Effect of the long-term use of proton pump inhibitors on the rate of pre-cancerous lesions in the stomach

Review question

Does long-term proton pump inhibitor (PPI) use increase the risk of having pre-cancerous lesions (changes in the stomach lining that are not cancer but could become cancerous over time) in the stomach?


PPIs are the most effective drugs used to reduce gastric acid secretion (called antacids) and they are commonly prescribed worldwide. Although generally safe, their effectiveness and safety for long-term use remains unclear. It has been suggested that the long-term use of PPIs could promote the development of pre-cancerous lesions in the stomach, which might subsequently increase the occurrence of stomach cancer. Therefore, the safety issues of long-term PPI treatment needs to be addressed.

Study characteristics

We searched databases in August 2013 for randomised controlled trials (clinical trials where people are randomly allocated to one of two or more treatment groups) conducted in adults (aged 18 years or over) who did not have gastric cancer at the start of the trial. Treatment had to be with PPI for six months or more and be compared with no treatment, surgery/endoscopic treatment (where a tube is passed down the food pipe and into the stomach), or any other antacid treatment.

We found seven randomised controlled trials with 1789 participants. Some trials only partially reported gastric pre-cancerous lesions, and there was a substantial proportion of participants with missing data.

Key results

We concluded that there was no clear evidence to support the notion that the long-term use of PPIs could promote the development of pre-cancerous lesions. However, there was a potentially elevated risk of developing a thickening of the stomach lining (hyperplasia) among participants with long-term PPI use, which is considered as a possible pre-condition of gastric carcinoid (a relatively benign (non-cancerous) tumour that develops within the stomach lining).

Quality of the evidence

Currently, available evidence was of low or very low quality, due to their study design and the large proportion of missing data. We therefore suggest future well-designed clinical trials should be performed for providing better understandings regarding this question.

Authors' conclusions: 

There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although results were imprecise. People with PPI maintenance treatment may have a higher possibility of experiencing either diffuse (simple) or linear/micronodular (focal) ECL cell hyperplasia. However, the clinical importance of this outcome is currently uncertain.

Read the full abstract...

Proton pump inhibitors (PPIs) are the most effective drugs to reduce gastric acid secretion. PPIs are one of the most commonly prescribed classes of medications worldwide. Apart from short-term application, maintenance therapy with PPIs is recommended and increasingly used in certain diseases, such as Zollinger-Ellison syndrome and gastro-oesophageal reflux disease, especially for people with erosive oesophagitis or Barrett's oesophagus. Although PPIs are generally safe, their efficacy and safety of long-term use remains unclear. The question of whether the long-term use of PPIs could promote the development of gastric pre-malignant lesions has been widely investigated, but results are inconsistent. Limited insight on this problem leads to a dilemma in decision making for long-term PPI prescription.


To compare the development or progression of gastric pre-malignant lesions, such as atrophic gastritis, intestinal metaplasia, enterochromaffin-like (ECL) cell hyperplasia, and dysplasia, in people taking long-term (six months or greater) PPI maintenance therapy.

Search strategy: 

We searched the following databases (from inception to 6 August 2013): the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL. In addition, we searched the reference lists of included trials and contacted experts in the field.

Selection criteria: 

We searched for randomised controlled trials (RCTs) in adults (aged 18 years or greater) concerning the effects of long-term (six months or greater) PPI use on gastric mucosa changes, confirmed by endoscopy or biopsy sampling (or both).

Data collection and analysis: 

Two review authors independently performed selection of eligible trials, assessment of trial quality, and data extraction. We calculated odds ratios (OR) for analysis of dichotomous data and mean differences for continuous data, with 95% confidence intervals (CI).

Main results: 

We included seven trials (1789 participants). Four studies had high risk of bias and the risk of bias in the other three trials was unclear. In addition, it was difficult to assess possible reporting bias. We pooled 1070 participants from four RCTs to evaluate corporal atrophy development revealing an insignificantly increased OR of 1.50 (95% CI 0.59 to 3.80; P value = 0.39; low-quality evidence) for long-term PPI users relative to non-PPI users. In five eligible trials, corporal intestinal metaplasia was assessed among 1408 participants, also with uncertain results (OR 1.46; 95% CI 0.43 to 5.03; P value = 0.55; low-quality evidence). However, by pooling data of 1705 participants from six RCTs, our meta-analysis showed that participants with PPI maintenance treatment were more likely to experience either diffuse (simple) (OR 5.01; 95% CI 1.54 to 16.26; P value = 0.007; very-low-quality evidence) or linear/micronodular (focal) ECL hyperplasia (OR 3.98; 95% CI 1.31 to 12.16; P value = 0.02; low-quality evidence) than controls. No participant showed any dysplastic or neoplastic change in any included studies.