Omeprazole and other proton-pump inhibitors

Serious harms

Proton-pump inhibitors (PPIs) are prescribed for acid reflux and peptic ulcers, and to prevent ulcers and bleeding ¹²³⁴.

Condition	How often	Who is at risk	Source
Acute interstitial nephritis, hospitalised or fatal	11.98 against 1.68 per 100,000 person-years, current against past use	Any time in therapy	⁵¹
Acute kidney injury	13.49 against 5.46 hospitalisations per 1000 person-years	Adults 66 or older, first 120 days	⁶
Chronic kidney disease	10-year risk 11.8% against 8.5% expected	US adults; causality not established	⁷
Low magnesium: tetany, seizures, arrhythmia	19.4% of users against 13.5% of non-users; 1 excess hospitalisation per 76,591 treated for 90 days	Use beyond 3 months, mostly a year; diuretics; hypoparathyroidism	⁸⁹¹⁰¹
Clostridioides difficile diarrhoea	Higher in 23 of 28 studies, mostly 1.4 to 2.75 times	Hospitalised patients	¹¹¹
Hip, wrist or spine fracture	10% to 40% higher; hip 2.02 against 1.51 per 1000 person-years in women	50 or older; high doses; a year or longer	¹²¹³¹⁴
Fracture in children	20.2 against 18.3 per 1000 person-years	Highest after a year; not significant against H2-receptor antagonists (H2RAs)	¹⁵
Asthma in children	21.8 against 14.0 per 1000 person-years	Highest when started before age 2	¹⁶
Vitamin B12 deficiency	At least 2 years’ supply in 12.0% of 25,956 deficient patients against 7.2% of 184,199 controls	Use beyond 3 years; higher doses	¹⁷¹
Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS	Not known; some fatal	Not specified	¹¹⁸
Lupus, cutaneous or systemic	OR 2.9 for subacute cutaneous lupus	Weeks to years after starting	¹⁹¹
Agranulocytosis, pancreatitis, liver failure	Agranulocytosis 1 in 10,000 to 1 in 1000; some fatal	Not specified	¹¹⁸

Nephritis can occur without fever, rash or joint pain ¹. Magnesium normalised a median 1 week after stopping and fell again a median 2 weeks after restarting ¹⁰. Lupus mostly improves 4 to 12 weeks after stopping ¹. Fractures did not increase in trials, generally 6 months long ¹⁴.

Unresolved questions

Observational and randomised estimates are discordant.

Harm	Observational studies	Randomised trials
Chronic kidney disease	HR 1.28 against H2RAs ²⁰	No difference in COMPASS ²¹
C. difficile infection	OR 1.99 in 56 studies ²²	60 of 14,946 against 49 of 14,934 ²³
Pneumonia	RR 1.49, possibly confounded ²⁴²⁵	Similar in intensive care ⁴²⁶
Gastric cancer	RR 1.3 to 2.9 in 20 of 21 meta-analyses; OR 1.49 fell to 1.03 with a 3-year lag ²⁷²⁸	ECL-cell hyperplasia OR 5.01; biopsy studies too short and small ²⁹¹
Dementia	HR 1.44 from claims, 0.88 with adjudicated diagnosis ³⁰³¹	Similar in COMPASS ²¹
Death	45.20 excess per 1000 over 10 years against H2RAs ³²	Not significantly increased in four trials ^2126433

Other pathways it affects

Less acid raises gastrin and stomach bacteria and reduces vitamin B12 freed from food ¹⁸¹³⁵.

Pathway or tissue	Mechanism	Measured in people
Gastrin and ECL cells	Gastrin stimulates acid secretion through CCK2 receptors of brain, pancreas and stomach, and acts on ECL cells ³⁶³⁷	Median gastrin 1.3- to 3.6-fold; ECL-cell hyperplasia; fundic gland polyps in 1 in 100 or more ¹¹⁸
Gut bacteria	Acid suppression raises gastric bacterial counts ¹	Lower faecal diversity and more oral bacteria in 1827 twins ³⁸
Vitamin B12	Pepsin, which frees food-bound B12, is not activated above pH 3.5 ³⁵	21% of 175 with Zollinger–Ellison syndrome deficient after a mean 10.2 years ³⁵
Calcium and bone	Acid aids mineral absorption ³⁹	Calcium absorption not reduced in 21 women after 30 days of omeprazole 40 mg ⁴⁰
Endothelium	DDAH1 hydrolyses ADMA, an inhibitor of nitric oxide synthase ³⁶	No significant ADMA rise or loss of vasodilation in 21 adults after 4 weeks of lansoprazole ⁴¹

Rats given omeprazole for 24 months at about 0.4 to 34 times a 40 mg human dose developed ECL-cell carcinoids, attributed by the EMA to massively raised gastrin ¹¹⁸.

What it is for and how it works

Acid rising into the gullet causes heartburn; acid can damage the stomach and duodenal lining, where ulcers form ⁴⁴².

PPIs are acid-activated prodrugs that bind cysteine 813 of ATP4A, the catalytic subunit of the parietal-cell acid pump, covalently ⁴⁵³⁶.

Acid activation of proton-pump inhibitorsSecretory canaliculus of the stimulated parietal cell

Prodrug (substituted pyridylmethylsulfinyl benzimidazole)
Non-enzymatic protonation of the pyridine (pKa about 4)Charged form concentrates about 1000-fold over blood at canalicular pH about 1
Pyridine-protonated prodrug
Non-enzymatic protonation of the benzimidazole (pKa about 1)Second protonation at the luminal surface of the pump
Benzimidazole-protonated prodrug
Non-enzymatic acid-catalysed conversionThiophilic species; the inhibitory form
Sulfenic acid or tetracyclic sulfenamide
Non-enzymatic reaction with luminal cysteine thiolsAlso Cys892 (omeprazole), Cys321 (lansoprazole), Cys822 (pantoprazole)
Disulfide-linked H+/K+-ATPase (ATP4A Cys813), arrested in E2

In the body

A dose leaves the blood within hours, yet acid stays low for about two days because the drug binds the pump ⁴⁵.

Omeprazole inhibits CYP2C19, which contributes substantially to clopidogrel activation, and at 80 mg reduced its antiplatelet effect even 12 hours apart; the FDA advises against the combination ⁴⁶¹⁴⁷.

Activation of clopidogrelAbsorbed in the intestine; oxidised on the hepatocyte endoplasmic reticulum membrane

Clopidogrel
CYP2C19, with CYP1A2 and CYP2B6O2, NADPH through cytochrome P450 oxidoreductase (POR)OmeprazoleEsterases hydrolyse 85% of the dose to an inactive acid
2-Oxo-clopidogrel
CYP2C19, with CYP3A4, CYP2C9 and CYP2B6O2, NADPH through cytochrome P450 oxidoreductase (POR)Omeprazole2-Oxo-clopidogrel is a thiolactone; ring opening frees the thiol
Active thiol metabolite
non-enzymatic binding to a free cysteine of P2RY12Irreversible; the platelet is affected for 7 to 10 days
Blocked P2Y12 receptor

Omeprazole lowers rilpivirine and atazanavir exposure and may prolong high-dose methotrexate levels; INR rises reported with warfarin may lead to bleeding and death; less acid reduces levothyroxine, mycophenolate and iron-salt absorption ¹⁴⁸.

Genetic variation

An inherited slow form of CYP2C19, a liver enzyme that breaks these drugs down, raises blood levels and effect: poor metabolisers, 3% of Caucasians and 15% to 20% of Asians, have about 7.5 times the omeprazole exposure of homozygous extensive metabolisers ⁴⁵.

Benefit against harm

Benefit was measured over weeks to months; in prevention trials of median 180 days, gastroprotectants prevented 12 bleeds per 1000 ².

Group	Benefit	Serious harm
Erosive oesophagitis	Healed at 8 weeks in 74% of 83 against 14% of 43 ¹	Fracture and magnesium risks rise after a year ¹²¹⁰
NSAID users, about 6 months	Ulcers 119 to 36 per 1000; complications 11 to 4, uncertain ³	Adverse events not pooled; 7 of 12 trials company-funded ³
Ventilated in intensive care	Bleeding 3.5% to 1.0% in 90 days ⁴	No excess death (29.1% against 30.9%); pneumonia similar ⁴

Without the medicine

How the recommendations were set

Non-prescription courses are limited to 14 days in the US, 4 weeks in the UK and EU ⁵²¹²¹⁸.

Stopping

After stopping, acid secretion recovers within days, and symptoms return in some people ⁴⁵⁵⁷. Symptoms were uncontrolled more often with on-demand than daily use (RR 1.71, low quality) ⁵⁷.

A prescription is changed together with the prescriber ¹⁰.

References

Regulator
Covis Pharma US, Inc.; approved by the US Food and Drug Administration. PRILOSEC (omeprazole magnesium) granule, delayed release: full prescribing information US Food and Drug Administration-approved labelling, published in DailyMed (National Library of Medicine); structured product label version 8, effective 19 March 2024; initial US approval 1989, 2024.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b6761f84-53ac-4745-a8c8-1e5427d7e179
Funding and finding
Funding
not stated; FDA-approved labelling carries no funding statement
Finding
No boxed warning. Warnings and precautions 5.1 to 5.13: symptomatic response does not preclude gastric malignancy; acute tubulointerstitial nephritis may occur at any point during therapy, sometimes without extra-renal signs, and requires discontinuation; Clostridium difficile-associated diarrhoea, especially in hospitalised patients; osteoporosis-related fractures of hip, wrist or spine with high-dose (multiple daily doses) and long-term (a year or longer) therapy; severe cutaneous adverse reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS and AGEP; cutaneous and systemic lupus erythematosus, new or exacerbated, within weeks to years of continuous therapy, most patients improving 4 to 12 weeks after stopping; avoid clopidogrel; daily acid suppression longer than about 3 years may cause cyanocobalamin malabsorption; hypomagnesaemia reported rarely after at least 3 months and in most cases after a year, with tetany, arrhythmias and seizures, possibly causing hypocalcaemia or hypokalaemia, in most patients requiring magnesium replacement and discontinuation; chromogranin A rises and gives false-positive neuroendocrine tumour tests (stop at least 14 days before testing); high-dose methotrexate toxicity; fundic gland polyps with risk rising with use beyond one year. Contraindicated with rilpivirine; hypersensitivity may include anaphylaxis, angioedema, bronchospasm and acute tubulointerstitial nephritis. Warfarin co-use raised INR, which may lead to abnormal bleeding and death. Postmarketing reports include pancreatitis, hepatic failure, agranulocytosis and SJS/TEN (each some fatal), microscopic colitis, hyponatraemia, hypoglycaemia and optic neuropathies. Serum gastrin rose in the first 1 to 2 weeks, median 1.3- to 3.6-fold with omeprazole 20 mg against 1.1- to 1.8-fold with H2-receptor antagonists, and returned to baseline 1 to 2 weeks after stopping; gastrin causes ECL-cell hyperplasia and chromogranin A rise. In biopsies from more than 3000 patients in long-term trials, ECL-cell hyperplasia increased with time without carcinoid, dysplasia or neoplasia, but the studies were of insufficient duration and size to rule out an influence on premalignant or malignant conditions. Omeprazole for 14 days raised intragastric viable bacteria, resolving within 3 days of stopping. In two 24-month rat studies at 1.7 to 140.8 mg/kg/day (about 0.4 to 34 times a 40 mg human dose by body surface area), omeprazole produced dose-related gastric ECL-cell carcinoids, more in females; ECL-cell hyperplasia occurred in all treated groups. Esomeprazole reduced femur weight and length in juvenile rats. Erosive oesophagitis healing at 8 weeks: 74% with 20 mg (n = 83), 75% with 40 mg (n = 87), 14% with placebo (n = 43); endoscopic remission at 6 months: 70% with 20 mg daily (n = 138) against 11% with placebo (n = 131). Efficacy beyond 8 weeks for erosive oesophagitis is not established; controlled maintenance studies do not extend beyond 12 months.
Independent research
Scally B, Emberson JR, Spata E, Reith C, Davies K, Halls H, et al. Effects of gastroprotectant drugs for the prevention and treatment of peptic ulcer disease and its complications: a meta-analysis of randomised trials The Lancet Gastroenterology & Hepatology, 2018.
doi:10.1016/S2468-1253(18)30037-2 PubMed 29475806
Funding and finding
Participants
142,485
Funding
UK Medical Research Council and the British Heart Foundation, through core funding of the MRC Population Health Research Unit, University of Oxford. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Finding
Prevention trials, gastroprotectants against control: endoscopic ulcer OR 0.27 (95% CI 0.25 to 0.29), 160 fewer per 1000 treated; symptomatic ulcer OR 0.25 (0.22 to 0.29), 67 fewer per 1000; upper gastrointestinal bleeding OR 0.40 (0.32 to 0.50), 12 fewer per 1000, PPIs OR 0.21 (99% CI 0.12 to 0.36); all-cause mortality OR 0.85 (0.69 to 1.04). Healing trials: endoscopic healing OR 5.22 (99% CI 4.00 to 6.80) for PPIs and 3.80 (3.44 to 4.20) for H2-receptor antagonists. Reductions in symptomatic ulcers and bleeds were smaller in trials with secure allocation concealment; the authors consider overestimation from small-study bias possible. H. pylori and NSAIDs are the most frequent causes of peptic ulcer; NSAID risk probably follows inhibited mucosal prostaglandin production.
Independent research
Garegnani L, Oltra G, Burgos MA, Ivaldi D, Varela LB, Díaz Menai S, et al. Proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug-induced ulcers and dyspepsia Cochrane Database of Systematic Reviews, 2025.
doi:10.1002/14651858.CD014585.pub2 PubMed 40337979
Funding and finding
Participants
8,760
Follow-up
up to 12 months; most trials about 6 months
Funding
This Cochrane review had no dedicated funding.
Finding
PPI against placebo: incident ulcers 36 against 119 per 1000 (RR 0.29, 95% CI 0.23 to 0.36; 11 trials, 7022 participants; moderate certainty); ulcer complications 4 against 11 per 1000 (RR 0.33, 0.10 to 1.07; 5 trials, 4394 participants; low certainty); global dyspepsia symptoms little or no effect (very low certainty); adverse events could not be pooled (very low certainty). PPI against H2-receptor antagonist: 154 against 77 ulcers per 1000 (1 trial, 26 participants). PPI against misoprostol: more ulcers (RR 2.32, 1.25 to 4.30) and fewer adverse events (RR 0.38, 0.25 to 0.57; 1 trial, 402 participants; very low certainty).
Independent research
Cook D, Deane A, Lauzier F, Zytaruk N, Guyatt G, Saunders L, et al. Stress ulcer prophylaxis during invasive mechanical ventilation New England Journal of Medicine, 2024.
doi:10.1056/NEJMoa2404245 PubMed 38875111
Funding and finding
Registration
NCT03374800
Participants
4,821
Follow-up
90 days
Funding
Abstract: 'Funded by the Canadian Institutes of Health Research and others.' Registry NCT03374800: lead sponsor McMaster University; collaborators Canadian Institutes of Health Research, Canadian Critical Care Trials Group, Australian and New Zealand Intensive Care Society Clinical Trials Group, National Health and Medical Research Council of Australia. PubMed also lists Hamilton Health Sciences, the National Institute for Health Research and the Physicians' Services Incorporated Foundation. The full funding statement was not read because the publisher page refused access.
Finding
Clinically important upper gastrointestinal bleeding in the ICU at 90 days: 25 of 2385 (1.0%) with pantoprazole against 84 of 2377 (3.5%) with placebo (HR 0.30, 95% CI 0.19 to 0.47). Death at 90 days: 696 of 2390 (29.1%) against 734 of 2379 (30.9%) (HR 0.94, 0.85 to 1.04). Patient-important bleeding was reduced; ventilator-associated pneumonia, C. difficile infection and other secondary outcomes were similar.
Independent research
Blank ML, Parkin L, Paul C, Herbison P. A nationwide nested case-control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use Kidney International, 2014.
doi:10.1038/ki.2014.74 PubMed 24646856
Funding and finding
Participants
572,661
Follow-up
new episodes of PPI use 2005 to 2009
Funding
Primary financial support was provided by the Health Research Council of New Zealand and Medsafe (grant number 10/031). Additional support was provided to M-LB through a University of Otago Masters' scholarship. The funders had no role in the design of the study, or in the collection, analysis, or interpretation of the data.
Finding
Acute interstitial nephritis resulting in hospitalisation or death: crude incidence 11.98 (95% CI 9.11 to 15.47) per 100,000 person-years during current PPI use against 1.68 (0.91 to 2.86) during past use; matched OR for current against past use 5.16 (2.21 to 12.05) among histologically confirmed cases, similar after adjustment and with probable cases included.
Independent research
Antoniou T, Macdonald EM, Hollands S, Gomes T, Mamdani MM, Garg AX, et al. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study CMAJ Open, 2015.
doi:10.9778/cmajo.20140074 PubMed 26389094
Funding and finding
Participants
581,184
Follow-up
120 days after starting therapy
Funding
Tony Antoniou is supported by a Canadian Institutes of Health Research/Ontario HIV Treatment Network New Investigator Award. This project was supported by research funds from Drug Safety and Effectiveness Research Network and by the Institute for Clinical Evaluative Sciences, which is funded by a grant from the Ontario Ministry of Health and Long-Term Care. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Finding
Hospital admission with acute kidney injury within 120 days: 13.49 against 5.46 per 1000 person-years (HR 2.52, 95% CI 2.27 to 2.79); acute interstitial nephritis 0.32 against 0.11 per 1000 person-years (HR 3.00, 1.47 to 6.14).
Independent research
Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J, et al. Proton pump inhibitor use and the risk of chronic kidney disease JAMA Internal Medicine, 2016.
doi:10.1001/jamainternmed.2015.7193 PubMed 26752337
Funding and finding
Participants
10,482
Follow-up
median 13.9 years; replication cohort median 6.2 years
Funding
The ARIC study is supported by National Heart, Lung, and Blood Institute contracts HHSN268201100005C to HHSN268201100012C; M. E. Grams receives support from the National Institute of Diabetes and Digestive and Kidney Diseases (K08DK092287). Some data were supplied by the United States Renal Data System.
Finding
ARIC: incident chronic kidney disease in 56 of 322 baseline PPI users (14.2 per 1000 person-years) and 1382 of 10,160 non-users (10.7 per 1000 person-years); adjusted HR 1.50 (95% CI 1.14 to 1.96); 10-year absolute risk 11.8% against an expected 8.5% without PPI (difference 3.3 percentage points). Replication: adjusted HR 1.17 (1.12 to 1.23); 10-year risk 15.6% against 13.9%. PPI users were more often obese and taking antihypertensive drugs; the authors state that the observational design does not establish causality.
Independent research
Srinutta T, Chewcharat A, Takkavatakarn K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, et al. Proton pump inhibitors and hypomagnesemia: a meta-analysis of observational studies Medicine (Baltimore), 2019.
doi:10.1097/MD.0000000000017788 PubMed 31689852
Funding and finding
Participants
131,507
Funding
The authors have no funding and conflicts of interest to disclose.
Finding
Hypomagnesaemia in 19.4% (95% CI 13.8% to 26.5%) of PPI users against 13.5% (7.9% to 22.2%) of non-users; pooled adjusted OR 1.71 (1.33 to 2.19); high-dose against low-dose use adjusted OR 2.13 (1.26 to 3.59). No randomised trials were available.
Independent research
Zipursky J, Macdonald EM, Hollands S, Gomes T, Mamdani MM, Paterson JM, et al. Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study PLoS Medicine, 2014.
doi:10.1371/journal.pmed.1001736 PubMed 25268962
Funding and finding
Participants
1,830
Follow-up
exposure within 365 days before the index date; Ontario databases April 2002 to March 2012
Funding
This project was supported by research funds from Canadian Drug Safety and Effectiveness Research Network (CDSERN) and by the Institute for Clinical Evaluative Sciences (ICES), which is funded by a grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Finding
Current PPI use (within 90 days) was associated with hospitalisation with hypomagnesaemia (adjusted OR 1.43, 95% CI 1.06 to 1.93); among patients receiving diuretics adjusted OR 1.73 (1.11 to 2.70), among those not receiving diuretics 1.25 (0.81 to 1.91). H2-receptor antagonists were not associated (adjusted OR 1.06, 0.54 to 2.06). The authors estimate one excess hospitalisation with hypomagnesaemia among 76,591 outpatients treated with a PPI for 90 days. Serum magnesium values were unavailable.
Regulator
US Food and Drug Administration. FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs) US Food and Drug Administration, Drug Safety Communication, 2 March 2011, 2011.
http://web.archive.org/web/20190424012705/https://www.fda.gov/Drugs/DrugSafety/ucm245011.htm
Funding and finding
Funding
US Food and Drug Administration
Finding
Review of 38 Adverse Event Reporting System cases and 23 published cases, at least 8 of them overlapping. Prescription PPIs may cause hypomagnesaemia when taken for prolonged periods, in most cases longer than one year; in about one quarter of cases magnesium supplementation alone was insufficient and the PPI was stopped. After stopping, magnesium normalised in a median of one week; after restarting, hypomagnesaemia recurred in a median of two weeks. Serious events included tetany, seizures, arrhythmias and hypocalcaemia with normal parathyroid hormone. The mechanism is unknown, possibly altered intestinal absorption. Serum magnesium should be considered before and periodically during prolonged treatment, especially with digoxin, loop or thiazide diuretics or other drugs causing hypomagnesaemia. Patients should not stop a prescription PPI without talking to their healthcare professional. Lists Dexilant (dexlansoprazole) among prescription PPIs.
Regulator
US Food and Drug Administration. FDA Drug Safety Communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs) US Food and Drug Administration, Drug Safety Communication, 8 February 2012, 2012.
http://web.archive.org/web/20190423141358/https://www.fda.gov/Drugs/DrugSafety/ucm290510.htm
Funding and finding
Funding
US Food and Drug Administration
Finding
Review of Adverse Event Reporting System cases and 28 observational studies in 26 publications: 23 studies showed a higher risk of C. difficile infection or disease with PPI exposure, mostly 1.4 to 2.75 times that without exposure. Many reported patients were elderly, had chronic conditions or took broad-spectrum antibiotics; data on dose and duration were limited. The weight of evidence suggests a positive association.
Regulator
Medicines and Healthcare products Regulatory Agency. Proton pump inhibitors in long-term use: increased risk of fracture MHRA Drug Safety Update, volume 5, issue 9, April 2012: A2 (republished on GOV.UK 11 December 2014), 2012.
https://www.gov.uk/drug-safety-update/proton-pump-inhibitors-in-long-term-use-increased-risk-of-fracture
Funding and finding
Funding
Medicines and Healthcare products Regulatory Agency
Finding
Observational studies suggest a modest increase in the risk of hip, wrist or spine fracture, especially with high doses and use longer than 1 year, observed mainly in elderly patients; other risk factors may contribute. Two meta-analyses of pharmacoepidemiological studies suggest a 10% to 40% increase above baseline; the primary studies varied in adjustment for other fracture risk factors and for calcium or vitamin D use. Patients at risk of osteoporosis should be treated according to guidelines with adequate vitamin D and calcium. Over-the-counter PPIs should not be used for more than 4 weeks without consulting a doctor.
Independent research
Khalili H, Huang ES, Jacobson BC, Camargo CA Jr, Feskanich D, Chan AT. Use of proton pump inhibitors and risk of hip fracture in relation to dietary and lifestyle factors: a prospective cohort study BMJ, 2012.
doi:10.1136/bmj.e372 PubMed 22294756
Funding and finding
Participants
79,899
Follow-up
565,786 person-years, 2000 to June 2008
Funding
This study was funded by the US National Institutes of Health (grant No NIH R01 CA137178, P01 CA87969). ATC is a Damon Runyon Cancer Research Foundation clinical investigator. BCJ is supported by a grant from the National Institutes of Health (NIH R01 DK088782). HK is supported by a career development award from the IBD Working Group. ESH is supported by a career development award from the American Gastroenterological Association.
Finding
893 incident hip fractures. Absolute risk 2.02 per 1000 person-years among regular PPI users against 1.51 among non-users; use for at least 2 years, age-adjusted HR 1.35 (95% CI 1.13 to 1.62), multivariable HR 1.36 (1.13 to 1.63), with longer use associated with higher risk. Current and former smokers HR 1.51 (1.20 to 1.91); never smokers HR 1.06 (0.77 to 1.46). Pooled with 10 earlier studies, OR 1.30 (1.25 to 1.36).
Regulator
US Food and Drug Administration. FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors US Food and Drug Administration, Drug Safety Communication, 25 May 2010, updated 23 March 2011, 2010.
http://web.archive.org/web/20170906123520/https://www.fda.gov/Drugs/DrugSafety/ucm213206.htm
Funding and finding
Funding
US Food and Drug Administration
Finding
Review of seven published epidemiological studies using claims databases: six reported an increased risk of hip, wrist or spine fracture with PPI use, greatest with high doses or use for one year or more, mainly in people aged 50 years or older. The databases lacked data on family history of osteoporosis, smoking, weight, height, alcohol, calcium and vitamin D intake, indication and falls. Randomised trials, generally six months long, found no increase in fractures. It is not clear whether PPI use causes the increased risk. The 2011 update judged fracture risk with short-term, low-dose use unlikely.
Independent research
Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B. Association between proton pump inhibitor use and risk of fracture in children JAMA Pediatrics, 2020.
doi:10.1001/jamapediatrics.2020.0007 PubMed 32176276
Funding and finding
Participants
231,866
Follow-up
mean 2.2 years (SD 1.6), up to 5 years
Funding
Swedish Research Council and Frimurare Barnhuset Foundation supported this study, and Dr Pasternak was supported by an investigator grant from the Strategic Research Area Epidemiology program at Karolinska Institutet. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Finding
Any fracture: 5354 among initiators against 4568 among non-initiators, 20.2 against 18.3 per 1000 person-years (HR 1.11, 95% CI 1.06 to 1.15). HR by cumulative duration: 1.08 (1.03 to 1.13) for 30 days or less, 1.14 (1.09 to 1.20) for 31 to 364 days, 1.34 (1.13 to 1.58) for 365 days or more. Against H2-receptor antagonists HR 1.06 (0.97 to 1.15).
Independent research
Wang YH, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B. Association between proton pump inhibitor use and risk of asthma in children JAMA Pediatrics, 2021.
doi:10.1001/jamapediatrics.2020.5710 PubMed 33555324
Funding and finding
Participants
161,740
Follow-up
median 3.0 years (interquartile range 2.1 to 3.0)
Funding
This study was supported by the Swedish Research Council and Frimurare Barnhuset Foundation and an investigator grant from the Strategic Research Area Epidemiology program at Karolinska Institutet (Dr Pasternak). The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Finding
Incident asthma 21.8 per 1000 person-years after PPI initiation against 14.0 among non-initiators (HR 1.57, 95% CI 1.49 to 1.64); HR 1.83 (1.65 to 2.03) for initiation before 6 months of age and 1.91 (1.65 to 2.22) from 6 months to under 2 years; high-dimensional propensity score matching HR 1.48 (1.41 to 1.55).
Independent research
Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency JAMA, 2013.
doi:10.1001/jama.2013.280490 PubMed 24327038
Funding and finding
Participants
210,155
Follow-up
January 1997 to June 2011
Funding
This project was supported by a Kaiser Permanente Community Benefit grant. Kaiser Permanente had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.
Finding
A 2-year or longer supply of PPIs was dispensed to 3120 of 25,956 cases (12.0%) and 13,210 of 184,199 controls (7.2%): OR 1.65 (95% CI 1.58 to 1.73); for H2-receptor antagonists without PPI OR 1.25 (1.17 to 1.34). More than 1.5 PPI pills a day OR 1.95 (1.77 to 2.15) against less than 0.75 pills a day OR 1.63 (1.48 to 1.78).
Regulator
European Medicines Agency; marketing authorisation holder Takeda GmbH. PANTOZOL Control 20 mg gastro-resistant tablets: summary of product characteristics (EPAR product information, Annex I) European Medicines Agency, European public assessment report, product information; EU/1/09/517; first authorised 12 June 2009, renewed 21 February 2014; PDF file dated May 2023, 2023.
https://www.ema.europa.eu/en/documents/product-information/pantozol-control-epar-product-information_en.pdf
Funding and finding
Funding
not stated; regulatory product information carries no funding statement
Finding
Non-prescription pantoprazole 20 mg once daily for short-term treatment of reflux symptoms in adults; treatment should not exceed 4 weeks without consulting a doctor. Section 4.4: reduced acidity raises gastric bacterial counts and slightly increases the risk of Salmonella, Campylobacter and Clostridium difficile infection; severe cutaneous adverse reactions (erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS), which can be life-threatening or fatal, frequency not known; very infrequent subacute cutaneous lupus erythematosus, with risk of recurrence on another PPI; chromogranin A rise interferes with neuroendocrine tumour investigations. Risks of long-term use: reduced vitamin B12 absorption; hip, wrist and spine fracture, predominantly in the elderly, with observational studies suggesting a 10% to 40% increase in overall fracture risk, some of it possibly due to other risk factors; severe hypomagnesaemia reported rarely after at least 3 months and in most cases a year, with fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia, possibly leading to hypocalcaemia and hypokalaemia, in most patients improving after magnesium replacement and discontinuation. Section 4.8: fundic gland polyps (benign) common; agranulocytosis rare; tubulointerstitial nephritis with possible progression to renal failure, hepatocellular failure, microscopic colitis, hyponatraemia and hallucination frequency not known. Section 5.1: fasting gastrin doubles in most cases during long-term treatment, with a mild to moderate increase in ECL cells in a minority; carcinoid precursors or gastric carcinoids, as seen in animals, have not been observed in humans. Section 5.3: 2-year rat studies produced gastric neuroendocrine neoplasms, attributed to massively elevated serum gastrin; liver tumours in rats and female mice and thyroid neoplastic changes in rats at 200 mg/kg; reduced bone growth in rat offspring at exposures about twice human clinical exposure.
Regulator
Medicines and Healthcare products Regulatory Agency. Proton pump inhibitors: very low risk of subacute cutaneous lupus erythematosus MHRA Drug Safety Update, volume 9, issue 2, September 2015 (published on GOV.UK 8 September 2015), 2015.
https://www.gov.uk/drug-safety-update/proton-pump-inhibitors-very-low-risk-of-subacute-cutaneous-lupus-erythematosus
Funding and finding
Funding
Medicines and Healthcare products Regulatory Agency
Finding
Very few cases of subacute cutaneous lupus erythematosus (SCLE) have been reported considering the extensive use of PPIs, but evidence from the literature and from Yellow Card and other regulatory reports supports a causal association. A Swedish register-based case-control study estimated an SCLE risk almost 3 times that of the general population with PPI use (OR 2.9, 95% CI 2.0 to 4.0); a Danish dermatology unit identified 19 PPI-associated cases over 19 years (3 definite, 14 probable). Across literature and licence-holder cases, 36 resolved on stopping the PPI and 4 recurred with a different PPI. Drug-induced SCLE can occur weeks, months or years after exposure; in most cases symptoms resolve on withdrawal, and a patient who develops SCLE with one PPI may react to another.
Funding unknown
Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z. Proton pump inhibitors and risk of incident CKD and progression to ESRD Journal of the American Society of Nephrology, 2016.
doi:10.1681/ASN.2015121377 PubMed 27080976
Funding and finding
Participants
193,591
Follow-up
5 years
Funding
Not read: the PubMed Central record holds a PDF only, which could not be retrieved, and the publisher page refused access.
Finding
Against H2-receptor antagonist users, PPI users had higher risk of incident eGFR below 60 mL/min/1.73 m2 (HR 1.22, 95% CI 1.18 to 1.26), incident CKD (1.28, 1.23 to 1.34), doubling of serum creatinine (1.53, 1.42 to 1.65), eGFR decline above 30% (1.32, 1.28 to 1.37) and end-stage renal disease (1.96, 1.21 to 3.18), with graded association by duration of exposure from 31 to 720 days.
Industry-funded
Moayyedi P, Eikelboom JW, Bosch J, Connolly SJ, Dyal L, Shestakovska O, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin Gastroenterology, 2019.
doi:10.1053/j.gastro.2019.05.056 PubMed 31152740
Funding and finding
Registration
NCT01776424
Participants
17,598
Follow-up
median 3.01 years (53,152 patient-years)
Funding
The funding statement of the article was not read because the publisher page could not be accessed; Europe PMC lists Bayer as grant agency. Registry NCT01776424: lead sponsor and responsible party Bayer; collaborators Population Health Research Institute and Janssen Research & Development. PubMed lists Bayer, Leverkusen, as the affiliation of two authors.
Finding
Pantoprazole 40 mg daily (n = 8791) against placebo (n = 8807): no statistically significant difference in pneumonia, Clostridium difficile infection, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalisation or all-cause mortality, except enteric infections (1.4% against 1.0%; OR 1.33, 95% CI 1.01 to 1.75). C. difficile infection was about twice as common with pantoprazole, from 13 events in total.
Funding unknown
Trifan A, Stanciu C, Girleanu I, Stoica OC, Singeap AM, Maxim R, et al. Proton pump inhibitors therapy and risk of Clostridium difficile infection: systematic review and meta-analysis World Journal of Gastroenterology, 2017.
doi:10.3748/wjg.v23.i35.6500 PubMed 29085200
Funding and finding
Participants
356,683
Funding
not stated
Finding
PPI users against non-users: pooled OR for C. difficile infection 1.99 (95% CI 1.73 to 2.30); case-control 2.00 (1.68 to 2.38), cohort 1.98 (1.51 to 2.59); adjusted 1.95 (1.67 to 2.27); age 65 or older 1.93 (1.40 to 2.68), younger 2.06 (1.11 to 3.81). Heterogeneity I2 85.4%. The abstract reports funnel-plot asymmetry (P = 0.002) indicating publication bias, whereas the results section reports a non-significant Egger test (Z = 0.3699, P = 0.711).
Independent research
Floria DE, Obeidat M, Váncsa S, Kávási SB, Földvári-Nagy L, Hegyi P, et al. Proton pump inhibitors are not associated with an increased risk of Clostridioides difficile infection: a systematic review and meta-analysis of randomized controlled trials Gut Microbes, 2025.
doi:10.1080/19490976.2025.2562341 PubMed 41047657
Funding and finding
Registration
CRD42023403322
Funding
Funding: None.
Finding
C. difficile infection, PPI against non-PPI: RR 1.19 (95% CI 0.75 to 1.89; 8 trials, 29,880 participants); against H2-receptor blockers RR 0.72 (0.49 to 1.07; 4 trials, 27,254 participants); against potassium-competitive acid blockers RR 1.23 (0.43 to 3.55; 3 trials, 1645 participants). Qualitative synthesis: other enteric infections and small intestinal bacterial overgrowth may be more common with PPIs; in COMPASS, enteric infections 119 of 8791 (1.4%) against 90 of 8807 (1.0%); in a trial in severe acute pancreatitis, duodenal aerobic bacterial overgrowth after 7 days in 29 of 33 given esomeprazole against 15 of 33 without (RR 1.93, 1.30 to 2.86).
Independent research
Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis PLoS One, 2015.
doi:10.1371/journal.pone.0128004 PubMed 26042842
Funding and finding
Participants
6,351,656
Funding
No funding was provided specifically for the conduct of this review. Dr. Lambert is supported by NIH Grant T32 HL007534 31A1, Dr. Drummond by NIH Grant K23 HL103192 04 and Dr. Crowell by NIH Grant T32 AI007291 23. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Finding
Pooled relative risk of community-acquired pneumonia with ambulatory PPI therapy RR 1.49 (95% CI 1.16 to 1.92; I2 99.2%); during the first month of therapy OR 2.10 (1.39 to 3.16), regardless of dose or age, which the authors state may partly reflect protopathic bias from PPI initiation around the onset of respiratory symptoms; hospitalisation for pneumonia OR 1.61 (1.12 to 2.31).
Independent research
Jena AB, Sun E, Goldman DP. Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia Journal of General Internal Medicine, 2013.
doi:10.1007/s11606-012-2211-5 PubMed 22956446
Funding and finding
Participants
54,490
Follow-up
11 years of quarterly claims
Funding
National Institute on Aging. The design, conduct, analysis, interpretation, and presentation of the data are the responsibility of the investigators, with no involvement from the funding sources.
Finding
Falsification analysis. Among PPI users, quarters with a filled PPI prescription had higher adjusted rates than quarters without of community-acquired pneumonia (111 against 68 per 10,000), chest pain (597 against 336) and urinary tract infection (186 against 151), all p<0.001; PPI users also had higher rates than non-users in quarters without a prescription (pneumonia 68 against 61 per 10,000). Associations with conditions without a known pathophysiological link indicate that the association with pneumonia may be confounded.
Independent research
Krag M, Marker S, Perner A, Wetterslev J, Wise MP, Schefold JC, et al. Pantoprazole in patients at risk for gastrointestinal bleeding in the ICU New England Journal of Medicine, 2018.
doi:10.1056/NEJMoa1714919 PubMed 30354950
Funding and finding
Registration
NCT02467621
Participants
3,298
Follow-up
90 days; 1 year for mortality in the registry results
Funding
Abstract: 'Funded by Innovation Fund Denmark and others.' Registry NCT02467621: lead sponsor Dr. Morten Hylander Møller (sponsor-investigator, Scandinavian Critical Care Trials Group); collaborators Copenhagen University Hospital, Rigshospitalet, and the Copenhagen Trial Unit. The full funding statement was not read because the publisher page refused access.
Finding
Death by 90 days: 510 of 1642 (31.1%) with pantoprazole against 499 of 1640 (30.4%) with placebo (RR 1.02, 95% CI 0.91 to 1.13). Composite of clinically important bleeding, pneumonia, C. difficile infection or myocardial ischaemia: 21.9% against 22.6% (RR 0.96, 0.83 to 1.11). Clinically important gastrointestinal bleeding 41 of 1644 (2.5%) against 69 of 1647 (4.2%). Infectious adverse events 276 against 279; 1-year mortality 610 of 1635 against 601 of 1626 (registry results).
Independent research
Brusselaers N, Khodir Kamal H, Graham D, Engstrand L. Proton pump inhibitors and the risk of gastric cancer: a systematic review, evidence synthesis and life course epidemiology perspective BMJ Open Gastroenterology, 2025.
doi:10.1136/bmjgast-2024-001719 PubMed 40253055
Funding and finding
Funding
Vetenskapsrådet - Scientific research council (Brusselaers): 2020-01058.
Finding
PPIs were consistently associated with increased gastric cancer risk: 20 of 21 meta-analyses reported pooled relative risks between 1.3 and 2.9. Available trials were underpowered. Reverse causation or protopathic bias, residual confounding by indication, lag time and disentangling Helicobacter pylori and its eradication were the largest methodological challenges. Age- and sex-specific data were insufficient, and no study addressed PPIs in young populations; the authors hypothesise that exposure in pregnancy and early life may be particularly harmful. Swedish gastric cancer incidence fell overall from 1970 to 2022 but rose in men younger than 40 years from the early 2000s.
Independent research
Liu P, McMenamin ÚC, Johnston BT, Murchie P, Iversen L, Lee AJ, et al. Use of proton pump inhibitors and histamine-2 receptor antagonists and risk of gastric cancer in two population-based studies British Journal of Cancer, 2020.
doi:10.1038/s41416-020-0860-4 PubMed 32367073
Funding and finding
Participants
478,292
Follow-up
UK Biobank cohort entry 2006 to 2010, cancer registry follow-up to 2014
Funding
Access to the UK Biobank was funded by a Cancer Research UK Population Research Postdoctoral Fellowship awarded to ÚCMcM. Liu P. was supported by a joint scholarship from Queen's University Belfast and the Chinese Scholarship Council (201708060458).
Finding
With a 1-year lag, PPI use was associated with gastric cancer in the case-control study (adjusted OR 1.49, 95% CI 1.24 to 1.80) and not significantly in UK Biobank (adjusted HR 1.28, 0.86 to 1.90); with a 2-year lag, adjusted OR 1.13 (0.91 to 1.40) and HR 1.15 (0.73 to 1.82). With a 3-year lag, OR 1.03 (0.80 to 1.33). The association did not follow exposure response, the shortest use carrying the highest risk, and weakened with longer lags, which the authors interpret as suggesting reverse causation; they observed little consistent evidence of increased risk.
Funding unknown
Song H, Zhu J, Lu D. Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions Cochrane Database of Systematic Reviews, 2014.
doi:10.1002/14651858.CD010623.pub2 PubMed 25464111
Funding and finding
Participants
1,789
Funding
Not read: the PubMed Central record holds the abstract and a PDF only, and the Cochrane Library page refused access.
Finding
Corpus atrophy OR 1.50 (95% CI 0.59 to 3.80; 4 trials, 1070 participants; low quality); corpus intestinal metaplasia OR 1.46 (0.43 to 5.03; 5 trials, 1408 participants; low quality); diffuse ECL-cell hyperplasia OR 5.01 (1.54 to 16.26; very low quality) and linear or micronodular ECL-cell hyperplasia OR 3.98 (1.31 to 12.16; low quality; 6 trials, 1705 participants). No dysplastic or neoplastic change was observed. Four trials had high and three unclear risk of bias.
Funding unknown
Gomm W, von Holt K, Thomé F, Broich K, Maier W, Fink A, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis JAMA Neurology, 2016.
doi:10.1001/jamaneurol.2015.4791 PubMed 26882076
Funding and finding
Participants
73,679
Follow-up
2004 to 2011, quarterly claims
Funding
No funding statement in the article information; Additional Contributions state: 'No compensation was received by the Scientific Research Institute from a funding sponsor for the study.' Authors are affiliated with the German Center for Neurodegenerative Diseases and the Federal Institute for Drugs and Medical Devices, Bonn.
Finding
Regular PPI users (at least one PPI prescription in each quarter of an 18-month interval; n = 2950) had a higher risk of incident dementia diagnosis than non-users (n = 70,729): HR 1.44 (95% CI 1.36 to 1.52), adjusted for age, sex, comorbidities and polypharmacy. Diagnoses were claims codes; 29,510 participants developed dementia. The authors cite mouse studies in which PPIs raised brain beta-amyloid and call for randomised trials.
Independent research
Mehta RS, Kochar B, Zhou Z, Broder JC, Chung P, Yang K, et al. Association of proton pump inhibitor use with incident dementia and cognitive decline in older adults: a prospective cohort study Gastroenterology, 2023.
doi:10.1053/j.gastro.2023.05.052 PubMed 37315867
Funding and finding
Participants
18,934
Follow-up
more than 6 years
Funding
The ASPREE clinical trial was supported by grants from the National Institute on Aging and the National Cancer Institute, the National Health and Medical Research Council of Australia, Monash University and the Victorian Cancer Agency; this work was also supported by NIH grant RF1 AG067744 and an MGH Research Scholar Award. The funders had no role in the design of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Finding
Baseline PPI use against non-use: incident dementia multivariable HR 0.88 (95% CI 0.72 to 1.08); cognitive impairment without dementia HR 1.00 (0.92 to 1.09); no association with change in cognitive test scores (B -0.002, SE 0.01). H2-receptor antagonist use was likewise not associated.
Independent research
Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study BMJ, 2019.
doi:10.1136/bmj.l1580 PubMed 31147311
Funding and finding
Participants
214,467
Follow-up
median 10 years (interquartile range 6.95 to 10.00)
Funding
This research was funded by the United States Department of Veterans Affairs and the Institute for Public Health at Washington University in St Louis, MO, USA (ZAA). The funders of this study had no role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.
Finding
Deaths over 10 years: 38.74 per 100 PPI users against 34.22 per 100 H2-receptor antagonist users (HR 1.17, 95% CI 1.10 to 1.24), an estimated 45.20 (28.20 to 61.40) excess deaths per 1000 PPI users, including circulatory diseases 17.47, neoplasms 12.94, infectious diseases 4.20 and genitourinary diseases 6.25 per 1000; cardiovascular disease 15.48 and chronic kidney disease 4.19 per 1000. Graded relation with cumulative duration. Among 116,377 without a documented indication, excess cardiovascular (22.91), chronic kidney disease (4.74) and upper gastrointestinal cancer (3.12) deaths per 1000. Negative-control outcomes (transport deaths, peptic ulcer deaths) were not associated. Data are available through the US Department of Veterans Affairs.
Independent research
Young PJ, Bagshaw SM, Forbes AB, Nichol AD, Wright SE, Bailey M, et al. Effect of stress ulcer prophylaxis with proton pump inhibitors vs histamine-2 receptor blockers on in-hospital mortality among ICU patients receiving invasive mechanical ventilation: the PEPTIC randomized clinical trial JAMA, 2020.
doi:10.1001/jama.2019.22190 PubMed 31950977
Funding and finding
Registration
ACTRN12616000481471
Participants
26,982
Follow-up
90 days in hospital
Funding
Funded by the Health Research Council of New Zealand, the Canadian Institutes of Health Research, the Australian and New Zealand Intensive Care Foundation, and the Health Research Board of Ireland. The PEPTIC trial was supported by the UK National Institute for Health Research Critical Care Clinical Research Networks and the UK Critical Care Research Group. The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Finding
Hospital death by day 90: 2459 of 13,415 (18.3%) in the PPI group against 2333 of 13,356 (17.5%) in the H2-receptor blocker group (RR 1.05, 95% CI 1.00 to 1.10; absolute difference 0.93 percentage points, -0.01 to 1.88; P = .054). Clinically important upper gastrointestinal bleeding 1.3% against 1.8% (RR 0.73, 0.57 to 0.92; -0.51 percentage points). C. difficile infection did not differ significantly. An estimated 4.1% of the PPI arm received H2-receptor blockers and 20.1% of the H2-receptor blocker arm received PPIs.
Industry-funded
Orenstein SR, Hassall E, Furmaga-Jablonska W, Atkinson S, Raanan M. Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease Journal of Pediatrics, 2009.
doi:10.1016/j.jpeds.2008.09.054 PubMed 19054529
Funding and finding
Registration
NCT00324974
Participants
162
Follow-up
4 weeks of double-blind treatment
Funding
The article's funding statement was not read because the publisher page could not be accessed. Registry NCT00324974: lead sponsor Takeda (industry); responsible party Sr. VP Clinical Sciences, Takeda Global Research & Development Center; study director a Takeda medical director.
Finding
Responders (at least 50% reduction in feeding-related crying): 44 of 81 (54%) with lansoprazole and 44 of 81 (54%) with placebo; no difference in any secondary efficacy measure. Treatment-emergent adverse events 62% against 46% (P = .058). Serious adverse events, particularly lower respiratory tract infections, in 10 infants on lansoprazole against 2 on placebo (P = .032).
Independent research
Ito T, Ramos-Alvarez I, Jensen RT. Long-term proton pump inhibitor-acid suppressive treatment can cause vitamin B12 deficiency in Zollinger-Ellison syndrome (ZES) patients International Journal of Molecular Sciences, 2024.
doi:10.3390/ijms25137286 PubMed 39000391
Funding and finding
Participants
175
Follow-up
mean 10.2 years of acid treatment, 5.6 years with PPIs
Funding
This research was partially supported by the NIDDK intramural program (NIDDK #DK053200-26) of the NIH.
Finding
21% had vitamin B12 deficiency. Deficiency was associated with a 12-fold lower drug-controlled acid output and a control pH of 6.4 against 3.7, and acid control secretory rates below those required for pepsin activation, which fails above pH 3.5; achlorhydria over 5 years in 73% against 24%. Food B12 is released from protein by pepsin, binds haptocorrin, is freed by pancreatic proteases and binds intrinsic factor for uptake in the terminal ileum. Mean PPI dose 60 mg omeprazole equivalent daily; 71% took more than one dose a day.
Textbook or database
UniProt Consortium. UniProt: the Universal Protein Knowledgebase in 2025 Nucleic Acids Research, 2025.
doi:10.1093/nar/gkae1010 PubMed 39552041
Funding and finding
Funding
National Human Genome Research Institute [HG002273]; NIH Office of the Director [U24HG007822]; NIAID; NIA; NIGMS [R35GM141873]; NIDDK; NEI; NCI; NHLBI; BBSRC [BB/T015608/1]; National Science Foundation Directorate for Biological Sciences [BB/X002179/1]; Open Targets; Horizon 2020 [825575]; Swiss State Secretariat for Education, Research and Innovation; EMBL Australia.
Finding
Reviewed human UniProtKB entries, release 2026_03 (2 September 2026), read through rest.uniprot.org on 2026-10-22. ATP4A (P20648): catalytic subunit of the gastric H+/K+-ATPase of the parietal-cell apical membrane, K+(out) + ATP + H2O + H+(in) = K+(in) + ADP + phosphate + 2 H+(out), generating a million-fold proton gradient that acidifies gastric juice to pH 1; expressed in gastric parietal cells (at protein level). ATP4B (P51164): beta subunit required for assembly and membrane targeting and stabilising the E2 conformation. ATP12A (P54707): the non-gastric H+/K+-ATPase of apical epithelial membranes, involved in K+ absorption in kidney and colon and in airway mucus acidification; expressed in airway epithelium, skin, kidney and prostate; inhibited by ouabain and SCH-28080. GAST (P01350): gastrin stimulates gastric HCl secretion and pancreatic enzyme secretion. CCKBR (P32239): receptor for gastrin and cholecystokinin, expressed in brain, pancreas and stomach (high in fundic mucosa); also reduces intestinal SGLT1 and GLUT2 expression (by similarity). HDC (P19113): histidine decarboxylase forms histamine from histidine. CHGA (P10645): chromogranin A, secreted from neuroendocrine vesicles. CBLIF (P27352): intrinsic factor of the gastric mucosa, required for ileal cobalamin absorption; deficiency causes megaloblastic anaemia. TRPM6 (Q9BX84): channel crucial for Mg2+ homeostasis and active Mg2+ absorption in gut and kidney, highly expressed in kidney and colon; loss of function causes hypomagnesaemia with secondary hypocalcaemia. DDAH1 (O94760): hydrolyses asymmetric dimethylarginine (ADMA) and monomethylarginine, inhibitors of nitric oxide synthase, to citrulline; detected in brain, liver, kidney and pancreas. TCIRG1 (Q13488): a3 subunit of the V-type H+-ATPase that acidifies the extracellular space in some cell types, highly expressed in osteoclastomas; loss causes autosomal recessive osteopetrosis.
Independent research
Fossmark R, Martinsen TC, Waldum HL. Adverse effects of proton pump inhibitors-evidence and plausibility International Journal of Molecular Sciences, 2019.
doi:10.3390/ijms20205203 PubMed 31640115
Funding and finding
Funding
This research received no external funding.
Finding
Narrative review by researchers of gastrin biology arguing that experimental and mechanistic evidence supporting causal adverse effects may have been underestimated by epidemiologists and meta-analysts. Rats given omeprazole or the H2-receptor antagonists loxtidine or ranitidine at doses causing prolonged acid inhibition and hypergastrinaemia developed corpus ECL-cell tumours; hypergastrinaemia induced by partial corpectomy or ciprofibrate, without hypoacidity, also produced them, and the gastrin-receptor antagonist YF476 inhibited tumour formation in Mastomys natalensis and may prevent it in female cotton rats. ECL-cell carcinoids in PPI users are, the authors argue, probably under-reported and may regress after stopping; patients homozygous for an inactivating ATP4A mutation develop ECL-cell carcinoids and adenocarcinoma in the third to fourth decade, suggesting that the exposure needed for neoplasia may be several decades. CYP2C19 poor metabolisers have higher intragastric pH and, the authors suggest without direct evidence, may be more prone to adverse effects; mice can hardly be dosed to sustained hypoacidity, which limits negative mouse studies.
Independent research
Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, et al. Proton pump inhibitors alter the composition of the gut microbiota Gut, 2016.
doi:10.1136/gutjnl-2015-310861 PubMed 26719299
Funding and finding
Participants
1,827
Funding
The TwinsUK microbiota project was funded the National Institutes of Health (NIH) RO1 DK093595, DP2 OD007444. TwinsUK received funding from the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013), the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. CJS is funded under a grant from the Chronic Disease Research Foundation (CDRF). DEF was funded by the National Center for Advancing Translational Sciences (NIH KL2 TR000081).
Finding
PPI users had lower abundance of gut commensals and lower microbial diversity, with increased oral and upper gastrointestinal commensals, in particular Streptococcaceae. Associations replicated in an interventional study and in monozygotic twin pairs discordant for PPI use. The authors propose that removal of the low-pH barrier lets upper gastrointestinal bacteria reach the lower gut.
Independent research
Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell Physiological Reviews, 2020.
doi:10.1152/physrev.00016.2019 PubMed 31670611
Funding and finding
Funding
Supported by National Institutes of Health grants R01 DK48370, R01 DK101332 and R01 DK70856, Department of Veterans Affairs Merit Review 1I01BX000930 and a gift from the Christine Volpe Fund (to J. R. Goldenring); A. C. Engevik was supported by NIH grants F32 DK111101 and T32 CA106183.
Finding
Narrative review. Parietal-cell HCl keeps luminal pH below 2 and promotes absorption of phosphate, calcium and iron. Histamine from enterochromaffin-like cells acts through Gs-coupled H2 receptors, adenylate cyclase, cAMP and protein kinase A, the rate-limiting trigger of secretion; acetylcholine acts through M3 and gastrin through CCK2 (CCKBR) receptors, both Gq-coupled with Ca2+ release; in humans gastrin acts mainly by releasing histamine from ECL cells. Somatostatin inhibits parietal, ECL and G cells; loss of acid secretion raises gastrin; CCK2R-deficient mice have fewer parietal and ECL cells. The H+/K+-ATPase, a P2-type ATPase of alpha (ATP4A) and beta (ATP4B) subunits in tubulovesicles that fuse with the canaliculus on stimulation, exchanges cytoplasmic H+ for luminal K+ supplied by KCNQ1-KCNE2. All PPIs bind Cys813 of the alpha subunit, arresting the pump in E2; Cys822, bound by pantoprazole, lies in the membrane domain and resists reducing agents. COX-1 (PTGS1) products PGE2 and PGI2 inhibit acid secretion and protect the mucosa; NSAIDs augment acid secretion.
Independent research
Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Ziegler TE, Penniston KL, et al. Do proton pump inhibitors decrease calcium absorption? Journal of Bone and Mineral Research, 2010.
doi:10.1002/jbmr.166 PubMed 20578215
Funding and finding
Participants
21
Follow-up
30 days of omeprazole
Funding
K. E. Hansen received salary support from the NIH (K23 AR050995). The project was supported by grants from the GCRC (NCRR M01 RR03186), the American College of Rheumatology Research and Education Foundation, the American Society for Specialty Physicians through the Hartford Foundation and Atlantic Philanthropies, and the University of Wisconsin Institute for Clinical and Translational Research (NIH Clinical and Translational Science Award 1UL1RR025011). Sponsors had no role in any portion of the study.
Finding
Fractional calcium absorption (mean ± SD) 20% ± 10% and 18% ± 10% at the two baseline visits and 23% ± 10% after 30 ± 3 days of omeprazole 40 mg daily (p = 0.07).
Independent research
Ghebremariam YT, Cooke JP, Khan F, Thakker RN, Chang P, Shah NH, et al. Proton pump inhibitors and vascular function: a prospective cross-over pilot study Vascular Medicine, 2015.
doi:10.1177/1358863X14568444 PubMed 25835348
Funding and finding
Participants
21
Follow-up
two 4-week treatment periods separated by a 2-week washout
Funding
This pilot study was funded by grants from the Translational Research and Applied Medicine (TRAM) Program in the Department of Medicine at Stanford University; also supported in part by NIH grants (1R01 EY02060901, 1U01 HL100397) and internal funding from the Houston Methodist Research Institute; YTG by Stanford, the Tobacco-Related Disease Research Program, NHLBI (1K01 HL118683-01) and HMRI.
Finding
Plasma ADMA rose more on lansoprazole than on placebo, more so in participants with vascular disease, but the differences were not statistically significant; PPI use did not impair flow-mediated vasodilation (EndoPAT). The authors call for larger, long-term blinded trials.
Industry-funded
Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine Circulation, 2013.
doi:10.1161/CIRCULATIONAHA.113.003602 PubMed 23825361
Funding and finding
Funding
Supported in part by grants to JPC from the NIH (RC2HL103400, 1U01HL100397, and K12HL087746), American Heart Association (11IRG5180026), Stanford SPARK Translational Research Program, Stanford Translational Research and Applied Medicine (TRAM) Program and the Tobacco-Related Disease Research Program of the University of California (18XT-0098); YTG by a Stanford Dean's fellowship and the TRDRP (20FT-0090); NHS and PL by NIH grant U54HG004028, Stanford seed funding and the Stanford Center for Biomedical Informatics Research; NHS also acknowledges support from U54LM008748 and Research Gift Support from Apixio, Inc.
Finding
PPIs bound to and inhibited dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor; PPIs raised plasma ADMA and reduced nitric oxide and endothelium-dependent vasodilation in mice and in ex vivo human tissue. Outcomes in people were not measured.
Funding unknown
William JH, Danziger J. Proton-pump inhibitor-induced hypomagnesemia: current research and proposed mechanisms World Journal of Nephrology, 2016.
doi:10.5527/wjn.v5.i2.152 PubMed 26981439
Funding and finding
Funding
not stated
Finding
Narrative review. Observational studies associate PPI exposure with lower serum magnesium, but no prospective controlled studies support causation. Proposed mechanism: active intestinal magnesium uptake through TRPM6 and TRPM7 decreases at higher luminal pH; renal magnesium is conserved in PPI-associated hypomagnesaemia.
Independent research
Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease Cochrane Database of Systematic Reviews, 2013.
doi:10.1002/14651858.CD002095.pub5 PubMed 23728637
Funding and finding
Funding
Internal sources: Department of General Practice, University Medical Center Utrecht, Netherlands. External sources: Division of Clinical Care Research, New England Medical Center, Boston, USA.
Finding
Remission defined as no more than one day a week with mild heartburn. Empirical treatment, PPI against placebo: heartburn persisting in 28 against 75 per 100 (RR 0.37, 95% CI 0.32 to 0.44; 2 trials of 2 and 8 weeks, 760 participants; high-quality evidence). PPI against H2-receptor antagonist: 45 against 68 per 100 (RR 0.66, 0.60 to 0.73; 7 trials, 3147 participants; moderate quality). Reflux disease denotes symptoms and mucosal damage from reflux of gastric acid into the oesophagus; about one adult in four in Western society has heartburn at least monthly and 5% daily.
Independent research
Shin JM, Sachs G. Pharmacology of proton pump inhibitors Current Gastroenterology Reports, 2008.
doi:10.1007/s11894-008-0098-4 PubMed 19006606
Funding and finding
Funding
This work was supported by a US Veterans Administration Merit Grant and grants DK053642 and DK58333 from the National Institute of Diabetes and Digestive and Kidney Diseases.
Finding
Narrative review. PPIs are acid-activated prodrugs: a pyridine with pKa about 4 (3.8 to 4.9) concentrates them about 1000-fold in the secretory canaliculus at pH about 1; a second protonation (benzimidazole pKa about 1) yields a sulfenic acid or tetracyclic sulfenamide that forms disulfides with luminal cysteines: Cys813 and Cys892 for omeprazole, Cys813 and Cys321 for lansoprazole, Cys813 and Cys822 for pantoprazole; pantoprazole binding resists glutathione reduction. The pump exchanges 2 H+ and 2 K+ per ATP at pH 6.1 and 1 of each below luminal pH 3.0. Plasma half-life about 1 hour; acid inhibition lasts about 48 hours; steady state after 2 to 3 days; once-daily dosing 30 to 60 minutes before breakfast inhibits about 66% of maximal acid output, twice-daily about 80%. Pump half-life about 54 hours in rats; half-time of recovery of acid secretion in humans about 24 hours after omeprazole and 46 hours after pantoprazole. Bioavailability 77% for pantoprazole, 80% to 90% for lansoprazole, 89% for esomeprazole; hepatic metabolism mainly by CYP2C19 and CYP3A4; hepatic impairment raises AUC sevenfold. CYP2C19 poor metabolisers are 3% of Caucasians and 15% to 20% of Asians; their AUC is about 7.5-fold that of homozygous extensive metabolisers for omeprazole and 4.5-fold for lansoprazole, with median intragastric pH about 6 against 3 to 4. Oesophagitis heals well when intragastric pH exceeds 4 for 16 hours a day, peptic ulcer when it exceeds 3 for 16 hours. Esomeprazole is the S-enantiomer of omeprazole.
Textbook or database
Sangkuhl K, Klein TE, Altman RB. Clopidogrel pathway Pharmacogenetics and Genomics, 2010.
doi:10.1097/FPC.0b013e3283385420 PubMed 20440227
Funding and finding
Funding
PharmGKB is supported by the NIH/NIGMS Pharmacogenetics Research Network (PGRN; UO1GM61374).
Finding
Clopidogrel is a prodrug absorbed in the intestine and activated in the liver by two sequential oxidative steps, the first forming 2-oxo-clopidogrel and the second the active metabolite. CYP1A2, CYP2B6 and CYP2C19 form 2-oxo-clopidogrel from clopidogrel in liver microsomes; with 2-oxo-clopidogrel as substrate, CYP3A4, CYP2C9, CYP2C19 and CYP2B6 produce the active metabolite. Kazui and colleagues concluded that CYP2C19 contributes substantially to both steps and CYP3A4 to the second. In a competing reaction about 85% of the drug is hydrolysed by esterases to an inactive carboxylic acid. The thiol group of the active metabolite binds a free cysteine of the P2Y12 receptor (P2RY12) and irreversibly blocks ADP binding, so the platelet is affected for its whole lifespan of about 7 to 10 days. Clopidogrel is not detected in human plasma. Between 20% and 40% of patients show low inhibition of ADP-induced platelet aggregation. ABCB1 takes part in intestinal absorption. Interactions have been reported with atorvastatin, verapamil and omeprazole.
Regulator
US Food and Drug Administration. FDA reminder to avoid concomitant use of Plavix (clopidogrel) and omeprazole US Food and Drug Administration, posted 27 October 2010, 2010.
http://web.archive.org/web/20171104220627/https://www.fda.gov/Drugs/DrugSafety/ucm231161.htm
Funding and finding
Funding
US Food and Drug Administration
Finding
FDA continues to warn against concomitant use of clopidogrel and omeprazole because co-administration can significantly reduce levels of the active metabolite of clopidogrel and its antiplatelet activity; the warning was added to the Plavix label in November 2009. The recommendation applies only to omeprazole, not to all PPIs, because PPIs differ in inhibition of CYP2C19; pantoprazole, a weak CYP2C19 inhibitor, may be an alternative.
Regulator
AbbVie Inc.; approved by the US Food and Drug Administration. SYNTHROID (levothyroxine sodium) tablets, for oral use US Food and Drug Administration, Drugs@FDA, NDA 021402, prescribing information revised February 2024, 2024.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/021402s038lbl.pdf
Funding and finding
Funding
Labelling prepared by the applicant, AbbVie Inc., and approved by the US Food and Drug Administration as supplement 038 to NDA 021402 on 20 February 2024.
Finding
Synthetic T4, chemically identical to thyroidal T4, indicated for primary, secondary and tertiary hypothyroidism and as an adjunct for TSH suppression in thyrotropin-dependent well-differentiated thyroid cancer. Narrow therapeutic index. Once daily on an empty stomach, half to one hour before breakfast, and at least 4 hours apart from drugs that interfere with absorption, including phosphate binders such as calcium carbonate and ferrous sulfate; gastric acidity is required for absorption, and proton pump inhibitors, sucralfate and antacids may reduce it. Absorption 40% to 80%, mostly in the jejunum and upper ileum, increased by fasting. T4 is 99.96% protein-bound; half-life 6 to 7 days in euthyroid patients, 9 to 10 days in hypothyroidism and 3 to 4 days in hyperthyroidism. About 80% of circulating T3 derives from peripheral monodeiodination of T4. Adult full replacement 1.6 mcg/kg/day, titrated by 12.5 to 25 mcg every 4 to 6 weeks; TSH is checked 6 to 8 weeks after a dose change; peak effect may take 4 to 6 weeks; in primary hypothyroidism the dose is titrated to a normal TSH, in secondary or tertiary hypothyroidism to free T4. Atrial fibrillation is the most common arrhythmia of overtreatment in the elderly; over-replacement may increase bone resorption and decrease bone mineral density, particularly in postmenopausal women. If cardiac symptoms develop or worsen, the dose is reduced or withheld for one week and restarted lower. Replacement therapy is generally taken for life.
Expert consensus
Lima JJ, Thomas CD, Barbarino J, Desta Z, Van Driest SL, El Rouby N, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and proton pump inhibitor dosing Clinical Pharmacology and Therapeutics, 2021.
doi:10.1002/cpt.2015 PubMed 32770672
Funding and finding
Funding
National Institutes of Health funding for CPIC (R24GM115264 and U24HG010135), PharmGKB (U24HG010615) and PharmVar (R24GM123930); additional grants to individual authors from the NIH, the CANSEARCH foundation, the Robert Bosch Stiftung, the Burroughs Wellcome Fund, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Foundation and the EU H2020 UPGx grant 668353.
Finding
CYP2C19*2 (rs4244285) and *3 (rs4986893) are no-function and *17 (rs12248560) increased-function alleles; *2 has an allele frequency of about 15% in Europeans and Africans and 25% to 30% in Asians; *17 about 20% in African, European and Near Eastern populations. CYP2C19 accounts for about 80% of clearance of omeprazole, lansoprazole and pantoprazole, CYP3A4 for less. Intermediate and poor metabolisers have 3- to 14-fold higher AUC. For omeprazole, lansoprazole, pantoprazole and dexlansoprazole: ultrarapid metabolisers, increase the starting daily dose by 100%; normal and rapid metabolisers, standard dose, consider 50% to 100% increase for H. pylori infection and erosive oesophagitis; intermediate and poor metabolisers, standard dose, consider a 50% reduction for chronic therapy beyond 12 weeks once efficacy is achieved. No recommendation for esomeprazole and rabeprazole. Strong CYP3A inhibitors may raise risk in intermediate and poor metabolisers; strong CYP2C19 inhibitors such as fluvoxamine raise exposure except in poor metabolisers; inducers such as rifampin reduce exposure. Current data are insufficient for strong recommendations on adverse events; most studies were in Asian populations with few rapid and ultrarapid metabolisers.
Independent research
Ness-Jensen E, Hveem K, El-Serag H, Lagergren J. Lifestyle intervention in gastroesophageal reflux disease Clinical Gastroenterology and Hepatology, 2016.
doi:10.1016/j.cgh.2015.04.176 PubMed 25956834
Funding and finding
Funding
ENJ is supported by the Norwegian and Swedish Research Councils. KH has no grant support covering his wages. HES is supported by NIH K24 DK04-107 and the Houston VA Health Services Research and Development Center of Excellence (HFP90-020). JL is supported by grants from the Swedish Research Council.
Finding
Weight loss: three randomised trials of gastric balloon against sham in severely obese people, with diet, exercise and behavioural therapy in both arms, reported reduced oesophageal acid exposure with weight loss (in one, 23 patients losing a mean 11.2 kg in 13 weeks went from 5.60% to 3.72% of time at pH < 4; in another, 17 sham-treated patients losing 12.5 kg went from 8.0% to 5.5% upright); in a trial of a structured weight-loss programme (n = 167) against telephone conferences (n = 165), reflux symptom prevalence fell from 37% to 15% after 6 months irrespective of group. A small randomised trial in obese patients with GERD (mean BMI 31.4), low-calorie diet of 430 kcal/day for 6 months (n = 10) against none (n = 9), found that a mean weight loss of 10.8 kg had no significant effect on symptoms, oesophagitis or pH measurements. Meal timing: crossover trial of 30 patients, late meal 2 hours before bedtime against early meal 6 hours before, more supine reflux after the late meal (mean change 5.2 percentage points). Head of bed: crossover trial of 15 patients, 10-inch wedge reduced time at pH < 4 from 21% to 15%. Smoking cessation reduced reflux symptoms in normal-weight people in a prospective cohort (OR 5.67). The authors note extensive data on acid-inhibiting medication against only few and heterogeneous trials of lifestyle intervention, consider commercial interests probably the main reason for this imbalance, and call for non-commercial funding of such trials.
Independent research
Albarqouni L, Moynihan R, Clark J, Scott AM, Duggan A, Del Mar C. Head of bed elevation to relieve gastroesophageal reflux symptoms: a systematic review BMC Family Practice, 2021.
doi:10.1186/s12875-021-01369-0 PubMed 33468060
Funding and finding
Registration
osf.io/2hz3j
Participants
228
Funding
No specific funding for this research.
Finding
All five trials were at high risk of performance bias and four of selection bias; heterogeneity precluded meta-analysis. The four trials reporting symptoms found improvement with head-of-bed elevation; a high-quality crossover trial showed a clinically important reduction in symptom scores at 6 weeks (RR 2.1, 95% CI 1.2 to 3.6), supported by intra-oesophageal pH measurements. The authors judge that the literature precludes definitive recommendations but that elevation could be considered a cheap and safe alternative.
Regulator
The Procter & Gamble Manufacturing Company. PRILOSEC OTC (omeprazole magnesium) tablet, delayed release: Drug Facts US over-the-counter drug labelling, published in DailyMed (National Library of Medicine); structured product label version 18, effective 5 October 2026, 2026.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=35a79458-79f6-44d6-b74c-b4f4aaf0dde0
Funding and finding
Funding
not stated; the label carries no funding statement
Finding
Use: frequent heartburn, occurring 2 or more days a week; not for immediate relief; full effect may take 1 to 4 days. Directions for adults: one tablet before eating in the morning every day for 14 days; a 14-day course may be repeated every 4 months; do not take for more than 14 days or more often than every 4 months unless directed by a doctor. Ask a doctor before use with heartburn for over 3 months, unexplained weight loss, frequent wheezing, nausea, vomiting or stomach pain. Stop use and ask a doctor if more than 14 days or more than one course every 4 months is needed, or with diarrhoea, rash or joint pain. Allergy alert: omeprazole may cause severe skin reactions.
Expert consensus
National Institute for Health and Care Excellence. Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management National Institute for Health and Care Excellence, clinical guideline CG184; published 3 September 2014, last updated 18 October 2019, 2019.
PubMed 31935049
Funding and finding
Funding
not stated
Finding
Offer simple lifestyle advice including healthy eating, weight reduction and smoking cessation; raising the head of the bed and having the main meal well before bedtime may help some people [2004]. Offer full-dose PPI for 4 weeks for uninvestigated dyspepsia and for 4 or 8 weeks for GORD [2004]; if symptoms recur, the lowest effective dose and as-needed use [2004, amended 2014]; full-dose PPI for 8 weeks to heal severe oesophagitis and long-term as maintenance [new 2014]; people who had dilatation of an oesophageal stricture remain on long-term full-dose PPI. Offer an annual review to people needing long-term management and encourage stepping down or stopping treatment unless an underlying condition or comedication requires it, with return to antacid or alginate self-treatment where appropriate [2004, amended 2014]. Leave a 2-week washout after PPI use before Helicobacter pylori breath or stool testing.
Expert consensus
Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association Gastroenterology, 2017.
doi:10.1053/j.gastro.2017.01.031 PubMed 28257716
Funding and finding
Funding
Not read: the publisher page refused access and the article is not in PubMed Central; PubMed indexes it as Research Support, Non-U.S. Gov't.
Finding
Expert opinion and literature to July 2016, graded by a modified GRADE approach and reviewed by the AGA Clinical Practice Updates Committee. Patients with complicated GERD should take a PPI for healing, maintenance and long-term control; patients with uncomplicated GERD who respond should attempt to stop or reduce; patients with Barrett's oesophagus and symptoms should take a long-term PPI, asymptomatic patients should consider one; patients at high risk of NSAID ulcer bleeding should take a PPI; the dose should be periodically re-evaluated. Long-term users should not routinely use probiotics, raise intake of calcium, vitamin B12 or magnesium above the RDA, or be routinely screened or monitored for bone mineral density, serum creatinine, magnesium or vitamin B12; specific PPIs should not be chosen on the basis of potential risks.
Regulator
Medicines and Healthcare products Regulatory Agency. Proton pump inhibitors in long-term use: reports of hypomagnesaemia MHRA Drug Safety Update, volume 5, issue 9, April 2012: A1 (republished on GOV.UK 11 December 2014), 2012.
https://www.gov.uk/drug-safety-update/proton-pump-inhibitors-in-long-term-use-reports-of-hypomagnesaemia
Funding and finding
Funding
Medicines and Healthcare products Regulatory Agency
Finding
Severe hypomagnesaemia has been reported infrequently with PPIs; the exact incidence is unknown. A review of case reports in the literature and to European regulators suggests that PPIs may cause hypomagnesaemia; some cases occurred after 3 months and most after 1 year of treatment. Serious manifestations include fatigue, tetany, delirium, convulsions, dizziness and ventricular arrhythmia, which may begin insidiously and be overlooked. In most case reports hypomagnesaemia improved after magnesium replacement and discontinuation of the PPI. Magnesium measurement should be considered before and periodically during prolonged treatment, especially with digoxin or diuretics. Over-the-counter PPIs should not be used for more than 4 weeks without consulting a doctor.
Expert consensus
Katz PO, Dunbar KB, Schnoll-Sussman FH, Greer KB, Yadlapati R, Spechler SJ. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease American Journal of Gastroenterology, 2022.
doi:10.14309/ajg.0000000000001538 PubMed 34807007
Funding and finding
Funding
not stated
Finding
For classic heartburn and regurgitation without alarm symptoms, an 8-week empirical trial of a PPI once daily before a meal (strong recommendation, moderate evidence), then an attempt to discontinue in responders (conditional, low evidence); PPI 30 to 60 minutes before a meal rather than at bedtime (strong, moderate). Rebound acid hypersecretion has been shown in healthy controls, but strong evidence for an increase in symptoms after abrupt withdrawal is lacking. Genetic testing for CYP2C19 has no established role in practice.
Independent research
Boghossian TA, Rashid FJ, Thompson W, Welch V, Moayyedi P, Rojas-Fernandez C, et al. Deprescribing versus continuation of chronic proton pump inhibitor use in adults Cochrane Database of Systematic Reviews, 2017.
doi:10.1002/14651858.CD011969.pub2 PubMed 28301676
Funding and finding
Participants
1,758
Funding
Internal sources: Bruyère Research Institute, Canada. External sources: Ministry of Health and Long-Term Care, Ontario, Health Services Research Fund, Canada; Ontario Pharmacy Research Collaboration (OPEN), Canada.
Finding
On-demand use against continuous PPI use: lack of symptom control 157 against 92 per 1000 (RR 1.71, 95% CI 1.31 to 2.21; 5 trials, 1653 participants; low-quality evidence); pill use 3.79 fewer per week (4.73 to 2.84 fewer; moderate quality). Data were insufficient for conclusions on long-term benefits and harms of discontinuation.
Funding unknown
Reimer C, Søndergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy Gastroenterology, 2009.
doi:10.1053/j.gastro.2009.03.058 PubMed 19362552
Funding and finding
Registration
NCT00526006
Participants
120
Follow-up
12 weeks
Funding
The funding statement of the article was not read because the publisher page could not be accessed. Registry NCT00526006 names Zealand University Hospital as lead sponsor and lists no collaborator; PubMed indexes the article as Research Support, Non-U.S. Gov't.
Finding
Esomeprazole 40 mg daily for 8 weeks followed by placebo for 4 weeks, against placebo for 12 weeks: at least one clinically relevant acid-related symptom in weeks 9 to 12 in 26 of 59 (44%) against 9 of 59 (15%), p < 0.001; dyspepsia, heartburn or acid regurgitation at week 12 in 12 of 58 (21%) against 2%.
Expert consensus
Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review Gastroenterology, 2022.
doi:10.1053/j.gastro.2021.12.247 PubMed 35183361
Funding and finding
Funding
Not read: the publisher page refused access and the article is not in PubMed Central; PubMed lists VA HSR&D grant I01 HX002693.
Finding
Not a systematic review; no formal rating of evidence quality. Best practice advice: every PPI user should have regular review and documentation of the indication by the primary care provider; patients without a definitive indication should be considered for a trial of de-prescribing; most twice-daily users with an indication should step down to once daily; complicated GERD, Barrett's oesophagus, eosinophilic oesophagitis or idiopathic pulmonary fibrosis and high upper gastrointestinal bleeding risk generally exclude de-prescribing; patients should be told they may develop transient symptoms from rebound acid hypersecretion; tapering or abrupt discontinuation can be considered. Advice 10: the decision to discontinue should be based solely on lack of an indication and not on concern for PPI-associated adverse events; a past or present adverse event or its risk factors is not an independent indication for withdrawal.

Updated 2026-10-22