ArticleCirculation2013
Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.
Article in Circulation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
118 citing papers in PubMed, 6 syntheses or guidelines pooled it, 249 citations in OpenAlex.
- Proton pump inhibitors and risk of hearing loss; a systematic review.Naunyn-Schmiedeberg's archives of pharmacology · 2025Pooled it
- Esomeprazole covalently interacts with the cardiovascular enzyme dimethylarginine dimethylaminohydrolase: Insights into the cardiovascular risk of proton pump inhibitors.Biochimica et biophysica acta. General subjects · 2022Pooled it
- Will Proton Pump Inhibitors Increase the Risk of Diabetes Mellitus? A Systemic Review and Meta-Analysis.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2022Pooled it
- Efficacy and safety of concomitant use of proton pump inhibitors with aspirin-clopidogrel dual antiplatelet therapy in coronary heart disease: A systematic review and meta-analysis.Frontiers in pharmacology · 2022Pooled it
- Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials.BMC medicine · 2021Pooled it
- Guideline
- Impact of proton pump inhibitors on efficacy of antiplatelet strategies with ticagrelor or aspirin after percutaneous coronary intervention: Insights from the GLOBAL LEADERS trial.Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions · 2022Trial
- Poor Relationship Between Fractionated Exhaled Nitric Oxide and Disease Activity in Eosinophilic Esophagitis.Dysphagia · 2019Trial
- Serum Asymmetric and Symmetric Dimethylarginine and Morbidity and Mortality in Hemodialysis Patients.American journal of kidney diseases : the official journal of the National Kidney Foundation · 2017Trial
- Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan.PloS one · 2017Trial
- Biochemical mechanisms underpinning impaired endogenous nitric oxide formation with the use of proton pump inhibitors.Medical gas research · 2027Article
- Relationship Between Hypovitaminosis C, Obesity, and Features of Metabolic Syndrome-A Narrative Review.Nutrition reviews · 2026Review
- Evaluation of the Molecular Docking of Potential Targets and the Time-Dependent Myocardial Effects of Omeprazole in Normotensive and Spontaneously Hypertensive Rats Subjected to Cardiac Ischemia and Reperfusion.International journal of molecular sciences · 2026Article
- Sexual Dysfunctions Associated with Proton Pump Inhibitors: Insights from VigiBase, the World Health Organization Pharmacovigilance Database.Drug safety · 2026Article
- Esomeprazole Decreases Soluble Fms-like Tyrosine Kinase-1 in Preeclamptic Pregnancy in Rats.International journal of molecular sciences · 2026Article
- Pantoprazole and other proton pump inhibitors, sleep, and cardiovascular safety: weak but plausible evidence.Revista da Associacao Medica Brasileira (1992) · 2026Article
- Proton pump inhibitor use and cardiovascular risk, all-cause, and cardiovascular mortality across baseline eGFR categories: a longitudinal study.Renal failure · 2025Article
- Association Between Clinical Use of Lansoprazole and the Risk of Coronary Heart Disease: A Nationwide Pharmacoepidemiological Cohort Study.Cardiovascular drugs and therapy · 2025Article
- Association Between Clinical Use of Lansoprazole and the Risk of Coronary Heart Disease: A Nationwide Pharmacoepidemiological Cohort Study.Cardiovascular drugs and therapy · 2025Article
- Association between exposure to proton pump inhibitors and hypertension: a descriptive and disproportionality analysis of VigiBase.BMJ open · 2025Article
58 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
backgroundProton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed. METHODS AND
resultsPlasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA.
conclusionsWe present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.
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What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.