Proton Pump Inhibitor Use and Risk of Gastric, Colorectal, Liver, and Pancreatic Cancers in a Community-Based Population

Abstract

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the association between PPI use and gastrointestinal cancers. METHODS: We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. RESULTS: PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]: 1.07, 95% confidence interval [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), compared to non-users. In exploratory analyses, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use, but no consistent associations were found for increasing PPI dose and/or duration of use. DISCUSSION: PPI use of ≥2 years was not associated with increased risks of gastrointestinal cancers. The cancer risks associated with PPI use of ≥10 years requires further study.

Does the Use of Proton Pump Inhibitors Increase the Risk of Pancreatic Cancer? A Systematic Review and Meta-Analysis of Epidemiologic Studies

“…They were published between 2012 and 2020 in six countries. Three studies were conducted in the UK [ 36 , 37 , 41 ], two in the USA [ 32 , 42 ], two in Taiwan [ 30 , 33 ], one in Korea [ 35 ], one in Denmark [ 34 ] and one in Sweden [ 43 ]. The follow-up duration was between 5 and 20 years.…”

“…The diagnosis of pancreatic cancer was based on the ICD codes in six studies [ 30 , 32 , 33 , 35 , 42 , 43 ], medical record code in two studies [ 36 , 37 ], and histological verification of PDA in two studies [ 34 , 41 ]. Stratified analysis according to the PPI dose and duration was performed in five studies [ 32 , 33 , 34 , 35 , 36 ] and in the five other studies [ 32 , 33 , 36 , 37 , 43 ], respectively, although they all used a different cutoff value of dose and duration. In six studies, pancreatic cancer cases that developed within 1 or 2 years after PPI introduction were excluded because PPI was probably used to help in treating and diagnosing cancer-associated symptoms [ 30 , 32 , 33 , 34 , 35 , 36 ].…”

“…Stratified analysis according to the PPI dose and duration was performed in five studies [ 32 , 33 , 34 , 35 , 36 ] and in the five other studies [ 32 , 33 , 36 , 37 , 43 ], respectively, although they all used a different cutoff value of dose and duration. In six studies, pancreatic cancer cases that developed within 1 or 2 years after PPI introduction were excluded because PPI was probably used to help in treating and diagnosing cancer-associated symptoms [ 30 , 32 , 33 , 34 , 35 , 36 ]. Table 1 lists the clinical characteristics of the included studies.…”

“…First, each study was inconsistent in defining the dose and duration of PPIs. Regarding the dose, one study used “pills/day” [ 32 ], whereas four studies used “defined daily dose (DDD)” as a unit [ 33 , 34 , 35 , 36 ]. Moreover, the cutoff value of dose was different in each study.…”

“…For the early undiagnosed pancreatic cancer symptoms that often present as nonspecific abdominal symptoms, PPIs may have been administered to alleviate these symptoms. Hence, to reduce protopathic bias, we excluded pancreatic cancer cases that were diagnosed within 1 or 2 years after PPI exposure in six of the selected articles [ 30 , 32 , 33 , 34 , 35 , 36 ]. In agreement with this decision, we extracted the data of long-term users in Kearns et al [ 37 ].…”