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The real-world safety profile of empagliflozin: a disproportionality analysis based on the FDA Adverse Event Reporting System (FAERS) database

BMC Pharmacology and Toxicology volume 26, Article number: 28 (2025) Cite this article

Abstract

Objective

This study aimed to investigate the entire adverse events (AEs) spectrum and to identify some new or rare AEs associated with empagliflozin based on the FAERS database.

Methods

A retrospective analysis was conducted on AE reports extracted from the FAERS, spanning from the first quarter of 2004 to that of 2023. Disproportionality analysis methods, including the ROR, PRR, BCPNN, and MGPS, were employed to quantify signals of AEs associated with empagliflozin. Additionally, demographic characteristics and time to onset were further elucidated.

Results

The results showed a total of 20,734 AE reports related to empagliflozin, identifying 322 significant preferred terms (PTs) covering 27 System Organ Classes (SOCs). Empagliflozin was significantly associated with pre-specified AEs compared to other novel antidiabetic medications. Beyond common AEs, unexpected significant AEs such as pancreatitis, gastroenteritis, cerebral infarction, and cardiac operations were identified. The median onset time for empagliflozin-related AEs was 28 days (interquartile range (IQR) 4–154 days), with the majority of AE cases (n = 2,112, 10.19%) occurring within the first month following initiation of empagliflozin therapy.

Conclusion

The clinically observed AEs, along with potential new AE signals associated with empagliflozin were identified based on the FAERS database, which could provide valuable evidence for clinical monitoring, risk identification, and further safety studies of identification.

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Introduction

Type 2 diabetes mellitus (T2DM) is the most common form of diabetes, and its incidence and prevalence are rising globally [1, 2]. Oral agents are currently the mainstay of pharmacological treatment for T2DM and are most readily accepted by patients. Sodium-dependent glucose transporters 2 inhibitors (SGLT-2i) are a relatively new class of hypoglycemia agents in the clinic. It can lower blood glucose levels by inhibiting glucose reabsorption in the kidney and increasing urinary glucose excretion [3, 4]. Empagliflozin, as one of the representative SGLT-2i, not only improves glycemic control of T2DM, but also has cardiovascular and renal protective effects, leading to a significant increase in clinical usage [5,6,7]. Therefore, the potential adverse events (AEs) induced by empagliflozin are increasingly highlighted.

Previous safety and pharmacovigilance studies have revealed the association between SGLT-2i and some particular AEs. For example, Zhichao He et al. reviewed the safety of SGLT-2i and investigated the most common AEs including euglycemic diabetic ketoacidosis (EDKA) and diabetic ketoacidosis (DKA) [8]. Chen Gang et al. compared acute kidney injury events in the real-world practice of various SGLT-2i among diabetic cases [9]. Gian Paolo Fadini et al. reported SGLT-2i may predispose to Fournier’s gangrene (FG) and other severe genital AEs [10]. However, these previous studies mainly focused on some common AEs of SGLT-2i [11], without fully investigating the entire spectrum of AEs and exploring new or rare AE for empagliflozin. Therefore systematic research on the overall safety profile of empagliflozin-related AEs based on real world and large international databases is still lacking.

Spontaneous reporting systems are an important source for monitoring adverse drug reactions [12], and the publicly available US Food and Drug Administration (FDA) adverse event reporting system (FAERS) is one of the key databases. FAERS contains a large repository of drug-associated adverse events reported by healthcare professionals, drug manufacturers, and patients from various countries [13]. It has been widely used to identify AE risk signals [14]. Moreover, previously unknown potential drug-AE associations and well-established clinical associations can be identified by mining the FAERS database [15].

In this study, we conducted a post-marketing surveillance to investigate AEs associated with empagliflozin in the FAERS database from the first quarter of 2004 to that of 2023. The demographic characteristics and time to onset of adverse event reports related to empagliflozin were elucidated. Furthermore, we comprehensively assessed the adverse event data of empagliflozin using the disproportionality analysis with various signal quantification methodologies from diverse perspectives, which could aid in identifying emerging safety concerns, so as to provide safety reference for its rational use in clinic. And we provided a comparison with other diabetes medications which would offer more relevant insights into empagliflozin’s safety profile.

Methods

Data sources and procedures

The FAERS data were downloaded from the FAERS Quarterly Data Extract Files, available at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. The data files contain seven datasets, including demographic and administrative information (DEMO), drug information (DRUG), adverse drug reaction information (REAC), patient outcome information (OUTC), information on report sources (RPSR), therapy start dates, and end dates for reported drugs (THER), and indications for drug administration (INDI). These files were interconnected in the FAERS architecture through specific identification numbers such as PRIMARYID.

We chose the latest FDA_DT with the same CASEID or selected the higher PRIMARYID when the CASEID and FDA_DT were the same to identify and remove duplicate reports [16]. In this study, we extracted all adverse event reports in FAERS ranging from the first quarter of 2004 (Q1 2004) to the first quarter of 2023 (Q1 2023) using the generic name “Empagliflozin” and trade name “Jardiance” as the primary suspected (PS) drugs.

AEs in FAERS are coded using the Preferred Term (PT) from the standardized Medical Dictionary for Regulatory Activities 26.0 (MedDRA26.0). The hierarchical structure of MedDRA allows for PT to be categorized into the relevant System Organ Class (SOC), which is the highest level of MedDRA.

Subsequently, the clinical characteristics of reports were described in detail, including gender, age, weight, reported countries, outcomes and occupation of reporters, etc. It is worth noting that the serious outcomes were defined as hospitalization-initial or prolonged (HO), life-threatening (LT), death (DE), disability (DS), required intervention to prevent permanent impairment/damage (RI) and other serious outcomes (OT). Additionally, the time to onset of AEs induced by empagliflozin was also assessed, calculated as the interval between the time of empagliflozin dosage initial (START_DT) and the time of AE onset (EVENT_DT). Reports with dates missing or incorrect were excluded. The flow diagram of our study is shown in Fig. 1.

Fig. 1
figure 1

The flow diagram of empagliflozin-related adverse events from the FAERS database

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Statistical analysis

Disproportionality analysis is an instrumental method for identifying and detecting drug-related adverse reaction signals in pharmacovigilance studies [17]. In this study, to improve the results’ reliability, the reporting odds ratios (ROR) [18], proportional reporting ratios (PRR) [19], Bayesian confidence propagation neural network (BCPNN) [20], and multi-item gamma Poisson shrinker (MGPS) [21] techniques from the disproportionality methods were used simultaneously to detect drug-related AE signals. The joint use of multiple algorithms allows for cross-validation to reduce false positives, and through the adjustment of thresholds and variance, it can detect more potential rare adverse reactions [22]. Four algorithms were based on 2 × 2 contingency tables (Table 1). Specific equations and criteria are shown in Table 2. In this study, the identification of AE signals required meeting the criteria stipulated by all four algorithms simultaneously. In addition, A disproportionality analysis of empagliflozin-related AEs as compared to other classes of antidiabetic drugs (other sodium-dependent glucose transporters-2 inhibitors except for empagliflozin (O-SGLT-2i), dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA)) from the full database was also provided. All data processing and statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, United States), Microsoft EXCEL 2016 and GraphPad Prism 8.0 (GraphPad Software, CA, United States).

Table 1 A 2 × 2 contingency table for disproportionality analysis
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Table 2 Four algorithms used to assess potential associations between empagliflozin and adverse events
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Results

Descriptive analysis

From January 2004 to January 2023, there were 19,494,698 reports in the FAERS database. As shown in Fig. 1, after the deduplication, culminating in the extraction of 16,549,987 AE reports. Of these, 20,734 AE reports were found to be related to empagliflozin. And there were 43,630 empagliflozin-related PTs (drug-event pairs).

The demographical characteristics are described in Table 3. The disparity between males and females was minimal (47.0% vs. 41.7%). Regarding age, a large amount of data (96.8%) did not provide age information, which limited our in-depth understanding of the association between age and AEs. In reports with clear age data, the elderly individuals (aged > 65 years) group was the most common. Analogously, a proportion of the data (80.6%) lacked weight-related information. The reported proportions of body weight in the categories of < 80 kg, 80–100 kg and > 100 kg were 7.2%, 6.3% and 5.8%, respectively. Notably, The number of reported AEs had gradually increased from 2014 to 2019, and then gradually leveled off in 2020 and 2021. Furthermore, more than half of the reports (59.3%) were submitted by health professionals. Most of the AEs were reported from the United States (62.9%), followed by the United Kingdom (5.1%), Germany (5.0%), Japan (3.9%), Canada (3.6%). In terms of clinical outcomes, apart from other serious medical events (34.4%), those leading to hospitalization or prolongation of hospitalization were most frequent (31.9%), followed by life-threatening (7.1%), death (2.8%), disability (2.0%) and required intervention (0.4%), respectively.

Signals detection at the system organ class level

The signal reports for empagliflozin at the SOC level are presented in Table 4. Statistically, empagliflozin-associated AEs occurrence targeted 27 organ systems. The SOCs that met all four criteria simultaneously and showed significant association with empagliflozin AEs were “metabolism and nutrition disorders (SOC code: 10027433, 7,250 reports)”, “renal and urinary disorders (SOC code: 10038359, 2,850 reports)”. Additionally, the SOCs of “infections and infestations (SOC code: 10021881, 5,603 reports)” and “reproductive system and breast disorders (SOC code: 10038604, 1,060 reports)” were met two criteria of PRR and EBGM methods while not ROR and IC methods, suggesting these signals might also be important and frequent.

Signals detection at the preferred term level

A total of 322 significant PTs of interest conforming to all of the four algorithms simultaneously were described in Table S1. We then ranked all the significant PTs with AEs case number exceeding 40 (n > 40) according to the value of ROR from largest to smallest, and selected a total of 40 PTs that met the screening criteria. Additionally, these data were grouped by SOC and the whole results are presented in Table 5. In this study, some PTs including diabetic ketoacidosis (PT code:10012671), euglycaemic diabetic ketoacidosis (PT code:10080061), urosepsis (PT code:10048709), gangrene (PT code:10017711), pyelonephritis (PT code:10037596), urinary tract infection (PT code:10046571), Fournier’s gangrene (PT code:10017068), genital infection fungal (PT code:10061180), necrotising fasciitis (PT code:10028885), vulvovaginal mycotic infection (PT code:10064899), polydipsia (PT code:10036067), polyuria (PT code:10036142), nocturia (PT code:10029446), toe amputation (PT code:10043913), balanoposthitis (PT code:10004078) complied with warnings in instructions and drug labels. Notably, there were unexpected significant AEs that are not listed in the drug label also identified, such as cardiac operation (PT code:10061026), altered state of consciousness (PT code:10001854), cerebral infarction (PT code:10008118), gastroenteritis (PT code:10017888), pancreatitis (PT code:10033645) and pancreatitis acute (PT code:10033647). This suggested that the occurrence of these AEs and empagliflozin administration were also closely related and deserved clinical attention, especially pancreatitis, a total of 213 cases were reported and the signal value intensity was high. In addition, compared to the DPP-4i or GLP−1 RA, empagliflozin was significantly associated with the following pre-specified AEs: Euglycaemic diabetic ketoacidosis, Diabetic ketoacidosis, Fournier’s gangrene, Fungal infection, Urinary tract infection, Dehydration, Toe amputation, Pollakiuria, and Pyelonephritis (Table S2).

Onset time of events

The onset times of empagliflozin-associated AEs were collected from the database. Excluding unreported or unknown onset time reports, a total of 4,112 AE cases reported onset time, and the median onset time was 28 days (interquartile range (IQR) 4-154 days). As shown in Fig. 2, the results indicated that most of the AE cases occurred within the first 1 (n = 2,112, 51.36%), 2 (n = 374, 9.10%) and 3 months (n = 244, 5.93%) after empagliflozin initiation. It was also worth noting that AEs were still likely to occur after 1 year of empagliflozin treatment, with a proportion of 13.74%.

Fig. 2
figure 2

Time to onset of empagliflozin-related adverse events (4112 cases were available)

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Table 3 Summary of basic demographic and clinical information of reports associated with empagliflozin based on the FAERS database
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Table 4 Signal strength of adverse events of empagliflozin at the System Organ Class (SOC) level in the FAERS database
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Table 5 Signal strength of reports of empagliflozin at the Preferred terms (PT) level in the FAERS database
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Discussion

Empagliflozin, a potent and highly selective inhibitor of SGLT-2, was initially developed for treating T2DM [23], and has also been approved for the treatment of chronic heart failure (CHF) [24] or chronic kidney disease (CKD) [25] in adults. Despite its multiple uses and favorable cardiometabolic and renal benefits, empagliflozin can also cause some serious AEs [26], even some new AEs. Therefore, it is crucial to closely monitor the real-world utilization and negative occurrences of empagliflozin. Drawing upon the extensive dataset within the FAERS database, our study provides a comprehensive analysis of the real-world safety profile of empagliflozin.

Our study uncovered a yearly increase in the number of adverse event reports associated with empagliflozin, beginning in 2014 and maintaining a relatively high level since 2018. This upward trend suggested not only the effectiveness of empagliflozin treatment, leading to its increased use in various indications and patient populations, but also emphasized the importance of analyzing these adverse events. Unfortunately, a large proportion of the data lacked precise age or weight information, thereby constraining our analysis of adverse events across various age or weight cohorts. Furthermore, more than half of the reports (59.3%) were submitted by health professionals, which might be considered a more reliable source of reporting. Results of this study indicated that the median onset time was 28 days (IQR 4-154 days), and most of the AE cases occurred within the first 1 month (51.36%) after empagliflozin initiation. It was also worth noting that AEs were still likely to occur after 1 year of empagliflozin treatment, with a proportion of 13.74%. Therefore, a longer follow-up period is needed to observe the AEs of empagliflozin in future clinical studies.

Based on the results of disproportionality analysis, significant signals at the SOC level were indicated for metabolism and nutrition disorders, renal and urinary disorders. On the one hand, renal and urinary adverse events were some of the most common AEs of empagliflozin, including pollakiuria, dysuria, micturition urgency and polyuria, which were included in the label, and our results precisely supported this. This might be related to the diuresis mechanism of empagliflozin.

On the other hand, among “metabolism and nutrition disorders” SOC level, diabetic ketoacidosis, dehydration, abnormal loss of weight, polydipsia were considered as the main signals for AEs of empagliflozin. Those were commonly reported in clinical trials and mentioned in the drug label [27, 28]. It was worth noting that DKA is an acute and significant life-threatening complication of diabetes, some patients with SGLT-2i-associated DKA had near normal or mildly elevated blood glucose levels, and therefore described by EDKA [29]. A multicenter cohort study revealed that empagliflozin has a high risk of DKA with a hazard ratio (HR) of 2.52 (CI, 1.23–5.14) [30]. In the EASE (Empagliflozin as Adjunctive to inSulin thErapy) trials, the rate of DKA in patients was higher in the empagliflozin 10- and 25-mg groups compared with placebo (4.3%, 3.3%, and 1.2%, respectively) corresponding to the incidence rate of 5.9, 5.1, and 1.8 per 100 patients-years [31]. In our research, both DKA and EDKA were reported as significant AEs of empagliflozin that met al.l four criteria simultaneously, of which EDKA showed a high correlation with significant signal strength being ROR 744.18 (684.33-809.26), PRR 728.70 (402327.22), IC 444.19 (414.10) and EBGM 8.80 (7.13), respectively. The number of DKA cases was higher than that of EDKA (2747 vs. 909). Due to the lack of typical manifestations in patients with EDKA, such as marked hyperglycemia and dehydration, the diagnosis of EDKA may be missed and initiation of treatment may be delayed [32]. Therefore, the identification of this life-threatening diabetic complication is essential, and clinicians need to pay more attention to it. As for the mechanisms of empagliflozin-associated EDKA, which is probably related to reduced insulin secretion and increased glucagon release, promoting the production of free fatty acids [33, 34].

In the SOC of “infections and infestations”, fungal infection (FI) and urinary tract infection (UTI) were the most common AEs of empagliflozin. This infection effect is because of the empagliflozin mechanism in which the glucose concentration in the urogenital region of the patient is increased, resulting in the possibility of bacterial and fungal infections [35]. Notably, Fournier’s gangrene (FG) showed a high correlation with significant signal strength being ROR 610.52 (548.96-678.98), PRR 603.18 (206109.86), IC 394.23 (360.69) and EBGM 8.62 (6.96), respectively. In August 2018, the FDA released a safety warning of FG with the use of SGLT-2i, a rare but serious perineal infection with a mortality rate of up to 88% in some cases [36]. There are numerous clinical trials and case reports aimed at exploring the potential association between FG and SGLT-2i. However, the total number, follow-up, and scale of trials are too low to draw reliable conclusions, and the patients enrolled in clinical trials cannot fully represent those who can accept drug prescriptions in the real world, although randomization procedures minimize the possibility of bias [37, 38]. Furthermore, pharmacovigilance research indicated that increased reporting frequency emerged for SGLT-2i compared with other drugs, with a PRR ranging from 5 to 10 [10]. Another research of SGLT-2i showed that empagliflozin was associated with the highest number of FG reports and had the strongest association with the onset of FG, with a higher ROR value than any other SGLT-2i [39]. Based on our study and on the well-known risk of genital infections associated with SGLT-2i, although FG remains rare, with the increased use of empagliflozin, close monitoring and constant epidemiological surveillance are needed. Patients should prioritize personal genital hygiene, drink plenty of water, urinate frequently, and then strive to minimize the risk of infection.

A total of 6 significant PTs existed that were not mentioned in the empagliflozin instructions based on our results of FAERS data, mainly related to cardio-cerebral diseases and gastrointestinal diseases. For example, pancreatitis, pancreatitis acute, gastroenteritis, cerebral infarction, and cardiac operation were identified as significant signals. Notably, the United States FDA and Health Canada expressed concern about the risk of acute pancreatitis for empagliflozin [40–41]. However, pancreatitis has not yet been included in the package insert, which may be related to the lack of a large number of clinical trials. The potential mechanisms behind pancreatitis may be linked to dehydration and lactic acidosis, and could also stem from the immune or cytotoxic effects of drugs or their metabolites on the body [42]. As for the AEs related to the cardio-cerebral system, although empagliflozin has been confirmed to have cardiovascular protective effects, a previous study noted that some patients developed some of these AEs after receiving treatment [43]. Whether empagliflozin contributes to these AEs is controversial, and there is no evidence from large pharmacoepidemiological studies or clinical trials. However, empagliflozin may cause a decrease in blood volume or even dehydration, and dehydration could potentially lead to thromboembolism, such as cerebral infarction and myocardial infarction [44]. And some serious cardio-cerebral diseases are also rare complications of DKA. Therefore, it is important to educate patients on drinking moderate amounts of water regularly. These unexpected and new AEs signals also remind clinicians to pay more attention to empagliflozin-associated cardio-cerebral diseases and gastrointestinal diseases in subsequent clinical trials. Additionally, it should be mentioned that there may be reporting bias for AEs that were already of concern. These AEs identified in this study but not listed in the empagliflozin instructions may warrant closer monitoring.

It should be noted that our study has certain limitations, particularly as the data primarily relies on spontaneous reporting, which may lead to reporting bias and incomplete information. For instance, consumer reports may not be as reliable and comprehensive as those from medical professionals; there could be sampling bias in countries and regions with a high number of reports. In addition, due to the absence of information regarding the population administered empagliflozin, it is impossible to calculate the true incidence of AEs. Granular data on patients’ characteristics, comorbidities, and diabetic complications are lacking in the FAERS. Those potential confounders may affect the results. To mitigate potential confounders, we used restricted comparator groups of DPP-4i, GLP-I RA and other SGLT-2i except for empagliflozin, representing a population sharing common features with empagliflozin. Then, the information presented in the reports remains unverified, and the disproportionality analysis neither quantified risk nor existed causality, but only provided an estimation of the signal of disproportionate reporting strength, which was only statistically significant. It is still necessary to undertake more rigorous prospective studies integrating clinical trials with epidemiological investigations. This approach will enable a more accurate evaluation of the safety risks associated with empagliflozin. Despite these limitations, our thorough analysis of the AE signals associated with empagliflozin and the discovery of unexpected signals could lay the groundwork for future clinical research on this medication.

Conclusion

In conclusion, our pharmacovigilance analysis of the FAERS database revealed the safety signal spectrum and time to AEs onsets with empagliflozin comprehensively and systematically. Despite the existence of inherent limitations of the FAERS database, our study finds some unexpected significant AEs and provides valuable evidence for the safety of empagliflozin. Further research and long-term clinical trials are still needed to verify these results and to further comprehend the safety of empagliflozin.

Data availability

The FAERS database undergoes regular quarterly updates and can be accessed online at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82204758).

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Authors and Affiliations

  1. Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Huiping Hu, Zhiwen Fu & Shijun Li

  2. Department of Pharmacy, Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Maochang Liu & Zi Huang

  3. Administrative Office, Beijing University of Chinese Medicine, Beijing, China

    Maochang Liu

  4. Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, Wuhan, China

    Kaiping Wang & Zi Huang

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Contributions

HH: Conceptualization, Methodology, Data curation, Software, Formal analysis. ML and ZF: Data curation, Validation, Revision. SL: Software, Formal analysis. KW: Methodology, Writing review and editing. ZH: Conceptualization, Methodology, Data curation, Supervision, Writing review & editing. All authors reviewed the manuscript and approved the final version.

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Correspondence to Zi Huang.

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Ethical approval was not provided for this study on human participants because FAERS (FDA Adverse Event Reporting System) is publicly available and anonymous database.

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Not applicable.

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The authors declare no competing interests.

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Hu, H., Liu, M., Fu, Z. et al. The real-world safety profile of empagliflozin: a disproportionality analysis based on the FDA Adverse Event Reporting System (FAERS) database. BMC Pharmacol Toxicol 26, 28 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40360-025-00861-y

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Keywords

BMC Pharmacology and Toxicology

ISSN: 2050-6511

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