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Proton Pump Inhibitor Side Effects PPI Considerations

last modified on: Mon, 05/06/2024 - 08:33

return to: Esophageal Reflux PrecautionsEsophagoscopy with narrow band imaging (NBI) for Reflux EsophagitisExtraesophageal reflux disease

Counseling patients about side effects of drugs warrants a risk-reward assessment in the context of the consideration that "All drugs have adverse effects" and "clinicians must weigh the benefits vs the risks and the seriousness of the disease vs the seriousness of the adverse effects" (Katz 2010).

Clear indications for use of proton pump inhibitor (PPI) therapy are established, for example: "Patients with BE (Barrett's Esophagus) should receive once-daily PPI therapy" (ACG Clinical Guideline Shaheen et al 2016).

Use of PPI therapy was supported for laryngo-pharyngeal reflux (LPR) in a recent meta-analysis of 14 eligible randomized controlled trials (RCT's) identified that "in patients with LPR, PPI therapy could improve reflux symptoms significantly compared with placebo" (Guo 2016).

Knowledge about potential adverse effects of proton pump inhibitor use has continued to evolve and recently (2016 Schoenfeld and Grady) have been classified adverse effecs according to Kidney Disease / Hypomagnesemia / Infections / Cardivascular Events / Fractures;

 to this scheme additional sections on malignant change, B12 absorption, and dementia are added


Proposed Mechanism



Kidney Disease


acute kidney injury from acute interstitial nephritis 

or hypomagnesemia

Observational Studies:

10,439 patients followed for 13.9 years = chronic kidney disease 50% higher in PPI users compared to nonusers (2016 Lazarus)

290,592 patients 66 and older rates of acute kidney injury 2.5 to 3.0 times higher in PPI users compared to nonusers (2015 Antoniou)




uncertain mechanism - potentially related to

PPI-use blocking intestinal absorption

(William 2015)

Observational Study:

109, 798 participants in meta-analysis of 9 observational studies: PPI users hav a 40% higher risk of hypmagnesemia (Cheungpasitporn 2015)

FDA warning in 2011 that prolonged use of PPI's may cause hypomagnesemia (accessed 3-14-2016)

kidney disease

severe hypomagnesemia: muscle weakness, tetany, convulsions, cardiac arrythmias and hypotension

Infections -

Clostridium difficile


reduced gastric acidity may promote

bacterial colonization

Observational Studies:

Meta-anaysis of 39 studies: 74% higher risk of recurrent C difficile infection among PPI users (Kwok 2012)

FDA warning in 2015 re: association betweeen PPI use and C difficile infection (accessed 3-14-2016)


Infections -



reduced gastric acidity and increased bacterial colonization

Observational Studies:

Meta-analysis of 5 studies - risk of community-acquired pneumonia 34% higher among PPI users (hospital acquired was not increased) (Eom 2011)

No increase in pneumonia (community or hospital acquired) in evaluation of the 2.35% of 4,238,504 new NSAID users concurrently started on PPIs (Filion KB 2014)

see also: (Duncan 2018) with invited commentary (Prager 2018) and also (Herzig 2014)

Comparing a cohort of patients with laryngeal/voice disorders - half having been on PPI therapy, half without - Cohen et al (Cohen 2019) reported a 30-50% increased risk of community acquired pneumonia by those on PPI therapy compared to those without PPI prescriptions


Cardiovascular Events


the same liver enzymes that metabolize clopidogrel to its

active form also metabolize PPIs; competitive metabolism

by PPIs might lead to reduced activation of clopidogrel (plavix)

Summary from Shoenfeld and Grady (2016): "we do not find clear evidence that PPIs increase risk for coronary events in patients on clopidogrel (plavix)

Observational Studies:

Meta-analysis of 31 observational studies of patients on clopidogrel, 30% increased risk of cardiovascular event with use of PPI's

In the same review, none of the 4 randomized clinical triasl reported showed an increased risk of coronary events among patient on

   clopidogrel who were also treated with the PPIs (either omeprazole or esomeprazole) (Melloni 2015)




reduced intestinal calcium absorption

Observational studies:

Meta-analysis of 18 observational studies including 244,109 fractures: PPI use associated with 26% higher incidence of hip fracture; 58% higher risk of spine fracture, 33% risk of fracture at any site (Zhou 2015)

FDA safety alert (2010): increase risk of fractures among PPI users (accessed 3-14-2016)


Gastric pre-malignant change


PPI's increase benign fundic polyps likely by neutralizing acid in the stomach leading to elevated gastrin production stimulating parietal cell and ECL hypertrophy and hyperplasia

(Ally 2009)

Observational Studies:

Meta-analysis of 7 trials (1,789 participants) conclude: "There is presently no clear evidence that the long-term use of PPIs can cause or accelerate the progression of corpus gastric atrophy or intestinal metaplasia, although the results were imprecise. (Song 2014)



most recent study suggests no link between PPI use and dementia (Lockhead 2017)


vitamin B12 deficiency

PPI's enhance beta-amyloid levels in brains of mice

Observational studies:

Analysis of 13,864 women in cohort of 100,000 followed for three decades (participant questionaire for cognitive function) - (Lockhead 2017): "Our data do not support the suggestion that PPI use increases dementia risk."

70,000 German participants over the age of 75 were studied to identify a significantly increased risk of dementia among PPI users (Gomm 2016)


Proton Pump Inhibitors (PPI) and H2 Receptor Blockers

ref: (search word: proton pump inhibitor)

(accessed 3-14-2016)

Prescription PPI's


Generic name

Brand Name(s)






esomeprazole magnesioum




esomeprazole magnesium and naproxen












omeprazole and Sodium bicarbonate




pantoprazole sodium




rabeprazole sodium


Over-the-Counter PPI's



Prevacid 24 HR



omeprazole magnesium

Prilosec OTC



omeprazole and sodium bicarbonate

Zegerid OTC





Prescription H2 Receptor Blockers









Pepcid, Duexis




Axid, Nizatidine




Zantac, Tritec

Over-the-Counter H2 Receptor Blockers





Tagamet HB




Pepcid Complete, Pepcid AC




Axid AR







Schoenfeld A and Grady Deborah:Adverse Effects Associated with Proton Pump Inhibitors  JAMA Internal Medicine 2016 vol 176 issue 2 pp 172-4

Lazarus B, Yuan C, Wilson FP et al Proton pump inhibitor use and the risk of chronic kidney desae JAMA Intern Med. pub online Jan 11, 2016

Antoniou T, Macdonald EM, Hollands S et al Proton pump inhibiotrs and the risk of acute kidney injury in older pateints: a popuation-based cohort studay   CMAJ Open 2015;3(2):E166-E171

Proton Pump Inhibitors Information 2015;

CheungpasitpornW, Thongprayoon C, Kittanamongkolchai W et al Protocon pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail. 2015;37(7):1237-1241

Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta analysis Am J Gastroenterol 2012; 107(7):1011-1019

Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS Use of acid–suppressive drugs and risk of pneumonia: a systematic review and meta-analysis. CMAJ 2011;183(3):310-319

Filion KB, Chateau D, Targownik LE et al CNODES Inverstigators. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis Gut 2014;63(4):552-228

Melloni C, Washam JB, Jones WS, et al Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when co-administered with dual antiplatelet therapy: systematic review. Circ Cardiovasc Qual Outcomes 2015; 8(1):47-55

Zhou B, Huang Y, Li H, Sun W, Liu J. Proton-pump inhibiotrs and risk of fratures: an update meta-analysis (published on-line Oc 13, 2015) Osteoporos Int. doi: 10.1007/soo198-015-3365-x

Katz MH Failing the acid test: benefits of proton pump inhibiotrs may not justify the risks for many users. Arch Intern Med 2010 May 10;170(9):747-8

Shaheen NJ, Falk GW, Iyer PG, and Gerson LB: ACG Clinical Guideline: Diagnosis and Mangaement of Barrett's Esophagus. Am J Gastroenterol 2016;111:30-50; published online Nov 3 2015

Guo H, Ma H, and Wang J: Proton Pump Inhibitor Therapy fo rhte Treatment of Laryngopharyngeal Reflux: A Meta-Analysis of Randomized Controlled Trials. J Clin Gastroenterol 2016 Apr;50(4):295-300

Song H, Zhu J, and Lu D: Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions Cochrane Database Syst Rev 2014 Dec 2;12 – on line

Gomm W, von Holt K, Thome F, Broich K, Maier W, Fink A, Doblhammer G and Haenisch B: Association of Proton Pump Inhhibitors with Risk of Dementia A Pharmacoepidemiooigcal Claims Data Analysis  JAMA Neurol on line Feb 15, 2016

William JH and Danziger J: Magnesium Deficiency and Proton-Pump Inhibitor Sue: A Clinical Review J Clin Pharmocol 2015 Nov 18

Ally M, Veerappan GR, Maydonovitch CL, Duncan TJ, Perry JL, Osgard EM, and Wong RKH: Chronic Proton Pump Inhibitor Therapy Associated with Increased Development of Fundic Gland Polyps  Dig Dis Sci (2009)54:2617-2622

Lochhead P, Hagan K, Joshi AD, Khalili H, Nguyen LH, Grodstein F, Chan AT.: Association Between Proton Pump Inhibitor Use and Cognitive Function in Women.Gastroenterology. 2017 Jul 18. pii: S0016-5085(17)35910-3. doi: 10.1053/j.gastro.2017.06.061

see also:

Duncan DR, Mitchell PD, Larson K McSweeney ME, and Rosen RL: Association of Proton Pump Inhibitors with Hospitalization Risk in Children with Oropharyngeal Dysphagia. Jama  Otolaryngol Head Neck Surg. 2018;144(12):1116-1124 

Herzig SJ, Doughty C, Lahoti S, et al Acid-suppressive medication usein acute stroke andhospital-acquired pneumonia. Ann Neurol. 2014;76(5):712-718

Prager JD: Empirical Proton Pump Inhibitor Therapy in Children. JAMA Otolaryngology-Head and Neck Surgery December 2018 Vol 144, Number 12 

Cohen SM, Lee H-J, Leiman DA, Roy N, and Misono S: Associations between Community-Acquired Pneumonia and Proton Pump Inhibitors in the Laryngeal/Voice-Disordered Population.Otolaryngology-Head and Neck Surgery 2019, Vol. 160(3) 519-525