Proton pump inhibitors (PPIs) are potent medications that reduce gastric acid secretion and are commonly prescribed for gastroesophageal reflux disease, peptic ulcer disease, and functional dyspepsia (1). In 2015, PPIs were in the top 10 of related drug expenditures in the United States (2).
Although PPIs are effective for certain gastrointestinal disorders, there is concern about their long-term safety, particularly for their carcinogenicity. One way by which PPIs could increase the cancer risk is through the hormone gastrin. PPIs block the gastric acid secretion by irreversibly inhibiting the H+/K+ adenosine triphosphatase pump (1), resulting in increased gastrin secretion and elevated systemic gastrin levels (3), which has progrowth effects (4). In vitro studies have shown that chronic hypergastrinemia can promote the growth of malignant epithelial cells and gastrin antagonism inhibits malignant colonic cell growth (5). In addition, large studies have shown that PPI use can lead to changes in the gastrointestinal microbiome, particularly a decrease in the biodiversity of bacterial species, which is associated with tumor formation (6–8).
Epidemiologic studies examining the relationship between PPI use and gastrointestinal cancers have yielded contradictory results. Although some studies have reported associations between PPI use and gastric (9), colorectal (10), pancreatic (11), and liver cancers (12), others have reported no associations (13–22). The discrepant findings may be because of the differences in the study design, limited follow-up time, and/or the presence of biases, including confounding by indication. A recent cohort study found that PPI use was associated with a 2.4-fold increased risk of gastric cancer among Helicobacter pylori –infected subjects who received eradication therapy, but the study had a 10-year age difference between the exposed and unexposed groups and was limited on several known confounders (e.g., gastric intestinal metaplasia) (23). Therefore, it remains uncertain whether PPI use is associated with a risk of gastric cancer and other gastrointestinal cancers. To address this uncertainty, we performed a nested case-control study within a large, community-based cohort to evaluate the association of PPI use and the risks of gastric, colorectal, liver, and pancreatic cancers compared to non-users.
The case-control study was conducted within Kaiser Permanente Northern California (KPNC), which provides comprehensive inpatient and outpatient services to over 4.3 million members. The KPNC membership closely resembles the demographic and socioeconomic distributions of the Northern California region. More than 90% of members access prescription drugs through KPNC pharmacies, with dose, directions for use, cumulative supply, and refills for all dispensed prescriptions stored in electronically accessible databases validated for as-needed and daily medications (24–26). Additional KPNC electronic databases were provided on membership, medical diagnoses and procedures, results, utilization, and vital statistics. The study was approved by the KPNC Institutional Review Board.
Case patients were KPNC members with an initial gastric, colorectal, liver, or pancreatic cancer diagnosis between January 1, 1996 and December 31, 2016. The index date was the date of the first diagnosis of these 4 cancers. Cases were identified using International Classification of Diseases for Oncology, 3rd Edition codes (see Table 1, Supplemental Digital Content 1, http://links.lww.com/AJG/B464). Cases were eligible if they were 18 years of age or older, had ≥1 year of continuous plan enrollment before the index date, and ≥2 years cumulative membership before the cancer diagnosis date. Individuals were excluded if they initiated PPI use ≤1 year before the index date to account for its use to treat and diagnose cancer symptoms; their primary medical facility was located outside the KPNC region; they had <2 years of cumulative membership; or if they were missing information related to their sex. Each cancer was examined separately, resulting in 4 case sets.
For each eligible case, up to 10 controls were randomly selected from the KPNC membership using incidence density sampling and individual matching by sex, race/ethnicity, primary medical facility at match date, and age and enrollment duration ( within 1 year). Control selection was performed separately for each cancer. Controls were eligible if they were 18 years of age or older, had ≥2 years of cumulative membership before the index date of their matching case, and lacked a diagnosis of the specific cancer at the time of the case diagnosis.
For PPI exposure, the cumulative supply dispensed to the patient (in days) was ascertained by combining the pills dispensed with instructions for use (e.g., 60 pills to be taken twice a day is a 30-day supply). For the primary analysis, exposed patients had a ≥2-year cumulative PPI supply before the index date (24), whereas unexposed patients (the reference population) had no record of PPI use per the KPNC pharmacy database. In secondary analyses, we evaluated the associations with gastrointestinal cancers stratified separately by mean daily PPI dose and duration of use. The mean daily PPI dose was defined as the total of pills dispensed over the entire duration of PPI use divided by the total of days and was separated into 3 categories: <0.75 pills/day, 0.75–1.49 pills/day, and ≥1.5 pills/day. The duration of use was defined as the interval between the dispense dates for the first and last PPI prescriptions plus the days supplied for the last prescription before the index date, including gaps in use, and was separated into 5 categories: 2.0–3.9, 4.0–5.9, 6.0–7.9, 8.0–9.9, and ≥10 years. Patients with shorter durations of use (i.e., <2 years) were not included because brief durations of PPI use can be related to acute events that could influence the risk of medication use and cancer (e.g., cancer-related complications or symptoms).
Confounding was evaluated by examining the factors associated with each cancer by using the International Classification of Diseases, Ninth and Tenth Revisions coding, Laboratory Utilization and Results databases, and Systematized Nomenclature of Medicine (SNOMED) codes. All covariates were ascertained up to 6 months before the index date. For all cancer types, confounders included chronic alcohol consumption, smoking, body mass index (BMI), and family history of each cancer. For gastric cancer, other confounders included H. pylori infection, vitamin B12 deficiency, gastric intestinal metaplasia and dysplasia, atrophic gastritis, Barrett's esophagus, and peptic ulcer disease. For colorectal cancer, confounders included Crohn's disease, ulcerative colitis, and colonoscopy utilization. For liver cancer, confounders included chronic hepatitis B/C, hemochromatosis, alpha-1 antitrypsin deficiency, cirrhosis, diabetes mellitus, glycogen storage disease, gastrointestinal bleeding, fatty liver disease (alcoholic and nonalcoholic), and autoimmune hepatitis. For pancreatic cancer, confounders included cystic fibrosis, chronic pancreatitis, diabetes mellitus, and pancreatic cysts.
Conditional logistic regression was used for point estimations of odds ratios (ORs) and 95% confidence intervals (CIs). The primary analyses examined the odds of each cancer among patients with PPI use of ≥2 years compared to non-users (referent). In secondary analyses, we examined the risks for trends for PPI dose and duration of use, and, in exploratory analyses, by strata for the combination of dose and duration (intensity of use). We compared each category of PPI use with non-users and examined whether the risk was associated linearly with increasing mean daily dose, duration of use, or the combination. All analyses were adjusted for the listed cancer-specific covariates.
Sensitivity analyses included models excluding BMI as a covariate due to incomplete data. In addition, because of an inability to capture medication purchases outside KPNC pharmacies, there was a potential for misclassification of the exposure after 2004 when PPIs became available over the counter. Therefore, an analysis was conducted by computing ORs for each cancer separately for those diagnosed between 1996 and 2005 (to account for 2 years of misclassified PPI use after becoming available over the counter) and 2006 and 2016.
Effect modification was evaluated using product terms in the models and by evaluating stratum-specific ORs. Potential confounders, by cancer, were evaluated for known cancer-specific risk factors to evaluate consistency of known associations within the study population. Significance was defined as a 2-sided P value of <0.05. All analyses were performed using SAS version 9.4 (SAS Institute).
After the application of eligibility criteria, there were 1,233 gastric cancer cases matched to 10,543 controls, 18,595 colorectal cancer cases matched to 160,122 controls, 2,329 liver cancer cases matched to 19,987 controls, and 567 pancreatic cancer cases matched to 4,820 controls (see Figure 1, Supplemental Digital Content 1, http://links.lww.com/AJG/B464). Patient characteristics are shown in Table 1.
Main analysis: PPI use of ≥2 years and gastrointestinal cancer risk
In adjusted models, there were no significant associations between PPI use of ≥2 years and the risks of gastric (OR: 1.07, 95% CI: 0.81–1.42), colorectal (OR: 1.05, 95% CI: 0.99–1.12), liver (OR: 1.14, 95% CI: 0.91–1.43), or pancreatic cancers (OR: 1.22, 95% CI: 0.89–1.67) (Figure 1).
Site-specific analyses for gastric cancer did not reveal any associations between PPI use and cancers in either the cardia (cases = 341, OR: 0.98, 95% CI: 0.68–1.40) or noncardia regions (cases = 405, OR: 0.93, 95% CI: 0.66–1.31).
There were no associations between PPI use and gastric cancer risk among patients with (OR: 1.08, 95% CI: 0.50–2.34) or without a history of H. pylori infection (OR: 1.08, 95% CI: 0.80–1.45) (Pinteraction = 0.998).
Secondary analysis: PPI mean daily dose and gastrointestinal cancer risk
There were no statistically significant trends or evidence of dose relationships between increasing mean daily PPI dose and the risks of gastric, colorectal, liver, or pancreatic cancers (Figure 2) compared to non-users.
Secondary analysis: PPI duration of use and gastrointestinal cancer risk
PPI duration of use was not associated with gastric cancer (Figure 3). There was a significant trend for colorectal cancer attributed to a small elevated risk for PPI use of ≥10 years (OR: 1.28, 95% CI: 1.15–1.44) compared with no PPI use, although no associations were found for shorter durations of use. Similarly, elevated risks for PPI use of ≥10 years were found for liver (OR: 1.48, 95% CI: 1.04–2.10) and pancreatic cancers (OR: 1.79, 95% CI: 1.06–3.00), although there were no significant trends for increasing risk with time and even slightly shorter durations among heavier users (e.g., 8–9.9 years with ≥1.5 pills/day) were not associated with increased risks (ORs: 0.81, 95% CI: 0.20–3.31 and 0.73, 95% CI: 0.08–6.40 for liver and pancreatic cancers, respectively; Table 2).
Exploratory analyses: PPI intensity of use and gastrointestinal cancer risk
In examining PPI intensity of use, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use; however, risks were only detected in the 2 low-dose categories for colorectal cancer (<0.75 pills/day: OR, 1.34, 95% CI: 1.12–1.60 and 0.75–1.49 pills/day: OR, 1.24, 95% CI: 1.06–1.44) and only in the low-dose categories for liver (OR: 1.88, 95% CI: 1.08–3.29) and pancreatic cancers (OR: 1.75, 95% CI: 1.01–3.06) (Table 2). The exception was for gastric cancer where there was an increase in risk at the highest dose and duration of use (OR: 2.95, 95% CI: 1.23–7.90); however, as with liver and pancreatic cancer, no association was found for even slightly shorter durations among heavier users (OR: 0.57, 95% CI: 0.11–2.91, for 8–9.9 years with ≥1.5 pills/day).
In supplemental analyses, the removal of BMI from the models did not materially change the associations between PPI use of ≥2 years and the risks of gastric (OR: 1.11 [95% CI: 0.87–1.43]), liver (OR: 1.11, 95% CI: 0.90–1.38) or pancreatic cancers (OR: 1.25, 95% CI: 0.93–1.70); however, there was a weak association for colorectal cancer (OR: 1.09, 95% CI: 1.03–1.16).
There was no evidence of misclassification associated with over-the-counter PPI use based on the analyses stratified by the year PPIs became available over the counter (i.e., 2004). Specifically, there were no associations between PPI use of ≥2 years and the risks of gastric (OR: 1.69, 95% CI: 0.80–3.54), colorectal (OR: 1.07, 95% CI: 0.89–1.28), liver (OR: 1.08, 95% CI: 0.48–2.47), or pancreatic cancers (OR: 0.74, 95% CI: 0.23–2.37) before 2006. The same was true for the period of 2006 and later for gastric (OR: 1.00, 95% CI: 0.74–1.35), colorectal (OR: 1.04, 95% CI: 0.98–1.13), liver (OR: 1.16, 95% CI: 0.92–1.47), and pancreatic cancers (OR: 1.27, 95% CI: 0.92–1.77).
The associations between other known risk factors and risks of gastric, colorectal, liver, and pancreatic cancers were generally in accordance with the expected values (see Table 2, Supplemental Digital Content 1, http://links.lww.com/AJG/B464).
In this population-based case-control study, we found no associations between PPI use of ≥2 years and the risks of gastric, colorectal, liver, or pancreatic cancers. In secondary analyses stratified separately by the mean daily dose and duration of use, we saw no associations by dose, but we did observe elevations in the risks of colorectal, liver, and pancreatic cancers among those with ≥10 years of use. To explore this further, we examined the risks by the combination of mean daily dose and duration of use (intensity of use); the elevated risks persisted in those with ≥10 years of use, but there was no consistent dose relationship for any cancer and no associations for even slightly shorter durations among heavier users, increasing the possibility of confounding for long durations of use (see below).
The present study substantially expands our knowledge regarding the association between PPI use and gastric cancer risk. In a case-control study from Canada, a weak but significant association was reported between PPI use and gastric cancer (OR: 1.46, 95%: 1.22–1.74); however, this study was unable to adjust for several important confounders such as H. pylori status (27). A population-based cohort study in Denmark included H. pylori eradication history as a covariate and reported no increased risk between PPI use (defined as ≥2 prescriptions) and gastric cancer (incidence rate ratio: 1.2, 95% CI: 0.8–2.0) (13). In contrast, a recent cohort study from Hong Kong showed an increased risk of gastric cancer among PPI users treated for H. pylori (hazard ratio 2.4; 95% CI: 1.42–4.20) (23). Although both cohort studies accounted for H. pylori status, other potential confounding factors such as peptic ulcer disease and gastric intestinal metaplasia, which can lead to PPI prescriptions, were not included in their analyses. In our study, we were able to adjust for additional confounders not accounted for in prior studies (e.g., gastric intestinal metaplasia, vitamin B12, peptic ulcer disease) and found no significant increased risk of overall or site-specific gastric cancer with PPI use ≥2 years.
Our results are generally consistent with prior studies evaluating PPI use and colorectal cancer risk. In a population-based case-control study from Denmark, Robertson et al. found no excess colorectal cancer risk among long-term PPI users (16). A subsequent meta-analysis, including the Danish study, also showed no significant excess colorectal cancer risk (OR: 1.09, 95% CI: 0.98–1.22) among patients with PPI use ≥1 year compared to those with no PPI use (17). However, many of these studies lacked information on prior colonoscopy history or other conditions potentially associated with health care access which may influence both PPI utilization and cancer screening/detection, or with colorectal cancer risk (e.g., inflammatory bowel disease). For example, patients receiving PPIs for abdominal pain may be more likely to undergo colonoscopic evaluation and benefit from the protective effect of adenoma removal during colonoscopy or, conversely, may be more likely to have detection of asymptomatic incidental cancers. In our study, we were able to account for prior colonoscopy utilization and inflammatory bowel disease and found no association between PPI use of ≥2 years and colorectal cancer.
Studies examining the association of PPI use and risk of liver cancer have been primarily limited to Asian countries with large populations of people with viral hepatitis (12,18,19). More recently, in a population-based case-control study from Scotland, Tran et al. (20) found an increased risk (OR: 1.80, 95% CI: 1.34–2.41) of liver cancer among PPI users compared with never users. However, the study was limited by the possibility of reverse causation, given the attenuation of associations when prescriptions before diagnosis were removed, and for residual confounding, given they were unable to ascertain family history of liver cancer and several liver diseases that can lead to cirrhosis. In our study, which included diverse individuals across racial/ethnic groups, after adjusting for several important confounders, we found no association between PPI use of ≥2 years and liver cancer.
Several studies have examined the relationship between PPI use and pancreatic cancer with conflicting results. In a case-control study from Denmark, no association was reported (21), and similar results were seen in a nested case-control study within the United Kingdom general practice research database (22). In contrast, another case-control study from the United Kingdom found an increased risk of pancreatic cancer with PPI use (11); however, this study had a disproportionate number of short-term PPI users in the case group compared to the controls, leading to concerns of reverse causality - initiation of PPIs occurring as a consequence of symptoms of yet undiagnosed pancreatic cancer. Also, all these studies were unable to capture potential confounders such as pancreatic cysts and chronic pancreatitis, which are often diagnosed from cross-sectional imaging because of symptoms (e.g., abdominal pain) that may be initially treated with PPIs. In our study, we adjusted for important confounders and found no association between PPI use of ≥2 years and pancreatic cancer.
There are potential limitations to our study. In both secondary and exploratory analyses, we observed some increases in gastrointestinal cancer risk among patients with PPI use of ≥10 years. These associations may have occurred by chance, given the limited power for these analyses, wide confidence intervals observed, and the multiple comparisons made across strata in the exploratory analyses. The possibility for chance associations is also suggested by the lack of consistent patterns for increasing risk associated with increasing dose, duration of use, or the combination, and with no associations among even slightly shorter durations (e.g. 8–9.9 years). These findings also are susceptible to confounding by indication given the mean daily dose and duration of use were calculated using the first and last PPI prescription dates, with some patients having intermittent use of PPIs during these intervals (even though all patients had at least two years supply dispensed). For example, a person who took PPIs twice a day for five years would meet the study definition for long-term use. If they stopped and then, six years later, developed abdominal pain from a pancreatic cancer and restarted their PPIs for a few months prior to that cancer being diagnosed, that use would be averaged into an eleven year duration of use, even if the cancer was not caused by the PPIs. Thus, the potential cancer risks associated with PPI exposure of ≥10 years require further investigation in even larger data sets. Although members received discounted prescriptions for generic medications, some may have taken over-the-counter PPIs not detected by the pharmacy databases, leading to misclassification of exposure status, likely non-differential. However, a sensitivity analysis showed similar results for the time periods before vs. after when over-the-counter PPIs became available. The databases also lacked anthropometric data (i.e., height, weight and BMI) prior to the launch of the electronic health records in 2004; however, sensitivity analyses did not demonstrate that these data influenced the results. There was incomplete information on family history for each cancer, as it relied upon providers to manually record these data elements into the electronic health records.
Strengths of this study include the extremely large size of the underlying cohort; the diverse, community-based nature of the population; the large number of cancer cases; the ability to ascertain all recorded gastrointestinal cancer diagnoses within the study population (thereby minimizing referral bias); detailed electronic pharmacy data for dispensed medications (eliminating recall bias); and the selection of controls from the underlying general population. Comprehensive electronic databases allowed for the inclusion of multiple potential confounders in our statistical models that were not accounted for in some prior studies. Confounding by indication was minimized by defining PPI exposure as ≥2 years, given that short-term PPI use may be for acute medical conditions and hospitalizations related to cancer diagnoses.
In summary, we found no associations between PPI use of ≥2-years and the risks of gastric, colorectal, liver, or pancreatic cancer, and no consistent associations between increasing PPI dose and duration of use up to 10 years and cancer risk. The potential cancer risks associated with PPI use of ≥10 years requires further investigation.
CONFLICTS OF INTEREST
Guarantor of the article: Jeffrey K. Lee, MD, MPH.
Specific author contributions: Study concept and design: J.K.L., S.A.M. J.L.S., D.A.C. Acquisition of data: J.K.L., S.A.M., J.L.S., D.A.C. Analysis and interpretation of data: J.K.L., S.A.M., J.L.S., C.D.J., B.H.F., C.P.Q., D.A.C. Drafting of the manuscript: J.K.L., S.A.M., J.L.S., C.D.J., D.A.C. Critical revision of the manuscript for important intellectual content: J.K.L., S.A.M., J.L.S., C.D.J., B.H.F., C.P.Q., D.A.C. Statistical analysis: J.K.L., S.A.M., J.L.S., C.D.J., B.H.F., C.P.Q., D.A.C. Obtained funding: D.A.C. Technical or material support: J.K.L., D.A.C. Study supervision: J.K.L., D.A.C.
Financial support: Part of the original acquisition was funded by Pfizer as part of an FDA safety assessment of cancer risks related to proton pump inhibitors. Pfizer had no role in the analysis or interpretation of the study. In addition, this study was supported by a career development grant (K07 CA212057) from the National Cancer Institute (J.K.L.) and an American Gastroenterological Association Research Scholar Award.
Potential competing interest: None to report.
WHAT IS KNOWN
- ✓ PPIs are potent medications that reduce gastric acid secretion and are commonly prescribed for gastroesophageal reflux disease, peptic ulcer disease, and functional dyspepsia.
- ✓ While PPIs are effective for certain gastrointestinal disorders, there is concern about their long-term safety, particularly their potential for carcinogenicity.
- ✓ Epidemiologic studies examining the relationship between PPI use and gastrointestinal cancers have yielded contradictory results.
WHAT IS NEW HERE
- ✓ In this population-based case-control study from a large community-based setting, we found no associations between PPI use of ≥2 years and the risks of gastric, colorectal, liver, or pancreatic cancer.
- ✓ In addition, we found no consistent associations between increasing PPI dose and duration of use up to 10 years and the risks of gastric, colorectal, liver, or pancreatic cancer.
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