Proton pump inhibitors (PPIs)—widely used medicines for treating heartburn, gastro-oesophageal reflux disease (GORD) and gastric ulcers—are effective and safe in the short term. However, their prolonged use has raised growing concern within the medical community due to a possible association with renal and cardiovascular problems.
This is one of the main conclusions of an international study led by Carlos Fernández Llatas, a researcher in the SABIEN group at the ITACA Institute of the Universitat Politècnica de València (UPV), in collaboration with the Karolinska Institutet (Sweden), which provides new scientific evidence on these potential long-term effects.
The research, published in Scientific Reports (Nature Portfolio), shows that continued use of PPIs is associated with a higher risk of chronic kidney disease (CKD) and increased mortality, although no significant direct relationship with adverse cardiovascular events was found.
A pioneering analysis using real-world data from almost 300,000 patients
To develope the study, the researchers analysed clinical data from 294,734 patients included in the SCREAM project (Stockholm Creatinine Measurements), one of the largest healthcare registries in Europe, with information on more than 1.6 million individuals in the Stockholm region.
The team compared the clinical progression of PPI users with that of patients treated with H₂-receptor antagonists (H₂RAs), a therapeutic alternative used for the same digestive disorders.
Using process mining techniques—a methodology developed by the SABIEN group at ITACA-UPV—the researchers reconstructed the temporal evolution of patients health and analysed how different medical events, such as chronic kidney disease, cardiovascular problems and mortality, were interrelated.
Results and conclusions
The results show that patients who took PPIs for long periods had a higher risk of developing chronic kidney disease compared with H₂RA users, higher mortality during follow-up, and, among those who already had kidney disease, a greater likelihood of experiencing adverse cardiovascular events.
However, statistical analysis revealed that the direct association between PPIs and cardiovascular problems is not significant when mortality is taken into account, suggesting that kidney disease may act as a mediating factor in this relationship.
“Proton pump inhibitors are very useful medicines, but their long-term use should be reviewed regularly. Our results reinforce the need to monitor renal function in patients undergoing prolonged treatment and to personalise therapeutic decision», explains Carlos Fernández Llatas, ITACA-UPV researcher and co-author of the study.
The analysis suggests that PPI use could increase cardiovascular risk indirectly through renal deterioration, a hypothesis that will need to be validated in future studies.
“Given how frequently these drugs are prescribed, the authors highlight the need for controlled clinical trials to further explore the long-term effects of PPIs, especially in patients with kidney disease or those at risk of developing it,” adds the ITACA researcher.
Clinical implications and future lines of research
The study underlines that PPIs are safe when used appropriately, but chronic use without a justified medical indication should be avoided. The authors recommend monitoring kidney function during long-term treatments and carrying out regular reviews to adjust dosages or consider alternatives.
In addition, the study highlights the potential of process mining techniques applied to real-world clinical data, which make it possible to analyse the progression of complex diseases and uncover patterns that often go unnoticed in traditional medical practice.
“Thanks to these artificial intelligence-based methodologies, we can identify temporal relationships and indirect effects that were previously invisible. This type of approach is essential for moving towards more preventive, personalised and safer medicine”, concludes Carlos Fernández Llatas.
REFERENCE: Kaile Chen, Farhad Abtahi, Carlos Fernandez-Llatas, Hong Xu & Fernando Seoane (2025). Longitudinal trajectories unravel the complex interplay of medication, cardiovascular events, chronic kidney disease, and mortality. Scientific Reports. DOI: https://www.nature.com/articles/s41598-025-23527-5
