Long-term PPI Use and Increased Cancer Risk: An Unrevealed Truth

Proton pump inhibitors (PPIs) are commonly prescribed to reduce stomach acid levels in managing gastroesophageal reflux disease (GERD) complications, including conditions like esophageal ulcers, bleeding, and peptic strictures. The safety and efficacy of PPIs in alleviating symptoms and preventing acid-related disorders such as heartburn are well-established. (1)

An association between PPIs and an increased risk of gastric cancer has been reported. PPIs work by reducing gastric acid production, which can accelerate the secretion of gastrin. This increase in gastrin levels has been linked to a higher risk of gastric cancer, particularly in the gastric corpus, where hypergastrinemia can contribute to the development of carcinomas. Long-term use of PPIs has been suggested to potentially raise cancer risk, even in patients treated for H. pylori eradication. (1)

Contributors to Malignancies: Modern Lifestyle & Medications

Emerging cancer burdens globally, particularly affecting middle-to-low socioeconomic countries like India, are attributed to various new and challenging causes. These include rapid urbanization, population aging, sedentary and unhealthy lifestyles, and indoor and outdoor air pollution. These factors collectively contribute to the increasing cancer incidence and pose significant challenges to public health. (2)

Among the most widely prescribed drugs, ARBs (angiotensin receptor blockers) raise the risk of lung cancer, in particular with increased cumulative exposure to the medicine (3), PPI increases the risk of gastric cancer [Relative Risk ratio 1.80, 95% Confidence Interval, 1.46-2.22, p<0.001] (1), long-term ACE (angiotensin-converting enzyme) suppression carry a higher risk of colorectal cancer. (4)

Mechanistic Insights: Examining Proposed Pathways for the PPI-Cancer Association

• The suppression of stomach acid at a significant level is believed to be a potential risk factor for gastric cancer. It is thought to occur by worsening gastric atrophy, leading to increased gastrin levels and bacterial overgrowth in the stomach. In individuals infected with H. pylori, a bacterium that causes inflammation primarily in the gastric antrum, acid production remains normal or high. However, when PPIs suppress acid production, the pattern of gastritis changes, impairing the function of parietal cells. This phenomenon is specific to H. pylori-positive patients. (5)
• PPIs, which suppress gastric acid production, trigger a compensatory increase in gastrin production. This rise in gastrin levels is believed to promote the growth of cells and potentially contribute to the development of gastric cancer. Extended use of PPIs has been linked to the hyperplasia of enterochromaffin-like (ECL) cells in the oxyntic mucosa, affecting around 10-20% of patients. (5)
• PPIs suppress gastric acid and can cause bacterial overgrowth in the stomach, even without H. pylori infection. This overgrowth worsens inflammation. Simultaneous infection with H. pylori and non-H. Pylori bacteria increases cytokine production and the risk of atrophic gastritis. Increased bacteria, including oral flora, can convert food nitrates into carcinogenic compounds. (5)

• Cheung et al. conducted a population-based study analyzing 63,397 individuals (46.5% men, 53.5% women). Among them, 153 individuals (0.24%) were diagnosed with gastric cancer despite successful H. pylori eradication. After adjusting for propensity scores, PPI users (with at least weekly use) had a significantly higher risk of gastric cancer (HR 2.44, 95% CI 1.42-4.20). Sensitivity analyses using multivariable analysis and propensity score adjustment without trimming supported this association (HR 2.19, 95% CI 1.31-3.66 and HR 2.14, 95% CI 1.27-3.58, respectively). These findings established a connection between PPI use and gastric cancer incidence. (6)
• Brusselaers et al. analyzed 797,067 subjects (41.5% men, 58.5% women) in a population-based study. 2,219 individuals (0.28%) developed gastric cancer during the follow-up. The study found that PPI-exposed individuals had a significantly increased risk of gastric cancer, with a standardized incidence ratio (SIR) of 3.38 (95% CI 3.25-3.52). This risk was observed for both cardia gastric and non-cardia gastric cancers. Across all age groups, the highest increase was seen in participants aged 19–40 (SIR 22.76, 95% CI 15.94-31.52). The study suggests that long-term PPI use may independently contribute to the risk of gastric cancer. (7)
• Chubak et al. conducted a case-control study with 641 case-control pairs with an average age of 70. The cohort included 51.6% females, and the average enrollment duration was 19 years. Compared to non-users of acid suppression medications, exclusive use of PPIs showed a modest association with colorectal cancer risk (OR = 1.7, 95% CI = 0.8, 4.0). The study suggests a potential modest association between PPI use and an increased risk of colorectal cancer. (8)

Evidence from scientific studies suggests that long-term PPI use is associated with an increased risk of gastric cancer. Guidelines for deprescribing PPI therapy have been developed to offer valuable recommendations for patients and healthcare professionals when considering the discontinuation of PPIs.

• Indian Society of Gastroenterology’s “Guidelines on optimizing the use of proton pump inhibitors” 2023 recommended discontinuing PPI if there is no definite indication (strong recommendation). The guideline also recommends against prolonged or continuous use of PPI in patients with uninvestigated dyspepsia without alarm features; for patients with NERD (non-erosive reflux disease) or mild GERD, if maintenance PPI is required, on-demand therapy is recommended. (strong recommendations)The guideline also recommended against routine PPI prophylaxis in patients on short- or long-term corticosteroids and all patients on non-steroidal anti-inflammatory drugs. Routine use of PPIs is not recommended in patients receiving pancreatic enzyme therapy. (strong recommendations) (9)
• The National Prescribing Service in Australia has devised an algorithm that follows a stepwise approach for patients with GERD, considering symptom control to determine the appropriate step-down or step-up approach in treating reflux symptoms. (10)
• The Canadian algorithm provides various deprescribing approaches (e.g., dose reduction, on-demand use, or abrupt discontinuation) without specifically favoring one optimal approach. It also recommends follow-up appointments at four and twelve weeks. (10)
• Lifestyle modifications and medications such as H2 receptor antagonists have also been recommended for use. (10)

• Proton pump inhibitors are commonly prescribed to treat gastric-related disorders by reducing stomach acid levels and treating acid-peptic diseases.
• An increased risk of gastric cancer has been associated with long-term PPI use.
• PPIs reduce gastric acid levels, leading to increased gastrin levels, which may contribute to the development of gastric cancer.
• Studies have supported the association between PPI use and increased risk of gastric cancer and a potential modest association with colorectal cancer.
• Guidelines for deprescribing PPI therapy have been developed, emphasising gradual dose reduction, on-demand therapy, and considering medications such as H2 receptor blockers like Ranitidine, Famotidine, etc and lifestyle modifications.