Cohort studyindependent cross-checkabstract checked★ key study I-PPI-110 in-depth review

PPI-death link fades when reverse causation is handled

Association of Proton Pump Inhibitor Use With All-Cause and Cause-Specific Mortality.

Overview

Lo CH et al.. Gastroenterology 2022 · PMID 35788344 · DOI 10.1053/j.gastro.2022.06.067

PPI users died somewhat more often, but when the analysis accounted for illness leading to PPI use, there was no clear extra risk.

Does the study support the specific claim? No · Methodological quality: high

Study explained simply

What did the researchers want to find out?: Check PPIs and mortality with better bias control.
How was the study done?: Two prospective cohorts, 14 years.
How many people, animals or samples were studied?: 71,887 adults, 22,125 deaths.
What was actually found?: HR 1.19 unlagged, 1.04 lagged; no duration effect.
How large was the observed effect?: 1.04 (0.97-1.11).
What do the results mean in everyday life?: PPIs are unlikely to shorten life by themselves.
What are the study's limitations?: Observational.
What does it say about Elawady's specific claim?: Contradicts 45 excess deaths per 1000 as a drug effect.
Do the results apply to Germany and Europe?: Moderately applicable.
What can explicitly not be concluded from this study?: Cannot exclude small risks in subgroups.

Authors: Lo CH et al.
Journal: Gastroenterology
Year: 2022
Identifier: PMID 35788344 DOI 10.1053/j.gastro.2022.06.067
Verification: verified – PubMed efetch 2026-10-26 + Crossref 2026-10-26
Retracted: no
Corrections: none
Extent checked: abstract only
Conflicts of interest and funding: NIH grants (NCI, NIDDK); COI not in abstract

Is regular PPI use associated with all-cause and cause-specific mortality after accounting for protopathic bias?

Study design: Cohort study – Prospective cohorts (Nurses' Health Study, Health Professionals Follow-up Study) with lag-time analysis
Population: US nurses and health professionals
Country: USA
Period: 2004-2018
Sample size: 71,887 (50,156 women, 21,731 men); 22,125 deaths
Inclusion and exclusion criteria: Cohort participants with PPI data from 2004

Results: Unlagged: all-cause HR 1.19 (1.13-1.24); cancer 1.30, CVD 1.13, respiratory 1.32, digestive 1.50. With lags up to 6 years: all-cause 1.04 (0.97-1.11); cancer 1.07 (0.89-1.28); CVD 0.94 (0.81-1.10); respiratory 1.20 (0.95-1.50); digestive 1.38 (0.88-2.18). Longer duration did not confer higher risk.
Absolute risks: Not reported in abstract
Authors' conclusion: After accounting for protopathic bias, PPI use was not associated with higher mortality.

Orienting tool: ROBINS-E
Type of assessment: simplified assessment (abstract only)
Full formal assessment: no
Overall risk of bias: some concerns
Rationale: Residual confounding possible; bias handling better than earlier studies.

Lagging removed about three quarters of the log-HR (stats/C-PPI-01_kidney_mortality.py), consistent with reverse causation.

Directly addresses the archive's excess-death figure: the association largely disappears when reverse causation is handled.

Xie 2019 (A-PPI-12) reported excess deaths vs H2RA in US veterans.

Moderate.

Strong counter-evidence to causal excess mortality.

Multidimensional assessment
Multidimensional assessment
Authenticity of the source	verified
Methodological quality	high
Risk of bias	some concerns
Precision of results	high
Directness	direct
Reproducibility	partly replicated
Consistency with the overall evidence	consistent
Regional transferability	moderate
Adequacy of the interpretation (by the archive)	not applicable

Specific subgroups (e.g., CKD).