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. 2026 Jul 31;26:988. doi: 10.1186/s12872-026-06387-3

Comparison of cardiac adverse event signal profiles for GLP-1 receptor agonists: an analysis of the FAERS database

Burak Ogulcan Yildirim 1, Ibrahim Furkan Sarkim 2,✉, Gizem Yalman 2, Bugra Arslantas 2, Can Berk Celik 2, Sahin Yildirim 2
PMCID: PMC13715166  PMID: 42947001

Abstract

Purpose

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the management of type 2 diabetes owing to their effectiveness in glycemic control and weight reduction. Given the increasing use of GLP-1RAs, further research is warranted to better understand their cardiac effects.

Methods

Individual Case Safety Reports from the U. S. Food and Drug Administration Adverse Event Reporting System database from July 6, 2007, to February 17, 2026, were evaluated for the post-marketing cardiac adverse events associated with dulaglutide, liraglutide, semaglutide, and tirzepatide. To detect signal differences among drugs, disproportionality analysis was conducted using the Proportional Reporting Ratio (PRR) and Reporting Odds Ratio (ROR) methods, along with standard statistical tests to evaluate categorical variables and to estimate odds ratios.

Results

A total of 7,023 cardiac adverse events were identified among 305,877 reports. GLP-1RAs were associated with a higher reporting frequency of tachyarrhythmias than bradyarrhythmias. In the 65–85-year age group, an increase in the signal for cardiac events was observed. Pairwise post hoc comparisons demonstrated no statistically significant differences in reporting frequency of cardiac events between semaglutide and liraglutide, whereas all other drug pairs demonstrated statistically significant differences.

Conclusion

Semaglutide and liraglutide had higher relative reporting of cardiac events whereas tirzepatide had lower PRR and ROR values against the total background of reports. These findings suggest a lower reporting tendency of cardiac events for tirzepatide. This study may assist healthcare professionals in recognizing the frequency of cardiac events associated with GLP-1RA use and drive new hypotheses to clarify underlying mechanisms.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12872-026-06387-3.

Keywords: Glucagon-like peptide-1 receptor agonists, FAERS, Dulaglutide, Liraglutide, Semaglutide, Tirzepatide

Introduction

Diabetes mellitus is an endocrine disorder characterized by hyperglycemia, which can be classified into type 1 diabetes, type 2 diabetes (T2DM), gestational diabetes, and other forms [1]. According to the International Diabetes Federation (IDF), the global prevalence of T2DM was estimated at 588.7 million in 2024 and is projected to reach approximately 852.5 million by 2050 [2]. Chronic complications of T2DM, such as diabetic nephropathy, neuropathy, and cardiovascular morbidities, impair quality of life, necessitating comprehensive and multidisciplinary T2DM management [3, 4]. The pathogenesis of T2DM primarily involves impaired insulin secretion and reduced sensitivity to insulin [5]. Lifestyle modifications, patient education, physical exercise, and a balanced diet are important for the management of T2DM. Furthermore, these interventions support lowering the required dosage and reduce complications [6]. Despite the availability of numerous compounds, many patients still fail to achieve adequate glycemic control [7]. Various pharmaceuticals, such as insulin, metformin, and sulfonylureas, have been conventionally used in the management of diabetes; however, adverse effects, loss of efficacy over time, and limited action on multiple disturbances linked to T2DM have necessitated new therapeutic strategies [8]. The discovery of glucagon-like peptide-1 (GLP-1) began in 1979 with the identification of pancreatic messenger RNA in anglerfish [9]. In 1987, it was confirmed that GLP-1 stimulates insulin secretion and reduces blood glucose [10]. An exopeptide discovered in the Gila monster in 1992, which was later designated as exenatide, was shown to stimulate insulin secretion [11]. This exopeptide became the first GLP-1 receptor agonist approved by the U.S. Food and Drug Administration (FDA) in 2005 for the treatment of T2DM [12]. Randomized controlled studies reported that GLP-1 receptor agonists (GLP-1RAs) have shown superior effectiveness in glycemic control and weight loss in T2DM [13]. Beyond diabetes, GLP-1RAs may be effective for weight loss in overweight individuals [14]. The use of GLP-1RAs in non-diabetic overweight individuals in the United States has increased by more than 700% over the last four years, leading to several ethical concerns [15]. The use of GLP-1RAs is supported from an ethical perspective for its ability to improve health and minimize harm by preventing the use of substandard compounds [16–18]. In contrast, opposing views highlight the risk of neglecting lifestyle modifications, stigmatization, and even misuse [16]. Alongside ethical concerns, GLP-1RAs are associated with various adverse effects. It has been demonstrated that the weight reduction associated with GLP-1RAs does not exclusively result from the reduction of adipose mass; indeed, there is a loss of muscle mass that is greater than the anticipated ratio of skeletal muscle mass decline observed in age-related weight loss secondary to a calorie-restricted diet [19, 20]. Potential adverse events may compromise treatment adherence by exacerbating patient concerns and prompting further investigation into these effects [21]. A rat study revealed that semaglutide reduced hypertrophic stressors and consequently decreased cardiac mass [22]. Another study suggested that the use of GLP-1RAs in patients with low ejection fraction was associated with an increased risk of hospitalization owing to heart failure [23]. However, evidence also supports cardioprotective properties of GLP-1RAs. In animal experiments, GLP-1RAs increased glucose metabolism in the heart [24]. Another study on an ischemia-perfusion model in pigs showed that exenatide reduced infarct size, preserved cardiac function, and decreased apoptosis [25]. Liraglutide-treated apolipoprotein E-knockout mice showed increased endothelial nitric oxide synthase levels and decreased expression of intercellular adhesion molecule 1 with improved endothelial function [26]. Clinical studies have also reported that GLP-1RAs have a positive impact on cardiovascular health in diabetic and obese populations. A large-scale study that evaluated the cardiovascular outcomes of patients with type 2 diabetes demonstrated that patients using GLP-1RAs had a lower risk of cardiovascular disease-associated death and fewer heart failure related hospitalizations, highlighting BMI-dependent cardiovascular and renal benefits [27]. It has been suggested that GLP-1RAs provide cardiovascular protection through their effects on body weight, blood pressure, and inflammatory mediators [28]. However, various studies have reported that the tachycardic effects of GLP-1RAs may be harmful in patients who are frequently hospitalized owing to severe left ventricular dysfunction, low ejection fraction, or chronic heart failure [29]. A multicenter study evaluating the effects of liraglutide on left ventricular function in patients with heart failure suggested that liraglutide treatment was associated with increased heart rate and cardiac adverse effects [30]. In view of these conflicting results regarding the cardiovascular effects of GLP-1RAs and considering their increasing use in the context of the high global prevalence of type 2 diabetes and obesity, the analysis of post-marketing adverse event data may provide real-world insights for healthcare professionals and drive new hypotheses to guide future research.

Methods

This retrospective observational study follows the Reporting of a Disproportionality Analysis for Safety Signal Detection Using Individual Case Safety Reports in Pharmacovigilance (READUS-PV) guidelines. Furthermore, we adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and Reporting of Studies Conducted Using Observational Routinely Collected Health Data (RECORD) statements to ensure rigorous and transparent presentation of our findings. Analyses based on data from advanced reporting systems can support research communities, evidence-based clinical decisions, and patient care. FAERS is a pharmacovigilance system established in 1969 that contains a large database of reports submitted to the FDA by drug manufacturers, the public, and healthcare professionals [31]. The patient information in the FAERS database is anonymized [32]. The FAERS database does not contain information on patients’ body mass index (BMI), baseline cardiovascular disease, or indication for use. This inherent limitation should be taken into account when interpreting the results of this study. In our study, we investigated cardiac adverse events of four GLP-1RA drugs (dulaglutide, liraglutide, semaglutide, and tirzepatide), which were selected based on their active pharmaceutical market status [33]. The Individual Case Safety Reports (ICSRs) used in this study were obtained through data analysis from the FAERS database, and reports related to the included drugs were collected from July 6, 2007 (the earliest date the FDA received the first report) to February 17, 2026. To identify and categorize cardiac adverse events, we used the Medical Dictionary for Regulatory Activities (MedDRA Version 28.1) terminology. Specifically, adverse events mapped to the System Organ Class (SOC) of “Cardiac disorders” were extracted. Within this SOC, primary endpoints were defined using specific Preferred Terms (PTs), including but not limited to palpitations, myocardial infarction, tachycardia, and cardiac failure. After this step, data cleaning and deduplication were performed to ensure data integrity and prevent duplication. To manage the potential for duplicate reporting, where a single patient may submit multiple reports for the adverse event or outcome over time, we grouped reports using their unique case identifiers (CASEID). In instances where multiple versions of a report existed for the same CASEID, we retained only the most recent version as it reflected the latest available data. The definitions and classifications of ‘serious adverse events’ and ‘death’ were adopted directly from the U.S. Food and Drug Administration (FDA) regulatory criteria (21 CFR 312.32, 21 CFR 314.80), where a serious adverse event encompasses any medical occurrence that results in death, is life-threatening, requires inpatient hospitalization, or causes persistent or significant incapacity. In addition to the definitions, the FAERS severity categories reflect reporter perception rather than adjudicated clinical outcomes. Following data extraction and deduplication, disproportionality analysis of the four drugs was conducted using the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods. The Pearson Chi-Square (χ2) Independence Test and the Cramer’s V (V) value were also calculated. To determine which drugs caused the difference in the chi-square test results, multiple comparisons (post hoc Z-tests) were performed between drug pairs, and Odds Ratios were calculated with 95% confidence intervals (CIs). A positive disproportionality signal was defined as PRR > 1 and ROR > 1, with the lower bound of the 95% confidence interval (CI) exceeding 1. These thresholds were supplemented by the Pearson Chi-Square (χ2) Independence Test and post-hoc pairwise comparisons. To evaluate fatal adverse events, data were stratified into two distinct denominators: total adverse event reports to assess the general proportion of death reports for the specific drug, and cardiac adverse event reports to isolate the proportion of death reports specifically within cardiac related cases. This stratification was performed to distinguish between general adverse event signals and cardiac specific outcomes, as case severity distributions differ significantly between these populations. A complete-case sensitivity analysis was performed to confirm the robustness of the primary findings and mitigate potential selection bias in demographic variables. In this step, individual case safety reports lacking documented age or sex were excluded from the analysis. Two-by-two contingency tables were constructed to assess the disproportionality of cardiac adverse events in the complete-case dataset. Categorical variables were evaluated using Pearson Chi-Square (χ2) Independence Test. Subsequently, odds ratios (ORs) and 95% confidence intervals (CIs) were recalculated for all four GLP-1RA subgroups. The statistical significance of the signals was confirmed to be robust to missing data. Statistical analyses and graphical representations were performed using GraphPad Prism 11.

Results

The analyses were stratified by age, sex, type of adverse reaction, severity, and clinical outcome. Additionally, temporal trends in both total and cardiac adverse events were examined for each drug separately and illustrated in Figs. 1 and 2. The total number of reported adverse events was 75,161 for dulaglutide, 39,378 for liraglutide, 64,333 for semaglutide, and 127,005 for tirzepatide. A total of 7,023 cardiac adverse events were identified among 305,877 reports related to the selected GLP-1RAs. Figure 1 illustrates the annual adverse event reporting trends for each drug. The number of reported cardiac events was 1,531 for dulaglutide, 1,398 for liraglutide, 2,379 for semaglutide, and 1,715 for tirzepatide. Figure 2 illustrates the annual cardiac adverse event reporting trends for each drug. The proportions cardiac cases to the total number of cases for each drug, from highest to lowest, were as follows: semaglutide (3.70%), liraglutide (3.55%), dulaglutide (2.04%), and tirzepatide (1.35%). Each drug pair was compared using pairwise comparisons (post hoc analysis). Pairwise post hoc comparisons demonstrated no statistically significant difference in cardiac adverse event reporting frequency between semaglutide and liraglutide (p > 0.05), whereas other drug pairs exhibited statistically significant differences (p < 0.001), as summarized in Fig. 3a. Disproportionality analysis of the four drugs was conducted using Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods (95% CI). Finally, disproportionality analysis yielded PRR values of 1.923, 1.682, 0.856, and 0.455, and ROR values of 1.959, 1.707, 0.853, and 0.448 for semaglutide, liraglutide, dulaglutide, and tirzepatide, respectively. Semaglutide and liraglutide showed positive signals in the disproportionality analysis (PRR and ROR > 1), as summarized in Fig. 3b. For all four GLP-1RA groups, the sex distribution in cardiac cases differed from the sex distribution in all non-cardiac cases (Tables 1 and 2). This effect was particularly notable for liraglutide; although male patients accounted for 32.80% of all cases, they comprised 49.43% of cardiac adverse event reports. In the case of tirzepatide, the proportions of male and female patients reporting cardiac adverse events were 25.83% and 60.93%, respectively. However, high imbalance in the proportion of unspecified cases (19.21% for tirzepatide vs. only 5.53% for liraglutide) limits the data quality. Tachyarrhythmias predominated over bradyarrhythmias in all drug groups as a cardiac adverse event. All adverse event cases and cardiac adverse event cases were categorized according to severity, and the number of reported serious adverse events, including death, was documented (Tables 3 and 4). For all drugs, the reporting frequency of serious adverse events and death in serious cases was significantly higher in cardiac cases compared with non-cardiac cases (p < 0.001). Among serious cases, the likelihood of death was significantly higher in cardiac than in non-cardiac adverse events (p < 0.001). However, the magnitude of the effect was lower than that observed for severity of the cardiac adverse events (V ≅ 0.20 vs. V ≅ 0.07). We observed statistically significant differences when comparing the severity of cardiac events (p < 0.001). The proportions of serious adverse events among cardiac cases ranked from highest to lowest as follows: semaglutide, liraglutide, dulaglutide, and tirzepatide. However, this effect was weak (V = 0.09). In terms of the proportion of death reports in serious cardiac cases, liraglutide had the highest reporting proportion among the four drugs (14.77%), whereas semaglutide had the lowest (7.38%), a nearly two-fold difference that was statistically significant (p < 0.001). Notably, despite a high proportion of serious cardiac adverse events, semaglutide had the lowest proportion of death reports. When cases were categorized by age, adverse event reporting was concentrated in the 18 − 85 age range. The reporting frequency of adverse events in the not specified group varied between 30.76% and 45.52% for cardiac event cases, and between 30.00% and 58.45% for all adverse event cases (Tables 5 and 6). In patients within the 65–85 age range, cardiac events were more frequent than general adverse events compared with other age groups in the adverse event profiles of the four GLP-1RAs, and this difference was statistically significant (p < 0.001). When the Odds Ratio calculations were performed, the ranking of the effects was as follows: dulaglutide (OR = 1.73), liraglutide (OR = 1.56), semaglutide (OR = 1.42), and tirzepatide (OR = 1.24).

Fig. 1.

Fig. 1

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Drug-specific annual distributions of all adverse event cases reported to the U.S. FDA Adverse Event Reporting System for selected GLP-1 Receptor Agonists (2007–2025). Note: Data for 2026 were excluded from the annual trend analysis only, to avoid a misleading downward trajectory caused by the incomplete reporting year

Fig. 2.

Fig. 2

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Drug-specific annual distributions of cardiac adverse event cases reported to the U.S. FDA Adverse Event Reporting System for selected GLP-1 Receptor Agonists (2007–2025). Note: Data for 2026 were excluded from the annual trend analysis only, to avoid a misleading downward trajectory caused by the incomplete reporting year

Fig. 3.

Fig. 3

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a Comparison of cardiac adverse events reporting frequency (Cardiac AE%) among selected GLP-1 receptor agonists. Data derived from the U.S. FDA Adverse Event Reporting System database from 2007 to 2026. ns = not statistically significant (p > 0.05); (b) Disproportionality analysis of cardiac adverse events associated with selected GLP-1 receptor agonists in the U.S. FDA Adverse Event Reporting System database from 2007 to 2026. Statistical significance is defined by the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) with corresponding 95% Confidence Interval (CI)

Table 1.

Sex distribution of all adverse event cases associated with selected GLP-1 receptor agonists reported to U.S. FDA adverse event reporting system (2007–2026)

All adverse event cases by sex Female Male Not Specified
Dulaglutide 38,891 (51.74%) 28,293 (37.64%) 7,977 (10.61%)
Liraglutide 24,284 (61.67%) 12,916 (32.80%) 2,178 (5.53%)
Semaglutide 39,277 (61.05%) 19,752 (30.70%) 5,304 (8.24%)
Tirzepatide 77,680 (61.16%) 24,922 (19.62%) 24,403 (19.21%)
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Table 2.

Sex distributions of cardiac adverse event cases associated with selected GLP-1 receptor agonists reported to U.S. FDA adverse event reporting system (2007–2026)

Cardiac adverse event cases by sex Female Male Not Specified
Dulaglutide 726 (47.42%) 695 (45.40%) 110 (7.18%)
Liraglutide 627 (44.85%) 691 (49.43%) 80 (5.72%)
Semaglutide 1,338 (56.24%) 884 (37.16%) 157 (6.60%)
Tirzepatide 1,045 (60.93%) 443 (25.83%) 227 (13.24%)
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Table 3.

Distribution of reported all adverse event cases by outcome severity associated with selected GLP-1 receptor agonists reported to U.S. FDA adverse event reporting system (2007–2026)

All adverse event cases by seriousness Total cases Serious cases (including deaths) Deaths (% among serious cases)
Dulaglutide 75,161 15,624 (20.79%) 1,083 (6.93%)
Liraglutide 39,378 16,581 (42.11%) 1,274 (7.68%)
Semaglutide 64,333 33,499 (52.07%) 949 (2.83%)
Tirzepatide 127,005 19,971 (15.72%) 633 (3.17%)
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Table 4.

Distribution of reported cardiac adverse event cases by outcome severity associated with selected GLP-1 receptor agonists reported to U.S. FDA adverse event reporting system (2007–2026)

Cardiac adverse event cases by seriousness Total cases Serious cases (including deaths) Deaths
(% among serious cases)
Dulaglutide 1,531 1,233 (80.54%) 163 (13.22%)
Liraglutide 1,398 1,192 (85.26%) 176 (14.77%)
Semaglutide 2,379 2,072 (87.10%) 153 (7.38%)
Tirzepatide 1,715 1,237 (72.13%) 102 (8.25%)
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Table 5.

Distribution of all adverse event cases by age associated with selected GLP-1 receptor agonists reported to U.S. FDA adverse event reporting system (2007–2026)

All adverse event cases by age Dulaglutide Liraglutide Semaglutide Tirzepatide
0–1 Month 6 (0.01%) 5 (0.01%) 13 (0.02%) 10 (0.01%)
2 Months–2 Years 12 (0.02%) 5 (0.01%) 13 (0.02%) 8 (0.01%)
3–11 Years 11 (0.01%) 7 (0.02%) 15 (0.02%) 6 (0.00%)
12–17 Years 30 (0.04%) 82 (0.21%) 112 (0.17%) 30 (0.02%)
18–64 Years 17,510 (23.30%) 16,394 (41.63%) 20,693 (32.17%) 66,809 (52.60%)
65–85 Years 13,199 (17.56%) 8,336 (21.17%) 13,405 (20.84%) 21,833 (17.19%)
More than 85 Years 465 (0.62%) 111 (0.28%) 320 (0.50%) 211 (0.17%)
Not Specified 43,928 (58.45%) 14,438 (36.67%) 29,762 (46.26%) 38,098 (30.00%)
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Table 6.

Distribution of cardiac adverse event cases by age associated with selected GLP-1 receptor agonists reported to U.S. FDA adverse event reporting system (2007–2026)

Cardiac adverse event cases by age Dulaglutide Liraglutide Semaglutide Tirzepatide
0–1 Month 1 (0.07%) 0 0 0
2 Months–2 Years 0 0 1 (0.04%) 1 (0.06%)
3–11 Years 0 0 1 (0.04%) 1 (0.06%)
12–17 Years 0 1 (0.07%) 5 (0.21%) 1 (0.06%)
18–64 Years 406 (26.52%) 552 (39.49%) 889 (37.37%) 806 (46.99%)
65–85 Years 409 (26.71%) 408 (29.18%) 640 (26.90%) 351 (20.47%)
More than 85 Years 18 (1.18%) 7 (0.50%) 18 (0.76%) 4 (0.23%)
Not Specified 697 (45.52%) 430 (30.76%) 825 (34.68%) 551 (32.13%)
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Discussion

This FAERS-based retrospective pharmacovigilance study provided a detailed comparative pharmacovigilance assessment of the cardiac adverse events of four GLP-1RAs. Chronological analysis of both cardiac and general adverse event reports revealed a distribution consistent with the market introduction of the selected drugs. Specifically, liraglutide and dulaglutide comprised a higher proportion of reports during earlier phases, whereas semaglutide and tirzepatide have emerged as the primary focus of reports within the preceding three years. This temporal dynamic is likely attributable to market penetration, clinical adoption, stimulated reporting and shifting patterns of prescription.

In recent years, reports of adverse events associated with semaglutide and tirzepatide have increased concurrently with their frequency of use. Although tirzepatide had the highest number of reported adverse events, the PRR and ROR values for the cardiac events point to a negative signal. Tirzepatide is a recently developed drug that has undergone modern drug development processes and clinical trials. While this could be considered an advantage in terms of cardiac adverse events, it could also be interpreted as a relative masking of cardiac adverse events owing to the more frequent reporting of mild adverse effects. Therefore, the increase in reporting volume associated with recently marketed drugs, such as tirzepatide, may be attributed to the temporal rise in vigilance observed during the post-approval phase, where heightened provider and patient awareness often precipitate an initial peak in reporting frequency. In addition to this interpretation, many studies evaluating GLP-1RAs indicate better cardiovascular adverse event profile and efficacy of tirzepatide, suggesting that the mechanism of cardioprotective activity may be attributed to its dual agonism [34, 35]. The decrease in PRR/ROR values, along with these statistical differences, cannot be directly attributed to the dual-agonist mechanism, nor do they inherently demonstrate a definitive clinical significance and safety profile. Further studies are required to determine both the underlying causes and the clinical significance of these findings. The relatively high PRR and ROR values of semaglutide reflect a higher reporting frequency of cardiac events. This finding may be related to the drug’s increasing misuse by non-obese and non-diabetic individuals without medical supervision for weight loss purposes. Reports concerning the misuse of semaglutide have become increasingly prevalent. A FAERS study from 2023 that retrospectively analyzed adverse event reports from 31,542 patients showed that semaglutide has a misuse potential 3.5 times higher than other GLP-1RAs [36]. Unlike diabetic patients, who often have comorbidities and differences in baseline cardiovascular disease, this group may have had fewer reports of multiple prescribed medications beyond the primary suspect drug, which may have resulted in fewer drug-drug interactions and may have also contributed to a lower frequency of death reports related to drug-induced cardiac events. Furthermore, polypharmacy can confound the identification and reporting of the primary suspect drug. These missing variables may influence the observed reporting patterns. Although we could make this prediction based on evidence from previous studies, we could not confirm this because the FAERS data did not include any information on patients’ BMI, baseline cardiovascular disease and comorbidities which was one of the limitations of our study. This analysis showed that the frequency of cardiac adverse events associated with the investigated GLP-1RAs was higher in terms of both the likelihood of serious consequences and the probability of these serious consequences resulting in death, compared with other general adverse event groups. Despite its higher reporting frequency of cardiac events, semaglutide exhibited the lowest proportion of death reports among severe cardiac adverse events; however, the proportion of death reports was higher with liraglutide and dulaglutide. This finding may be attributable to a longer duration of diabetes among patients receiving earlier-generation drugs. Longer duration of diabetes is associated with a higher relative risk of heart failure, and cardiovascular risk rises significantly as the disease progresses [37, 38]. In addition to diabetes, the importance of weight maintenance within a target range has been demonstrated through multicenter analyses, and patients who have failed to achieve long-term weight control may suffer from greater cardiometabolic multimorbidity [39]. The reported lower frequency of fatal cardiac adverse events associated with semaglutide may also stem from its misuse for weight management in individuals lacking established cardiovascular risk factors such as diabetes or obesity.

Although non-specific terms such as arrhythmia, cardiac disorder, and cardiovascular disorder were identified in reports submitted to FAERS; analysis of the types of adverse events reported by the FAERS system revealed that tachyarrhythmias were reported more frequently than bradyarrhythmias with all GLP-1RAs. Sinus tachycardia is a widely documented adverse effect associated with GLP-1RA use, and pacemaker cells in the sinoatrial node express GLP-1 receptors. It has been suggested that tachycardia develops because of direct stimulation of these receptors [40]. However, it has been proposed that tachycardia associated with GLP-1RAs often does not precipitate serious arrhythmias and that the cardiac benefits outweigh these risks [41]. More studies are needed to confirm the nature of the relationship between GLP-1RAs and tachycardia. In the 65–85-year-old population, the increase in cardiac adverse event signals compared with general adverse event signals can be attributed to increased pharmacodynamic sensitivity and age-related decline in pharmacokinetic clearance in older adults. The higher frequency of serious adverse events in spontaneous reporting systems compared with clinical trials may be attributed to the nature of the reactions compelling their submission, as regulatory authorities prioritize the documentation of significant events over minor reactions, such as injection site erythema.

The lack of data on patient-specific confounders, such as baseline cardiac health, disease duration, and polypharmacy, is a key limitation. Dulaglutide, liraglutide, semaglutide, and tirzepatide differ in market entry timelines, indication, reporting era, and media attention. GLP-1RAs are frequently prescribed for different patient populations with varying cardiovascular risk profiles, obesity severity, diabetes duration, and comorbidity burden. These differences may influence reporting frequencies. Despite conducting a complete-case sensitivity analysis to mitigate potential selection bias, missing data in the reporting process, particularly regarding age and sex, remain a limitation. Spontaneous reporting systems cannot establish incidence or causality, and clinicians should interpret our findings as signal analysis rather than definitive clinical evidence. Although the substantial number of patients in the dataset contributed to statistically significant results, statistical significance does not equate to clinical significance.

Future directions

One of the limitations of our study is the absence of data on BMI, diabetes duration, ejection fraction, concomitant medications, and baseline cardiovascular disease. The future availability of these records in the FAERS system would enable broader analyses. However, although the FAERS system is anonymized, it must be ensured that this very large dataset does not contain personally identifiable information. Furthermore, broad reporting terms such as arrhythmia, cardiac disorder, or cardiovascular disorder that could in fact be classified more specifically at the time of reporting could benefit from the development of software-based methods that allow for more specific categorization.

Across all drugs, the finding that the magnitude of the effect for cardiac adverse events being more frequently reported as serious compared with non-cardiac adverse events was greater than the magnitude of the effect for death occurring more frequently among serious cardiac versus non-cardiac cases is a notable finding, indicating that serious non-cardiac adverse events also necessitate detailed analysis in future studies.

Further research including randomized controlled trials, prospective cohort studies, registry-based analyses, and comparative effectiveness studies is needed to establish whether these pharmacovigilance signals reflect clinically meaningful differences.

Conclusion

In this study, we compared the profile of cardiac adverse events associated with GLP-1RAs using the FAERS database with the broader background of overall adverse event reports. Analyses included reporting frequencies, longitudinal trends, age distributions, and sex differences, as well as the characterization of clinical outcomes in terms of reported event severity and mortality. Pharmacovigilance signals for cardiac events associated with GLP-1RAs were identified, analyzed, and interpreted. The available data suggest a potential relative increase in the frequency of cardiac adverse events associated with GLP-1RA use in older age groups; however, these findings are limited by missing demographic data and require validation through future studies. GLP-1RAs were associated with a higher reporting frequency of tachyarrhythmias than bradyarrhythmias. Tirzepatide demonstrated lower PRR and ROR values for cardiac adverse events. However, this reflects a relative reporting frequency rather than confirmed safety, likely confounded by its recent market entry, shorter duration of use, and reporting biases that disproportionately expand the overall adverse event denominator. In contrast to tirzepatide, the first-generation drugs dulaglutide and liraglutide exhibited a higher reporting frequency of serious cardiac adverse events. Although cardiac events are reported more frequently with semaglutide, the relative reported mortality associated with these events is lower. Despite the limitations of this study, these findings may help healthcare professionals recognize the frequency of cardiac adverse events associated with GLP-1RA use, highlight current trends, and drive new hypotheses for future studies.

Supplementary Information

Supplementary Material 1. (78.4KB, docx)
Supplementary Material 2. (20KB, docx)

Acknowledgements

The authors acknowledge the U.S. Food and Drug Administration for the FAERS database that provides publicly available data.

Authors’ contributions

Conceptualization, Ibrahim Furkan Sarkim and Bugra Arslantas; methodology, Gizem Yalman; software, Ibrahim Furkan Sarkim; validation, Burak Ogulcan Yildirim, Gizem Yalman, and Can Berk Celik; formal analysis, Ibrahim Furkan Sarkim; investigation, Ibrahim Furkan Sarkim; resources, Burak Ogulcan Yildirim; data curation, Ibrahim Furkan Sarkim, Gizem Yalman, and Bugra Arslantas; writing—original draft preparation, Ibrahim Furkan Sarkim; writing—review Burak Ogulcan Yildirim, Sahin Yildirim, and Gizem Yalman; editing, Burak Ogulcan Yildirim and Can Berk Celik; visualization, Ibrahim Furkan Sarkim; supervision, Burak Ogulcan Yildirim; project administration, Sahin Yildirim and Ibrahim Furkan Sarkim. The authors declare that all data were generated in-house, that no paper mill was used and that no AI tool has been used for the generation of text or figures. All authors have reviewed and agreed to the published version of the manuscript.

Funding

The authors declare that no grants, funds, or other support from any source were received related to this work.

Data availability

The data used in this study are publicly available from the FDA Adverse Event Monitoring System (AEMS) [formerly the FDA Adverse Event Reporting System (FAERS)] public dashboard at https://fis.fda.gov/hub/. Processed datasets, including but not limited to standardized case sets and computational workflow for deduplication, disproportionality analysis, and associative statistical testing, are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

As this observational study used publicly available anonymized data from the FDA Adverse Event Monitoring System (AEMS) [formerly the FDA Adverse Event Reporting System (FAERS)] database, institutional ethical approval is not required.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1. (78.4KB, docx)
Supplementary Material 2. (20KB, docx)

Data Availability Statement

The data used in this study are publicly available from the FDA Adverse Event Monitoring System (AEMS) [formerly the FDA Adverse Event Reporting System (FAERS)] public dashboard at https://fis.fda.gov/hub/. Processed datasets, including but not limited to standardized case sets and computational workflow for deduplication, disproportionality analysis, and associative statistical testing, are available from the corresponding author upon reasonable request.

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