,207 of 24,601) of all adverse event cases with DPP-4 inhibitors.
In disproportionality analyses, excessive reporting of gallbladder or biliary diseases was found for DPP-4 inhibitors compared with other noninsulin and nonincretin antidiabetes drugs (Fig. 1A), with a proportional reporting ratio of 10.57 (9.21–12.13) for gallbladder or biliary diseases as a whole, 15.88 (12.17–20.71) for cholecystitis, 9.89 (7.47–13.07) for cholelithiasis, and 11.19 (9.16–13.67) for biliary diseases. Sensitivity analyses by including only SGLT2 inhibitors as the control groups (data not shown) showed consistent results. The excessive reporting of gallbladder- or biliary-related events was also observed for GLP-1 receptor agonists compared with other noninsulin and nonincretin antidiabetes drugs (Fig. 1B).
A post hoc subgroup analysis was conducted to consider sitagliptin and other DPP-4 inhibitors separately (Fig. 1A). A high probability of reporting gallbladder- or biliary-related events was observed for both groups of sitagliptin and other DPP-4 inhibitors, regardless of the subcategory of gallbladder- or biliary-related events (data not shown).
Our study revealed increased reporting of gallbladder- or biliary-related events with DPP-4 inhibitors compared with other noninsulin and nonincretin antidiabetes drugs through a large-scale pharmacovigilance analysis, which also showed excessive reporting of gallbladder or biliary diseases with GLP-1 receptor agonists. The potential mechanisms are that GLP-1 inhibits gallbladder motility and delays gallbladder emptying by suppressing the secretion of cholecystokinin (1) and that GIP impacts gallbladder relaxation (2). However, further studies are required to explore the possible mechanisms.
An earlier retrospective study reported no association between DPP-4 inhibitors and gallbladder or biliary diseases, but gallbladder or biliary diseases were not systematically collected in that study (3). The reporting of gallbladder- or biliary-related events in pivotal randomized controlled trials on DPP-4 inhibitors has been inconsistent (4,5), which might result from the reporting bias. As these events were not predefined safety outcomes, there might be underreporting in trials. A recent meta-analysis of randomized controlled trials found increased cholecystitis risks associated with DPP-4 inhibitors (2). Our study might complement the findings from clinical trials using real-world data.
Nevertheless, the inherent limitations of disproportional analysis with FAERS data could not be ignored; these mainly included possible underreporting or overreporting of events, inability to establish the incidence of events, selective reporting bias, temporal reporting bias toward newer medications, and incapability to establish causality.
Conclusively, we observed consistent signals of gallbladder- or biliary-related events associated with DPP-4 inhibitors with real-world data. Clinicians should be aware of these in clinical practice and are encouraged to monitor and report gallbladder- or biliary-related events through appropriate channels.
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Acknowledgments. The authors thank the staff of the Peking Union Medical College Hospital and all who actively participated and provided statistical support in the study.
Funding. The current work was partially supported by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-015), the Beijing Municipal Natural Science Foundation (no. M22014), the CAMS Innovation Fund for Medical Sciences (no. 2021-1-I2M-002), and the National Natural Science Foundation of China (no. 91846106). H.Z. received all funding. Y.L. also received financial support from the CAMS Innovation Fund for Medical Sciences (2021-1-I2M-002).
The funding sources had no direct impact on the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. L.H. and H.Z. were responsible for the conception and design of the study. L.H., J.W., and H.Z. acquired the data from the FAERS database and did all statistical analyses. J.W. and Z.L. were involved in data review and interpretation. L.H. and H.Z. wrote the first draft of the manuscript. L.H., Y.L., and H.Z. contributed to the discussion and revision of the intellectual content. All authors participated in the final approval of the manuscript and agreed to be accountable for all aspects of the work. H.Z. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
