By Seema Gupta, MD, MSPH
Synopsis: A large retrospective cohort study demonstrated that long-term use of proton pump inhibitors is associated with an increased risk of developing colorectal adenocarcinoma.
Source: Liu Q, Wang X, Engstrand L, et al. Maintenance proton pump inhibitor use and risk of colorectal cancer: A Swedish retrospective cohort study. BMJ Open 2024;14:e079591.
Proton pump inhibitors (PPIs) have become one of the most commonly prescribed classes of medications in the United States. Their use has surged, particularly since the early 2000s, because of their effectiveness in treating acid-related disorders, such as gastroesophageal reflux disease and peptic ulcers. There also is widespread “off-label” use, including over-the-counter use for prophylaxis against gastritis associated with a number of medications, such as corticosteroids, nonsteroidal anti-inflammatory drugs, anticoagulants, and chemotherapy.
Although PPIs generally are considered safe for short-term use, evidence of serious side effects with long-term use is mounting. These potential risks include increased risk of pneumonia, enteric infection, bone fracture, reduced absorption of vitamins and minerals, and gastrointestinal tract cancers.1 Several studies have suggested a link between long-term PPI use and an increased risk of developing certain cancers, including gastric, esophageal, and pancreatic.2
A potential mechanism by which PPIs may contribute to cancer development is their effect on the gut microbiome, leading to dysbiosis.3 By raising the gut pH, PPIs may alter the gut microbiome, thus reducing the diversity and number of beneficial bacteria while promoting the overgrowth of harmful bacteria that produce carcinogens. The resulting hypergastrinemia from an increased pH in the stomach also has been associated with the proliferation and hyperfunction of enterochromaffin-like (ECL) cells, which is closely associated with an increased risk of cancer.4 While some studies have demonstrated elevated colorectal adenocarcinoma (CRA) risk with the long-term use of PPIs, others have dismissed this finding.5,6
Liu et al conducted a retrospective cohort study by using data from Swedish national registries to identify all adults who had ≥ 180 days of cumulative PPI use between July 2005 and December 2012, excluding participants who were followed up for < 1 year. Overall, 754,118 maintenance PPI users were enrolled and followed up for a median duration of 5.3 years. The primary outcome was the CRA risk in the exposed population presented as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs).
The researchers found that the maintenance PPI users exhibited a small, elevated risk of CRA compared to the general population (SIR, 1.10; 95% CI, 1.06 to 1.13). Both men (SIR, 1.13; 95% CI, 1.08 to 1.18) and women (SIR, 1.10; 95% CI, 1.06 to 1.15) had a potentially high risk of developing CRA compared to the general population. Study participants aged 18-39 years (SIR, 2.79; 95% CI, 1.62 to 4.47) and 40-49 years (SIR, 2.02; 95% CI, 1.65 to 2.45) had a significantly higher risk compared with the general population. Right-sided colorectal adenocarcinoma was linked with a higher risk than in the general population (SIR, 1.26; 95% CI, 1.20-1.32). The study authors concluded that maintenance PPI use may be associated with an increased risk of CRA.
Commentary
Liu et al found a 10% higher risk of CRA in patients using maintenance PPIs compared to the general population in this large study. However, those aged 18-49 years may be at an even higher risk. Colorectal cancers grow slowly, sometimes taking decades to develop from polyp to adenocarcinoma. Therefore, while the current study had a median follow-up of 5.3 years, a longer follow-up time and evaluating the prevalence of other factors, such as obesity, smoking, alcohol, and diet may be more informative.
However, it is important to note that there is evidence that the incidence of colorectal cancer is increasing among younger adults in the United States and other high-income countries because of a number of factors, including lifestyle changes, dietary habits, obesity, and decreased physical activity.7 Early-onset disease (< 50 years of age) accounts for 10% of colorectal cancer cases, and that is perhaps why screening is now recommended to begin at 45 years of age.
Longer term studies to further evaluate the risk of CRA with the use of maintenance PPIs are needed. However, in a clinical practice, it may be prudent to balance the benefits of using maintenance PPIs in certain clinical scenarios with the potential risks, including CRA, associated with their long-term use particularly in specific high-risk populations.
Seema Gupta, MD, MSPH, is Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
References
- Koyyada A. Long-term use of proton pump inhibitors as a risk factor for various adverse manifestations. Therapie 2021;76:13-21.
- Sawaid IO, Samson AO. Proton pump inhibitors and cancer risk: A comprehensive review of epidemiological and mechanistic evidence. J Clin Med 2024;13:1970.
- Bruno G, Zaccari P, Rocco G, et al. Proton pump inhibitors and dysbiosis: Current knowledge and aspects to be clarified. World J Gastroenterol 2019;25:2706-2719.
- Waldum HL, Rehfeld JF. Gastric cancer and gastrin: On the interaction of Helicobacter pylori gastritis and acid inhibitory induced hypergastrinemia. Scand J Gastroenterol 2019;54:1118-1123.
- Ma T, Wu M, Jia S, Yang L. Proton pump inhibitors and the risk of colorectal cancer: A systematic review and meta-analysis of observational studies. Int J Colorectal Dis 2020;35:2157-2169.
- Patel A, Spychalski P, Antoszewska M, et al. Proton pump inhibitors and colorectal cancer: A systematic review. World J Gastroenterol 2021;27:7716-7733.
- Sifaki-Pistolla D, Poimenaki V, Fotopoulou I, et al. Significant rise of colorectal cancer incidence in younger adults and strong determinants: 30 years longitudinal differences between under and over 50s. Cancers (Basel) 2022;14:4799.
A large retrospective cohort study demonstrated that long-term use of proton pump inhibitors is associated with an increased risk of developing colorectal adenocarcinoma.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content