Clinical Question

Is there an association between gastric cancer and the use of proton pump inhibitors (PPIs)?

Bottom Line

This is the strongest evidence to date that there is a small but clinically significant increase in the risk of gastric cancer for patients taking a PPI (number needed to harm = 1,191 over 10 years). Physicians initiating antacid therapy should begin with a histamine H₂ receptor antagonist and, if prescribing a PPI, should use the lowest dose and duration possible. Another study using data from a Korean registry produced similar findings (Gut. 2021;70:2066–2075). (Level of Evidence = 2b)

Synopsis

PPIs cause hypergastrinemia and can lead to hyperplasia of the gastric mucosa. Several studies have shown an association between PPI use and gastric cancer. This study is the largest and most methodologically sound; it addresses several potential sources of confounding better than previous studies. The authors identified more than 1.1 million people who had received a new prescription for a PPI between 1990 and 2018, and another 220,825 people who had received a new prescription for an H₂ receptor antagonist during the same period. This is a better comparison group than the general population because it avoids confounding by indication (i.e., patients who take PPIs may have different risk factors and health habits than patients who do not). People with a familial syndrome associated with gastric cancer or a history of gastric cancer, and those who had less than one year of follow-up were excluded, leaving 973,281 patients who take PPIs and 198,306 patients who take an H₂ receptor antagonist. The authors matched patients using propensity scores that incorporated an array of potential confounders, including age, comorbidities, tobacco and alcohol use, and medications. In the fully adjusted model, the authors found a significantly increased risk of gastric cancer in patients taking PPIs compared with patients taking an H₂ receptor antagonist (hazard ratio [HR] = 1.45; 95% CI, 1.06 to 1.98; numbers needed to harm = 2,121 after five years and 1,191 after 10 years). The Kaplan-Meier survival analysis showed that the risk increased linearly with the duration of PPI use. Greater doses were associated with increased risk: HR = 1.22 for less than 14,600-mg cumulative omeprazole (Prilosec) dose equivalents; HR = 1.81 for 14,600-mg to 28,199-mg dose equivalents; and HR = 2.03 for 29,200-mg and higher dose equivalents (although the CIs overlap).