SIADH is defined by euvolemic hyponatremia due to inappropriate retention of free water under the influence of antidiuretic hormone. The etiologies are divided into four major groups: tumors, drugs, central nervous system disorders, and lung disorders [24, 25]. Clinical features include water retention, increased urinary excretion, and dilutional hyponatremia [26]. As we know, Tricyclic antidepressants, selective serotonin reuptake inhibitors, chlorpromazine, and carbamazepine can cause SIADH. However, apart from case reports for drug-related SIADH, there are few reports on PPI-related SIADH [27]. Moreover, the precise mechanism of SIADH secondary to PPI is currently unclear because PPI-induced SIADH is uncommon, and it is not yet clear whether there is a difference between individual PPIs.
SIADH is considered a side effect of PPI-induced hyponatremia [28]. However, some scientists disagree with the SIADH side effect, suggesting renal salt waste instead [28, 29]. It remains unclear whether peripheral processes are responsible for the difference in PPI-induced severe hyponatremia between individual PPIs. The present research results are based on the reported adverse reactions in the FAERS database, where all SIADH diagnoses have been verified through the reports. The data and results were related to SIADH but PPI-related hyponatremia.
Although SIADH related to PPI has received clinical attention, the current related research are limited to case reports due to its extremely low incidence [11,12,13, 30]. No randomized controlled trials and cohort studies are identified. Therefore, we cannot make a clear conclusion regarding the safety of PPIs. The present research shows that the number of reports with an increasing trend contributed to more than 26.37% of cases in 2019. It is worth noting that SIADH was not found to be related to dexlansoprazole in the FAERS database, which is consistent with previous publications of PPI-related SIADH [11,12,13, 30]. A large case-control study showed that there is an association between any newly started PPI treatment except for lansoprazole and hospitalization caused by hyponatremia [27]. There are two possible reasons for the association. First, there may be fewer reports on dexlansoprazole, since it is the latest drug on the market among the six PPIs. Second, the search was limited to the articles written in English. Dexlansoprazole was developed in Japan, and FAERS data primarily focuses on the products in European and American countries.
In this literature search, healthcare professionals’ reports accounted for the largest proportion of studies, indicating that PPI-related SIADH did not attract the attention of other researchers. Literature on PPI-related SIADH mainly published as case reports indicate that the clinicians are concerned with this topic. It was also found that the elderly are more likely to develop PPI-related SIADH, indicating that age is a risk factor for SIADH. The older is a patient, the greater is the chance of incidence. The elderly usually have comorbidities, poor physical fitness, and a higher incidence of SIADH [25]. The incidence in women was also greater than that in men (48.72% vs. 41.76%), demonstrating gender differences in the adverse reactions to PPIs. Also in other large studies, women and the elderly are more affected by hyponatremia [31]. Previous studies have shown that men are more likely to suffer from peptic ulcers and gastroesophageal reflux gastritis compared to women [32,33,34], indicating that men have a greater chance of using PPIs. The present study shows that women are more likely to develop PPI-related SIADH, which may be due to the missing data in the FAERS database or incorrect reporting. Thus, a larger sample is needed to demonstrate the gender difference in PPI-related SIADH.
It was also found that the median time to onset of SIADH is 22 days with PPI use, suggesting that monitoring of the phenomena may be needed as soon as PPIs are started. From the perspective of the average time of SIADH occurrence, the onset time for the five PPIs ranges from half a month to three years, indicating that individual monitoring strategies need to be implemented after managing PPIs. Oral urea and vasopressin 2 antagonists are effective treatments for treating SIADH when conservative measures fail [35].
The present research has certain advantages. First, FEARS, the FDA’s adverse event reporting database provides a great opportunity to find rare adverse reactions, such as PPI-related SIADH. Second, to the best of our knowledge, this study is the first and largest real-world pharmacovigilance study comparing SIADH after using PPIs based on the FAERS database. Third, the comparison between the onset time and prognosis of SIADH is expected to serve as a reference for clinical decision-making.
Although this study has some advantages, some restrictions are specific to the FAERS database and should be considered when interpreting these results. First, the FAERS database includes some wrong information and may bias the results. Second, the available Aviation Safety Reporting System (ASRS) data only applies to patients with side effects. Despite the FAERS database has indicated it is improper to use the data to infer the prevalence of any adverse events, we must emphasize that the total number of patients being treated is unavailable, and thus some relevant statistics cannot be calculated. Third, non-proportional analysis results can only demonstrate an association but causality. Fourth, submission of a report may be biased, and it does not mean that the information included in it has been medically confirmed nor it is an admission from the reporter that the drug caused or contributed the event. They may be biased because of increased awareness affected by negative news and biased in their reporting of adverse events, which may result in spurious time trends. On the contrary, the bias may be applicable to under-reporting. There also exists a higher likelihood of adverse effects of newer drugs being reported recently, while drugs with well-known adverse effects are probably not reported as often. Formal pharmacoepidemiologic studies may be needed to overcome such biases. Although the FAERS database has some limitations, it illustrates some important aspects of PPI-related SIADH and provides clues for further studies.
omeprazole;
, esomeprazole;
,lansoprazole;
, dexlansoprazole;
, rabeprazole;
, pantoprazole
, Hospitalization rate;
, Fatality rate;
, Hospitalization number;
, Fatality number