Veettil SK, Sadoyu S, Bald EM, et al. Association of proton-pump inhibitor use with adverse health outcomes: A systematic umbrella review of meta-analyses of cohort studies and randomised controlled trials. Br J Clin Pharmacol. 2021 Oct 7. doi: 10.1111/bcp.15103.

AIMS: The aim was to perform an umbrella review to summarise the existing evidence on proton-pump inhibitor (PPI) use and adverse outcomes and to grade the certainty of evidence.

METHODS: Electronic databases were searched up to July 2021 for meta-analyses of cohort studies and/or randomised controlled trials (RCTs). Summary effect sizes from a random-effects model, between-study heterogeneity, 95% prediction interval, small-study effect, excess significance and credibility ceilings were devised to classify the credibility of evidence from meta-analyses of cohort studies, whereas the GRADE approach was used for meta-analyses of RCTs.

RESULTS: In meta-analyses of cohort studies, 52 of the 91 examined associations were statistically significant (P = .05). Convincing evidence emerged from main analysis for the association between PPI use and risk of all-site fracture and chronic kidney disease in the elderly population. However, none of these associations remained supported by convincing evidence after sensitivity analyses. The use of PPI is also associated with an increased risk of mortality due to COVID-19 infection and other related adverse outcomes, but the quality of evidence was weak. In meta-analyses of RCTs, 38 of the 63 examined associations were statistically significant. However, no associations were supported by high or moderate-quality evidence.

CONCLUSION: This study's findings imply that most putative adverse outcomes associated with PPI use may not be supported by high-quality evidence and are likely to have been affected by underlying confounding factors. Future research is needed to confirm the causal association between PPI use and risk of fracture and chronic kidney disease.

Ratings by Clinicians (at least 3 per Specialty)
Specialty Score
Hospital Doctor/Hospitalists
Internal Medicine
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Infectious Disease
Comments from MORE raters

Family Medicine (FM)/General Practice (GP) rater

This "super meta-analysis" examined the significance of various meta-analyzes from cohort studies on the possible harmful effects of proton pump inhibitors. They consistently found only very weak connections. Certainly, in very few cases, we can clearly assume a causality; there are often simply too many confounders. In daily practice, on the other hand, we notice that PPIs can induce a kind of physical dependence, especially in the case of heartburn. We should only use these substances as briefly as possible. The connections between fragile bones and infections are particularly worrying.

Hospital Doctor/Hospitalists rater

This is a critical look at ADRs of one of the world's most commonly used class of drugs. It's new and useful.

Infectious Disease rater

Risk of fracture, CKD and C. difficile infection were most likely related to PPI use, but it remains difficult to confirm rare events in RCTs. It is recognized that PPI overuse is common, and should be curtailed for other reasons. More study or less unnecessary use?