Proton pump inhibitors (PPIs) are a class of effective medications used to treat various acid-related disorders. Their use in the clinical setting has increased rapidly and tremendously (1). PPIs are among the most commonly used medications worldwide (2). However, the widespread availability of these agents has also contributed to inappropriate prescriptions and medication overuse. Currently, the administration of PPIs is increasing in daily clinical practice, and there is growing concern regarding the potential long-term risks associated with these agents (3). Mounting clinical data have suggested that chronic exposure to PPIs increases the susceptibility of patient to serious adverse sequelae, including gastric cancer (4), fractures (5), kidney disorders (6), cardiovascular events (7), and dementia (8).

Among these complications, cardiac and vascular events (CVEs) have garnered considerable attention because of their potentially fatal effects. Although there are several published studies on this issue, the findings are controversial. Moreover, existing real-world evidence on the cardiovascular safety profile of different PPIs is scarce despite their wide PPIs are widely use in clinical settings. Therefore, it is vital to assess their overall adverse cardiovascular risks. Herein, the current study aimed to evaluate the real-world pattern of cardiac and vascular adverse events (AEs) among PPI users and summarize and prioritize signals that warrant further attention.

PPIs have been a cornerstone for the treatment of several acid-related diseases for the past few years. PPIs are one of the most commonly prescribed medications in clinical practice, and their overall use has increased dramatically since the 1990s. However, concerns regarding the inappropriate use and overdosing of PPIs are also growing simultaneously (19–21). Due to the wide application of PPIs, many unanticipated AEs have also been reported. Numerous articles have raised alarm about the long-term use of PPIs due to their wide range of potential risks. Cardiovascular AEs have been particularly regarded for patients administered PPIs. However, the currently available studies present contradictory findings on this issue.

Based on real-world clinical evidence, there is a growing need for comprehensive and accurate safety profiles for CVEs in patients taking PPIs. The current study is the largest and most extensive characterization of potentially PPI-associated CVEs by mining the FAERS database to date. By analyzing a large number of records, we were able to detect signals for even relatively rare AEs. We enumerate the notable and interesting findings as follows:

PPIs might adversely affect vascular and cardiac physiology in multiple ways. PPI-associated vascular dysfunction has gained increasing attention and proposed mechanisms have been investigated in several studies. Ghebremariam et al. found that PPIs can reduce the activity of dimethylarginine dimethylamino-hydrolase (DDAH), thereby increasing the plasma level of asymmetrical dimethylarginine (ADMA), an endogenous and competitive inhibitor of nitric oxide synthase (NOS). Elevated ADMA may attenuate the vasoprotective effects of endothelial NOS and increase the risk of vascular inflammation and thrombosis (34). Additionally, Yepuri et al. found that chronic exposure to PPIs can speed endothelial aging, which seemed a result of an inhibition of lysosomal acidification and subsequent disruption of proteostasis (35).

Taken together, such a disruption of vascular homeostasis and broad impairment in endothelial function may cause vascular disorders. As a result, long-term exposure to PPIs exposed patients to an augmented risk of cardiac diseases, which may explain the increased cardiovascular events (36). Our finding that vascular signals were overwhelmingly dominant compared to cardiac signals also supports that vascular function is much more directly and heavily affected than cardiac function. Future in-depth research is needed to reveal the underlying mechanism in this process.

Several studies have reported the association between PPI treatment and acute kidney injury (40–42). Our study supplements this existing literature by revealing novel potential kidney AEs following PPI use. We also observed some new disproportionate associations in specific PPI drugs. Taken together, our findings suggest that since the cardiac and vascular risk profiles of PPIs are significantly different, physicians should consider the potential risks of each PPI and select the optimal drug for individual patients.

There were several limitations in the present study that should be recognized. First, our analysis had inevitable and unquantifiable bias due to the nature of the spontaneous reporting mechanism of the FAERS database, such as over-reporting, under-reporting, and missing variable values in large proportions. Second, due to the absence of the total number of patients exposed to PPIs in FAERS, we could not calculate AE incidence and establish a causal relationship. Lastly, although the disproportionality calculation methods are efficient and popular in hypotheses generation, they fall short of controlling for confounding factors, such as the masking effect and co-prescription (43). Notwithstanding the limitations mentioned above, our findings from this extensive analysis of a large database generated and prioritized several AE signals that merit further investigation. Our work provides the scientific community with several important clues for future in-depth clinical research.

Patients undergoing PPI treatment may experience cardiac and vascular AEs, with a higher possibility of vascular disorders. It is important to understand that despite some similarities, the safety profiles of various PPI medications regarding CVEs are significantly different. As the population exposure to PPIs is expected to continually rise en masse, a comprehensive understanding of the toxicity profile of different PPIs is needed. Caution should be exercised when selecting optimal PPI medications for corresponding indications, and the likelihood of potential cardiac and vascular complications should be considered.

Publicly available datasets were analyzed in this study. This data can be found here: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

YZ, XY, and FH: conception and design of the work and analysis and interpretation of data. YZ and FH: acquisition and review of data. JX and XG: categorization and verification of data. YZ: drafting the article. YC, XY, and FH: manuscript reviewing. All authors contributed to the article and approved the submitted version.

This study was supported by the National Nature Science Foundation of China (No. 82073671), the Leading Talents of Public Health in Shanghai (No. GWV-10.2-XD22), the Shanghai Municipal Commission of Health and Family Planning Fund for Excellent Young Scholars (No. 2018YQ47), the Excellent Young Scholars of Public Health in Shanghai (No. GWV-10.2-YQ33), three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (GWV-10.1-XK05), Big Data and Artificial Intelligence Application, and Military Key Discipline Construction Project (Health Service-Naval Health Service Organization and Command) (No. 03).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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