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Regular use of proton pump inhibitors (PPIs) was significantly associated with a greater risk for inflammatory bowel disease (IBD) and its subtypes, a pooled analysis of three observational studies found.

In examining the Nurses' Health studies and U.K. Biobank cohort, multivariate analyses showed that individuals taking PPIs regularly were at increased risk for IBD compared with non-regular PPI users (HR 1.42, 95% CI 1.22-1.65) and with those taking H2 receptor antagonists (HR 1.38, 95% CI 1.16-1.65), reported Changhua Zhang, MD, of Sun Yat-sen University in China, and colleagues in .

The results for regular PPI versus non-regular PPI use were also consistent for both ulcerative colitis (HR 1.36, 95% CI 1.02-1.81) and Crohn's disease (HR 1.62, 95% CI 1.27-2.09), with analyses adjusting for numerous confounders, including the underlying conditions for which the drugs are indicated.

"This association should be interpreted with caution as the study design is observational," the group noted. "Besides, the associated absolute risk was modest as compared with the well-documented benefits of PPIs for acid-related gastrointestinal disorders."

Absolute risk for IBD increased by 26.52 per 100,000 person-years, with a number needed to harm of 3,770 (95% CI 3,668-4,369), according to the authors.

Long-term use of PPIs can alter the gut , posing a potential risk for IBD. Some studies have also suggested increased presence of Escherichia coli and Clostridium difficile species with PPI use, as well as a reduction in Faecalibacterium, both of which are also observed in IBD patients. have shown that PPIs may benefit patients with ulcerative colitis by decreasing risk for pouchitis.

For their study, Zhang and colleagues pooled data from three population-based cohorts: the Nurses' Health Study () I (1976; n=82,869) and II (1989; n=95,141), and the (2006; n=469,397). In all, 647,407 participants were included, with a median follow-up of 12 years with the NHS cohorts and 8.1 years for the U.K. Biobank cohort. Participants who used PPIs were excluded if they had a prior IBD or cancer diagnosis (other than non-melanoma skin cancers). Validated questionnaires were given to patients to obtain their medical history and demographics, which were followed by verified interviews.

There were 271 IBD cases among the NHS cohorts (57 in regular PPI users and 214 in non-regular PPI users) and 1,419 IBD cases (243 and 1,176, respectively) in U.K. Biobank.

Mean participant age in the NHS cohorts (100% women; over 96% white) was 55 years for non-regular PPI users and 57 for regular PPI users. Mean participant age in the U.K. Biobank study (54% women; 94% white) was 56 for non-regular PPI users and 59 for regular PPI users.

Compared to non-PPI users, regular PPI users were more likely to be smokers, have obesity, be less physically active, and be post-menopausal or use hormones. PPI users were more likely to take non-steroidal anti-inflammatory drugs (NSAIDs), H2 receptor antagonists, and aspirin, and were more likely to have gastroesophageal reflux disease (GERD), gastrointestinal ulcers, and upper gastrointestinal bleeding.

Researchers observed consistent results across the NHS and U.K. studies. Analyses by individual type of PPIs, including omeprazole (Prilosec) and lansoprazole (Prevacid), also showed significant associations with risk for IBD.

The multivariate analysis controlled for age, race, sex, body mass index, menopausal status, smoking history, alcohol use, physical activity, and diet quality; incidence of GERD, ulcers, or gastrointestinal bleeding; as well as regular use of NSAIDS or aspirin, statins, or oral contraceptives or hormonal therapy. Sensitivity analyses that controlled for other medications and diseases yielded similar results, as did an analysis using propensity score matching.

Study limitations included the risk for PPI use to be misclassified due to a lack of reevaluation beyond baseline, and residual confounding factors, the authors acknowledged. Furthermore, time exposure analysis, and PPI dosing and frequency were unavailable, with Helicobacter pylori eradication left unexplored. The cohorts also consisted of "healthy volunteers," with the NHS studies solely comprising female healthcare workers and lacking diversity.

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