Introduction

Proton pump inhibitors (PPIs) irreversibly inhibit the proton pump, the final step in gastric acid secretion, and are the most powerful inhibitors of gastric acid known to date. PPIs are frequently used to treat gastric acid-induced gastrointestinal diseases and prevent stress ulcers. In recent years, there has been a trend towards PPI overuse. This is largely attributable to their insufficient use, resulting from premature transition to as-needed or intermittent treatment [1]. This phenomenon has resulted in an increased dependence on PPIs, resulting in their prolonged use. Another reason for the overprescription of PPIs for extended periods is the perceived need for continued prescription and lack of periodic re-evaluation. Thus, there are increasing concerns about the side effects of long-term PPI use. Several recent studies have indicated the side effects of long-term PPI therapy [2]. However, to the best of our knowledge, no studies have clearly identified a causal relationship between long-term PPI therapy and these side effects. Therefore, there is a need for more robust long-term studies.

Although there has been interest in the side effects of long-term PPI use, a recent study found that PPI use was not associated with an increased risk of colorectal cancer [3]. However, other observational studies have provided evidence for a scientific link between PPI use and the development of colorectal cancer [4]. It has been consistently argued that the long-term use of PPIs may slightly increase the risk of colorectal cancer, but studies conducted to date have been limited by small sample sizes, short follow-up periods, and other methodological shortcomings. Considering the adenoma-carcinoma sequence, which is a multistep carcinogenesis process in colon cancer, we aimed to investigate the association between long-term PPI therapy and the risk of developing adenomatous polyps of the colon. Previous studies evaluating the impact of PPIs on the survival of patients with colorectal cancer have several limitations [5,6]. In particular, the dose-response association between the PPI dose and mortality was not investigated [7]. Although the present study is a single-institution study, the fact that several conditions were controlled, relatively long-term follow-up was conducted, and a large number of patients were included enhances the reliability of the results.

Methods

Ethical statements: This study was approved by the Institutional Review Board (IRB) of the Catholic University of Korea, St. Vincent’s Hospital (IRB No: VC23RIST0363). The requirement for informed consent was waived because of the retrospective nature of the study and because the analysis used anonymous clinical data.

We retrospectively reviewed a consecutive series of neurosurgery outpatients who underwent two or more colonoscopies at a single center between January 2014 and April 2023. Patients with a history of surgery, malignant tumors, or inflammatory bowel disease were excluded. The use of medications including aspirin and non-vitamin K oral anticoagulants such as dabigatran etexilate, rivaroxaban, apixaban, and edoxaban was also recorded. In addition, the use of various statins was investigated as a variable. Among concomitant diseases, diabetes mellitus (defined as a documented diagnosis of diabetes or prescription of oral hypoglycemic agents or insulin) was considered to be involved in the development of colonic polyps.

Cases in which the interval before the second colonoscopy did not meet the guidelines, and patients with advanced polyps or multiple adenomatous polyps on primary colonoscopy were excluded. The researchers analyzed all colonoscopy images recorded on a picture archiving and communication system and summarized the size, number, and location of the polyps, along with the biopsy results. Advanced colorectal polyps (ACPs) were defined as any one of the following: (1) tubular adenoma >1 cm or any adenoma with villous features or high-grade dysplasia, regardless of size; (2) sessile serrated lesion >1 cm or sessile serrated polyp with cytologic dysplasia; and (3) traditional serrated adenoma of any size. ACPs are immediate precursors of colorectal cancer and critical target lesions for screening colonoscopy [8]. Patients with multiple adenomatous polyps were defined as those with two or more polyps.

Results

A total of 788 neurosurgery outpatients who underwent two or more colonoscopies at The Catholic University of Korea, St. Vincent’s Hospital during the reference period were reviewed. Of these, 23 patients were excluded because of previous surgery, malignancy, or inflammatory bowel disease. In addition, patients in whom the timing of endoscopy did not meet the guidelines, those who had no previous colonoscopy (n=183), and those who had ACPs or multiple colon polyps on the first colonoscopy (n=62) were excluded. In the first standard colonoscopy evaluation, 520 patients were included. In the second colonoscopy, the risk of adenomatous colon polyps was evaluated depending on whether the patient was taking a PPI (Fig. 1). In the univariate analysis to determine factors involved in the development of adenomatous polyps in the colon, age, presence of diabetes, use of new oral anticoagulants, and use of statins were found to be statistically significant factors. In contrast, age and a history of aspirin use for >5 years were identified as significant factors in the multivariate analysis related to the risk of adenomatous colon polyps (Table 1).

Patients who had been prescribed aspirin for >5 years (n=114) were excluded because aspirin use seemed likely to have affected the results (Fig. 2). The remaining 406 patients were divided into three groups: those who had taken PPIs for >12 months, those who had taken PPIs for >3 months but <12 months, and those who had not taken PPIs. The frequencies of detection of adenomatous polyps in the second colonoscopy in these three groups were 35.2%, 32.8%, and 22.8%, respectively (p=0.10). In the post-hoc analysis, there was a significant difference in the occurrence of colon adenomatous polyps between patients who received PPIs and those who did not (p=0.03). The risk of adenomatous colon polyps was significantly higher in patients who used PPIs for >12 months than in patients who did not use PPIs (p=0.04) (Fig. 3).

The risk of advanced colon polyps at the second colonoscopy was 5.5% (7/128), 1.1% (2/177), and 2.0% (2/101), respectively (p=0.06). In the multivariate analysis of the occurrence of ACPs, the only significant factor was the use of a PPI for >12 months (Table 2). For multiple polyps, the numbers were 35.6% (16/45), 55.2% (32/58), and 30.4% (7/23), respectively (p=0.05) (Fig. 4).

Discussion

A recent meta-analysis found that PPI use was not associated with an increased risk of colorectal cancer compared with H₂-receptor antagonist use, but that long-term PPI use may be associated with an increased risk of colorectal cancer [4]. Big data research is necessary to observe the association between the occurrence of colorectal cancer and long-term PPI use, but it seems necessary to start with small-scale studies that exclude related complex variables. Moreover, the primary preventive effects of colon polyp removal should be excluded, as should patients taking drugs to prevent colon cancer. Most colorectal carcinomas arise from adenomas, and their lifecycle varies. However, given that it takes an average of 10 to 15 years, as suggested by the multistep carcinogenesis model [9], scientific evidence related to long-term PPI use can be inferred directly or indirectly by looking at the occurrence of adenomatous polyps rather than looking for direct evidence of colorectal cancer. Considering the relatively long time required for the progression of colorectal adenomatous polyps to colorectal cancer, studies investigating the risk of colorectal cancer with long-term PPI use seem unreasonable.

In this study, we selected neurosurgery outpatients who received regular long-term medications and underwent two or more colonoscopies. There are several reasons for these selection criteria. First, recognizing the seriousness of the disease (hemorrhage and infarction), these patients tended to attend follow-up visits over a relatively long time without changing hospitals. Second, they lived a relatively normal life with minor physical limitations. Third, many patients had gastrointestinal symptoms caused by long-term use of antiplatelet agents, including aspirin. Therefore, these patients comprised a large proportion of long-term PPI users. Fourth, due to the use of antiplatelet agents, colonoscopy examinations tended to be performed regularly. Overall, we investigated the risk of long-term PPI use by controlling for various variables and measuring the risk of adenomatous polyps. Patients whose schedules of the first standard and second endoscopies deviated from existing guidelines were excluded. Patients in whom advanced or multiple adenomatous polyps were detected during the first standard colonoscopy were also excluded. Furthermore, patients who received aspirin for >5 years were excluded because this regimen could have affected the occurrence of polyps. Thus, only patients with a normal first standard colonoscopy or a small solitary polyp <1 cm in size were included in the analysis. It is noteworthy that the risk of adenomatous colorectal polyps was significantly higher in patients who took PPIs for >12 months than in those who did not take them, when relevant variables were excluded relatively extensively.

Moreover, the risk of advanced colon polyps was slightly higher in patients who took PPIs for >12 months. Of course, most of these patients were unlikely to have polyps; however, the possibility that long-term PPI therapy fostered an environment that could cause rapid polyp growth cannot be completely ruled out. A small percentage of these advanced polyps are assumed to have arisen from endoscopically normal mucosa (or very small precancerous lesions) that grew rapidly. Such rapidly progressive lesions may involve the inactivation of DNA mismatch repair (MMR) genes in the alternative pathway [10,11]. MMR gene inactivation accounts for approximately 15% of sporadic colorectal cancer cases [12]. MMR gene inactivation can be detected by testing cancer tissues for microsatellite instability (MSI). Previous studies have detected Fusobacterium nucleatum signatures in colorectal cancer tissues of these cases [13]. Proximal tumor location, shorter patient survival, MSI-high, CpG island methylator phenotype-high, long interspersed nuclear element-1 hypomethylation, and BRAF mutations were other identified risk factors [13]. From this perspective, it can be inferred that changes in the intestinal flora may cause alterations in colon tissues and induce malignant changes. Further research is required to explore these issues in depth.

Theoretically, long-term PPI use can induce hypergastrinemia, leading to an increased risk of adenomatous colon polyp formation [14,15]. Animal experiments have suggested that hypergastrinemia leads to adenoma progression, an important precursor of colorectal cancer [14]. However, the association between PPI use and adenomatous colon polyps has not been consistently demonstrated in humans. Observational studies examining the association between PPI use and colorectal cancer have produced conflicting results (relative risks ranging from 0.85 to 2.54), and these studies had significant methodological shortcomings [4,16,17]. Biases in existing literature may lead to exaggerated associations. Another hypothesis is that chronic PPI treatment affects the small intestinal microflora, and the resultant dysbiosis of the gut microbiota can lead to various systemic diseases. The effect of PPIs on the small intestinal flora is particularly notable, given the close relationship between the latter and the occurrence of colon polyps. The suppression of gastric acid by PPIs can lead to changes in the composition of bacteria in the stomach, duodenum, and intestinal tract, which are risk factors for small intestinal bacterial overgrowth (SIBO) [18]. In one study, the examination of cultured duodenal fluid revealed greater bacterial overgrowth in the PPI group [19]. The glucose breath test for measuring SIBO was more positive in the PPI group than in the irritable bowel syndrome or control groups [20]. Analysis of the duration of PPI use showed that >12 months was associated with significantly increased SIBO.

In general, calcium intake and aspirin are effective in preventing the development of adenomatous colon polyps, and patients who regularly take low-dose aspirin tend to develop less-advanced tumors. According to a meta-analysis, aspirin administration significantly reduced the occurrence of new colon polyps by 17% [21]. According to these studies, expectations are growing in Europe that aspirin therapy for 3 to 4 years can reduce the risk of colon cancer by approximately 20% [22]. Additionally, in April 2016, the U.S. Preventive Services Task Force issued a recommendation that people in their 50s and 60s should take low-dose aspirin daily to prevent colon cancer [23]. In contrast, an early clinical trial conducted by the Association pour la Prevention par Aspirine du Cancer Colorectal found that aspirin did not reduce adenoma recurrence over 4 years [24]. We believe that cyclooxygenase-2 is activated during the late adenomatous stage of colon polyp development. Therefore, aspirin is unlikely to inhibit adenomatous polyp formation. It is plausible that aspirin suppresses the development of advanced polyps or cancer. Given the conflicting results on aspirin, factors related to aspirin use were excluded from this study. More robust studies are required to obtain definitive conclusions regarding the protective effects of aspirin against the development of adenomatous polyps.

This study had some limitations that should be considered when interpreting the results. This was a single-center retrospective study, which may have introduced bias. Moreover, colonoscopy examinations in our study were performed by multiple colonoscopists. However, we controlled for several variables in the analysis, used a meticulously selected cohort with relatively long-term follow-up, and derived the results through consistent testing.

According to current expert advice [25,26], PPIs should be used at the lowest effective dose and, where possible, intermittent dosing should be implemented. Patients should be evaluated with caution against overprescription, and in the case of long-term use, periodic re-evaluation of calcium, magnesium, and vitamin B12; regular bone densitometry; and kidney function tests are required. Additionally, this study found that long-term use of PPIs for >3 months increased the risk of developing adenomatous colon polyps. Therefore, colonoscopies to detect these polyps should be performed more strictly during long-term PPI use. To identify the related mechanisms, large-scale prospective studies that control for various variables over the long-term are required.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author contributions

Conceptualization, Data curation, Investigation, Validation: NRL, WCC; Formal analysis, Methodology, Project administration, Visualization, Supervision: WCC; Writing-original draft: NRL, WCC; Writing-review & editing: WCC.

Fig. 1.

Initial study flowchart. PPI, proton pump inhibitor.

Fig. 2.

Study flowchart excluding patients using aspirin for >5 years. PPI, proton pump inhibitor.

Fig. 3.

Frequency of detection of adenomatous polyps and advanced polyps in the second colonoscopy. PPI, proton pump inhibitor.

Fig. 4.

Frequency of detection of multiple adenomatous colon polyps in the second colonoscopy. PPI, proton pump inhibitor.

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Figure & Data

References

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