Peer-reviewed studies on proton pump inhibitors, including observational cohorts, systematic reviews, and meta-analyses covering infection risk, kidney outcomes, fractures, mortality, cognition, and cancer. The list is weighted toward studies published from 2016 through 2025.
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This 2025 systematic review and meta-analysis included 29 studies and found significantly higher SIBO prevalence among PPI-treated patients than controls. It also reported a duration-dependent relationship, with longer treatment linked to progressively higher SIBO risk.
This 2025 systematic review and dose-response meta-analysis found that PPI use remained a meaningful modifiable risk factor for C. difficile infection, with quantitative analyses across hundreds of thousands of patients evaluating both defined daily dose and treatment duration.
This 2024 systematic review and meta-analysis concluded that PPI use was associated with a higher incidence of chronic kidney disease, reinforcing the long-running renal safety signal seen in earlier observational work.
Analyzing over 2 million participants across five prospective cohorts, this Nature Communications study linked PPI use with higher risk of 15 major diseases, including ischemic heart disease, diabetes, respiratory infections, and chronic kidney disease. Absolute risk was concentrated in higher-baseline-risk patients.
In a multicentre cohort of 1,485 cirrhotic patients with prior hepatic encephalopathy, high-dose PPI treatment was independently associated with higher mortality (adjusted HR 1.71). The study also examined recurrent HE, spontaneous bacterial peritonitis, and hepatorenal syndrome.
Using Swedish national registries from 2005 to 2019, this self-controlled case series found PPI-exposed periods were followed by a 73% increased pneumonia risk (IRR 1.73), while H2 blockers showed only a small signal.
This systematic review and meta-analysis included 24 studies and more than 8 million participants. PPI use was associated with higher gastric cancer risk (RR 1.82), with a stronger signal at longer durations, but not with a statistically significant increase in colorectal cancer risk.
This 2023 meta-analysis of 20 studies found no statistically significant relationship between PPI use and esophageal adenocarcinoma risk (OR 0.67, 95% CI 0.39-1.29), suggesting PPIs were neither clearly protective nor clearly harmful in this setting.
This systematic review and meta-analysis of 16 cohort and case-control studies found PPI use was associated with gastric cancer risk (OR 1.75), with a stronger signal for non-cardia gastric cancer. The authors stressed that association does not prove causation.
This 2022 meta-analysis included eight studies with 157,758 participants and found a significantly higher risk of inflammatory bowel disease with PPI exposure (adjusted OR 2.43), with stronger signals for collagenous and lymphocytic colitis.
This 2022 umbrella review synthesized 21 meta-analyses covering 10 cancer types and found stronger evidence for associations with gastric, pancreatic, colorectal, and liver cancer, but not with esophageal cancer.
In 501,002 UK Biobank participants followed through 2018, regular PPI use was associated with higher incident all-cause dementia (HR 1.20), Alzheimer’s disease (HR 1.23), and vascular dementia (HR 1.32), with stronger associations in APOE ε4 heterozygotes.
In a UK cohort comparing 733,885 new PPI users with 124,410 H2 blocker users, PPI prescription was associated with higher all-cause mortality in observational analyses. The authors noted that residual confounding likely explains at least part of the association.
An updated meta-analysis of 23 studies involving 10,386 cirrhotic patients found a statistically significant but weaker-than-previously-estimated association between PPI use and spontaneous bacterial peritonitis (overall OR 1.80).
This 2020 observational study reported a dose-dependent association between cumulative PPI exposure and gastric intestinal metaplasia, with stronger signals among Helicobacter pylori-positive patients than H. pylori-negative patients.
This 2020 systematic review and meta-analysis pooled eight studies with 40,295 participants and found that cirrhotic patients with PPI exposure had a significantly higher pneumonia risk, with a pooled risk ratio of 1.36.
This 2020 systematic review and meta-analysis evaluated pregnancy exposure to PPIs and did not find a significant increase in major congenital malformations, spontaneous abortion, or preterm delivery, supporting a more reassuring safety profile in this setting.
This meta-analysis pooled 16 observational studies with 131,507 patients and found that PPI use was associated with hypomagnesemia (adjusted OR 1.71). Higher-dose PPI exposure was linked to even greater odds.
This updated 2019 meta-analysis of 10 studies involving 642,305 participants found no significant association between PPI use and dementia (HR 1.04) or Alzheimer’s disease (HR 0.96), despite high heterogeneity.
This meta-analysis pooled nine studies in advanced liver disease and found elevated hepatic encephalopathy risk in PPI users. The pooled RR for cohort studies was 1.67, while case-control studies showed a pooled OR of 2.58.
This updated fracture meta-analysis found that PPI use was associated with increased hip, spine, and any-site fracture risk, while evidence for major changes in bone mineral density remained less consistent.
The reported prevalence of small intestinal bacterial overgrowth (SIBO) among individuals with irritable bowel syndrome (IBS) is highly variable. This study estimates the prevalence and identifies predictors of SIBO in IBS.
Long-term maintenance therapy with PPIs was associated with an increased risk for esophageal cancer, even in patients taking PPIs for indications not previously linked to this cancer risk.
Among 63,397 eligible subjects, 153 developed gastric cancer during a median follow-up of 7.6 years. PPI use was associated with an increased GC risk (HR 2.44). Risk increased with duration of use.
Fifty-six studies (40 case-control, 16 cohort) involving 356,683 patients showed increased risk for CDI despite substantial statistical heterogeneity among studies.
PPI use was not associated with an increased risk for cognitive decline in an analysis of data from the Nurses' Health Study II — a large prospective study of 13,864 women.
A US study of 350,000 veterans found PPI users had a 25% increased risk of death compared with H2 blocker users over five years. The effect strengthened with longer use.
PPI use was associated with a 64% increased risk of acute kidney injury (AKI) and a 40% higher risk of chronic kidney disease progression.
Among 10,482 incident PPI users and 15,067 incident H2 blocker users, PPI use was associated with a 20–50% higher risk of CKD compared with H2 blocker use.
Using more than 16 million clinical documents from 2.9 million individuals, this study found PPI exposure was associated with a 1.16-fold higher myocardial infarction signal in GERD patients. A prospective cohort within the analysis also showed higher cardiovascular mortality.
The study demonstrates that PPIs significantly increase the risk of hip fractures in young adults, which may be due to reduced calcium absorption caused by the drugs.
Meta-analysis shows current PPI use is associated with a significant increased risk of community-acquired pneumonia (OR 1.27), while past use is not.