Proton Pump Inhibitors Not Linked to Increased All-Cause, Major Cause Mortality Risk

Mixed race woman holding medication pills
Researchers examined the association between proton pump inhibitor use and mortality among patients.

Proton pump inhibitor (PPI) use was not significantly associated with an increased risk for all-cause mortality or mortality due to major causes after lag times of up to 6 years were applied and protopathic bias was accounted for, according to a study published in Gastroenterology.

For the prospective cohort study, researchers used data from the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) to assess the association between PPI use and mortality. NHS enrolled 121,700 female registered nurses aged 30 to 55 years in 1976, and the Health Professionals Follow-up Study (HPFS) included 51,529 male health professionals aged 40 to 75 years in 1986. Researchers used Cox proportional hazards models to calculate hazard ratios, 95% confidence intervals (CI) for mortality, and applied modified lag times to the analysis.

With the modified lag time approach, any increased PPI use during the excluded period, which could result from comorbid conditions before death, was not considered in the quantification of the exposure, which helped avoid protopathic bias.

Information regarding PPI use was obtained from biennial follow-up questionnaires beginning in 2000 in the NHS and 2004 in the HPFS and was updated every 2 years. The main outcome was death from all and different causes that occurred after the 2004 questionnaire was returned and before June 1, 2018.

The analysis included 50,156 women and 21,731 men with 831,407 person-years during a median follow-up of 13.8 years. The women had a mean age at baseline of 68.9 years, and the men had a mean age of 68.0 years. A total of 22,125 deaths were confirmed, including 4592 deaths from cancer, 5404 from cardiovascular diseases, and 12,129 from other causes.

Of the cohort, 10,998 women (21.9%) and 2945 men (13.6%) initiated PPI use during the study period, and PPI use increased from 6.1% to 10.0% in women and from 2.5% to 7.0% in men.

PPI users had a significantly increased risk for all-cause mortality after adjustment for time-varying confounding compared with nonusers (hazard ratio [HR], 1.19; 95% CI, 1.13-1.24). PPI use also was associated with an increased risk for cause-specific mortality, including mortality from cancer (HR, 1.30; 95% CI, 1.17-1.44), cardiovascular disease (HR, 1.13; 95% CI, 1.02-1.26), respiratory diseases (HR, 1.32; 95% CI, 1.12-1.56), digestive diseases (HR, 1.50; 95% CI, 1.10-2.05), and renal diseases (HR, 2.09; 95% CI, 1.50-2.90).

Use of a 6-year lag time led to reduced HRs for all-cause mortality (HR, 1.04; 95% CI, 0.97-1.11) and mortality due to cancer (HR, 1.07; 95% CI, 0.89-1.28), cardiovascular disease (HR, 0.94; 95% CI, 0.81-1.10), respiratory diseases (HR, 1.20; 95% CI, 0.95-1.50), and digestive diseases (HR, 1.38; 95% CI, 0.88-2.18). However, PPI use was still associated with a significantly elevated risk for mortality due to renal diseases (HR, 2.45; 95% CI, 1.59-3.78).

The mortality risk for upper gastrointestinal cancer (HR, 1.06; 95% CI, 0.73-1.54) and colorectal cancer (HR, 1.27; 95% CI, 0.83-1.95) was attenuated after a 2-year lag time was applied. No significant association was observed between PPI use and mortality due to lung cancer (HR, 1.16; 95% CI, 0.84-1.60) and ovarian cancer (HR, 0.57; 95% CI, 0.26- 1.25) after a 4-year lag time was applied.

Regarding all-cause mortality and mortality due to cancer, cardiovascular diseases, respiratory diseases, and digestive diseases, the highest HRs were found primarily in individuals who reported PPI use for 1 to 2 years. A longer duration of PPI use was not associated with a higher risk for mortality for these endpoints.

Study limitations included using mostly White health professionals, and that information on PPI brand, dosage, and schedule was not obtained. Also, the number of events for certain outcomes among PPI users was relatively small compared with other studies, especially when longer lag times were applied. Furthermore, data were not available for all potential confounding medical conditions, and the inability to adjust for specific medical conditions could have led to residual confounding.

“Despite the lack of association with risk of death, it remains prudent to recommend the use of these agents to patients with appropriate indications and for the minimally effective duration,” the researchers commented.

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Lo C-H, Ni P, Yan Y, et al. Association of proton pump inhibitor use with all-cause and cause-specific mortality. Gastroenterology. Published online June  30, 2022. doi:10.1053/j.gastro.2022.06.067