Editing Proton-pump inhibitor (section)

== Adverse effects ==
In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. The range and occurrence of [[adverse effect (medicine)|adverse effects]] are similar for all of the PPIs, though they have been reported more frequently with [[omeprazole]]. This may be due to its longer availability and, hence, clinical experience.{{citation needed|date=May 2022}}

Common adverse effects include [[headache]], [[nausea]], [[diarrhea]], [[abdominal pain]], [[fatigue (physical)|fatigue]], and [[dizziness]].<ref name="Rossi">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. {{ISBN|0-9757919-2-3}}{{page needed|date=March 2013}}</ref> Infrequent adverse effects include [[rash]], [[itch]], [[flatulence]], [[constipation]], [[anxiety]], and [[Depression (mood)|depression]]. Also infrequently, PPI use may be associated with occurrence of [[Myopathy|myopathies]], including the serious reaction [[rhabdomyolysis]].<ref>{{cite journal | vauthors = Clark DW, Strandell J | title = Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? | journal = European Journal of Clinical Pharmacology | volume = 62 | issue = 6 | pages = 473–9 | date = June 2006 | pmid = 16758264 | doi = 10.1007/s00228-006-0131-1 | s2cid = 33139851 }}</ref>

Long-term use of PPIs requires assessment of the balance of the [[risk-benefit ratio|benefits and risks]] of the therapy.<ref>{{cite journal | vauthors = Hendrix I, Page AT, Korhonen MJ, Bell JS, Tan EC, Visvanathan R, Cooper T, Robson L, Sluggett JK | title = Patterns of High-Dose and Long-Term Proton Pump Inhibitor Use: A Cross-Sectional Study in Six South Australian Residential Aged Care Services | journal = Drugs - Real World Outcomes | volume = 6 | issue = 3 | pages = 105–113 | date = September 2019 | pmid = 31264165 | pmc = 6702506 | doi = 10.1007/s40801-019-0157-1 }}</ref><ref name=Corleto2014>{{cite journal | vauthors = Corleto VD, Festa S, Di Giulio E, Annibale B | title = Proton pump inhibitor therapy and potential long-term harm | journal = Current Opinion in Endocrinology, Diabetes, and Obesity | volume = 21 | issue = 1 | pages = 3–8 | date = February 2014 | pmid = 24310148 | doi = 10.1097/MED.0000000000000031 | s2cid = 205791135 }}</ref><ref name="pmid28257716">{{cite journal | vauthors = Freedberg DE, Kim LS, Yang YX | title = The Risks and Benefits of Long-term Use of Proton Pump Inhibitors: Expert Review and Best Practice Advice From the American Gastroenterological Association | journal = Gastroenterology | volume = 152 | issue = 4 | pages = 706–715 | date = March 2017 | pmid = 28257716 | doi = 10.1053/j.gastro.2017.01.031 | quote = Conclusions:Baseline differences between PPI users and non-users make it challenging to study potential PPI adverse effects retrospectively. Despite a large number of studies, the overall quality of evidence for PPI adverse effects is low to very low. When PPIs are appropriately prescribed, their benefits are likely to outweigh their risks. When PPIs are inappropriately prescribed, modest risks become important because there is no potential benefit. There is currently insufficient evidence to recommend specific strategies for mitigating PPI adverse effects. }}</ref><ref name="pmid28528705">{{cite journal | vauthors = Vaezi MF, Yang YX, Howden CW | title = Complications of Proton Pump Inhibitor Therapy | journal = Gastroenterology | volume = 153 | issue = 1 | pages = 35–48 | date = July 2017 | pmid = 28528705 | doi = 10.1053/j.gastro.2017.04.047 | quote = In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered, along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged. | doi-access = free }}</ref> As of March 2017, various adverse outcomes have been associated with long-term PPI use in several primary reports, but reviews assess the overall quality of evidence in these studies as "low" or "very low".<ref name="pmid28257716"/>  They describe inadequate evidence to establish [[Causality#Biology, medicine and epidemiology|causal relationships]] between PPI therapy and many of the proposed associations, due to study design and small estimates of effect size.<ref name="pmid28528705"/> 

As of March 2017, benefits outweighed risks when PPIs are used appropriately, but when used inappropriately, modest risks become important.<ref name="pmid28257716"/><ref>{{cite journal | vauthors = Yang M, He Q, Gao F, Nirantharakumar K, Veenith T, Qin X, Page AT, Wong MC, Huang J, Kuo ZC, Xia B, Zhang C, He Y, Meng W, Yuan J, Pan Y | title = Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials | journal = BMC Medicine | volume = 19 | issue = 1 | pages = 316 | date = December 2021 | pmid = 34856983 | pmc = 8641218 | doi = 10.1186/s12916-021-02180-5 | doi-access = free }}</ref> They recommend that PPIs should be used at the lowest effective dose in people with a proven indication, but discourage dose escalation and continued chronic therapy in people unresponsive to initial empiric therapy.<ref name="pmid28528705"/>

With regard to iron and vitamin B<sub>12</sub>, the data is weak and several [[confounding factors]] have been identified.<ref name="Corleto2014" />  [[Hypomagnesemia|Low levels of magnesium]] can be found in people on PPI therapy and these can be reversed when they are switched to [[H2-receptor antagonist|H<sub>2</sub>-receptor antagonist]] medications.<ref name=Corleto2014 /><ref name="pmid25394217">{{cite journal | vauthors = Park CH, Kim EH, Roh YH, Kim HY, Lee SK | title = The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis | journal = PLOS ONE | volume = 9 | issue = 11 | pages = e112558 | year = 2014 | pmid = 25394217 | pmc = 4230950 | doi = 10.1371/journal.pone.0112558 | bibcode = 2014PLoSO...9k2558P | doi-access = free }}</ref><ref name="FDA magnesium">{{cite web | title=Low magnesium levels can be associated with long-term use of PPIs | website=U.S. [[Food and Drug Administration]] (FDA) | date=17 November 2009 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-low-magnesium-levels-can-be-associated-long-term-use-proton-pump | access-date=23 February 2020}}</ref>

===Bone ===
High dose or long-term use of PPIs carries an increased risk of [[bone fracture]]s which was not found with short-term, low dose use; the FDA included a warning regarding this on PPI drug labels in 2010.<ref name="fda">{{cite web |url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-possible-increased-risk-fractures-hip-wrist-and-spine-use-proton-pump |title=FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors |date=23 March 2011 |publisher=U.S. [[Food and Drug Administration]] (FDA) |access-date=23 August 2015}}</ref>

In infants, acid suppression therapy is frequently prescribed to treat symptomatic gastroesophageal reflux in otherwise healthy infants (that is: without [[gastroesophageal reflux disease]]). A study from 2019 showed that  PPI use alone and together with histamine H2-receptor antagonists was associated with an increased bone fracture hazard, which was amplified by days of use and earlier initiation of therapy.<ref name="ped">{{cite journal |last1=Malchodi |first1=Laura |last2=Wagner |first2=Kari |last3=Susi |first3=Apryl |last4=Gorman |first4=Gregory |last5=Hisle-Gorman |first5=Elizabeth |date=July 2019 |title=Early Acid Suppression Therapy Exposure and Fracture in Young Children |journal=Pediatrics |volume=144 |issue=1 |pages=e20182625 |doi=10.1542/peds.2018-2625 |issn=1098-4275 |pmid=31175146|s2cid=182948146 |doi-access=free }}</ref> The reason is not clear; increased bone break down by [[osteoclast]]s has been suggested.<ref>{{cite journal |last1=Nehra |first1=Avinash K. |last2=Alexander |first2=Jeffrey A. |last3=Loftus |first3=Conor G. |last4=Nehra |first4=Vandana |date=2018 |title=Proton Pump Inhibitors: Review of Emerging Concerns |journal=Mayo Clinic Proceedings |language=en |volume=93 |issue=2 |pages=240–246 |doi=10.1016/j.mayocp.2017.10.022|pmid=29406201 |s2cid=20212012 |doi-access=free }}</ref>

A recent 2024 study published in the ''Journal of Clinical Endocrinology & Metabolism'' found that chronic use of PPIs in men is linked to lower trabecular bone quality.<ref>{{Cite web |date=2024-09-25 |title=Chronic PPI Use Affects Bone Quality Among Men |url=https://www.endocrinologyadvisor.com/news/chronic-ppi-use-affects-bone-quality/ |access-date=2024-09-29 |website=Endocrinology Advisor |language=en-US}}</ref> Specifically, PPI use was associated with reduced lumbar spine trabecular bone score (TBS), as well as lower bone mineral density (BMD) T-scores in the lumbar spine, total hip, and femoral neck.<ref>{{Cite journal |last1=Bioletto |first1=Fabio |last2=Pusterla |first2=Alessia |last3=Fraire |first3=Federica |last4=Sauro |first4=Lorenzo |last5=Presti |first5=Michela |last6=Arvat |first6=Emanuela |last7=Ghigo |first7=Ezio |last8=Procopio |first8=Massimo |last9=Barale |first9=Marco |date=2024-08-28 |title=Sex-specific Association of Chronic Proton Pump Inhibitor Use With Reduced Bone Density and Quality |url=https://academic.oup.com/jcem/advance-article-abstract/doi/10.1210/clinem/dgae598/7743296?redirectedFrom=fulltext |journal=The Journal of Clinical Endocrinology & Metabolism |pages=dgae598 |doi=10.1210/clinem/dgae598 |pmid=39197024 |issn=0021-972X|doi-access=free }} 

=== Nutritional ===
Gastric acid is important for breakdown of food and release of [[Micronutrient|micronutrients]], and some studies have shown possibilities for interference with absorption of [[iron]], [[calcium]], [[magnesium]], and [[Cyanocobalamin|vitamin B<sub>12</sub>]].<nowiki><ref name="pmid20882439"></nowiki>{{cite journal |vauthors=Ito T, Jensen RT |date=December 2010 |title=Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium |journal=Current Gastroenterology Reports |volume=12 |issue=6 |pages=448–57 |doi=10.1007/s11894-010-0141-0 |pmc=2974811 |pmid=20882439}}</ref> These findings suggest that long-term PPI use may negatively affect bone health in men.

=== Gastrointestinal ===
Some studies have shown a correlation between use of PPIs and [[Clostridioides difficile infection|''Clostridioides difficile'' infection]]. While the data are contradictory and controversial, the FDA had sufficient concern to include a warning about this adverse effect on the label of PPI medications.<ref name=Corleto2014 /> Concerns have also been raised about [[spontaneous bacterial peritonitis]] (SBP) in older people taking PPIs and in people with [[irritable bowel syndrome]] taking PPIs; both types of infections arise in these populations due to underlying conditions and it is not clear if this is a class effect of PPIs.<ref name=Corleto2014 /> PPIs may predispose an individual to developing  [[small intestinal bacterial overgrowth]] or fungal overgrowth.<ref name="SIBO">{{cite journal | vauthors = Fujimori S | title = What are the effects of proton pump inhibitors on the small intestine? | journal = World Journal of Gastroenterology | volume = 21 | issue = 22 | pages = 6817–9 | date = June 2015 | pmid = 26078557 | pmc = 4462721 | doi = 10.3748/wjg.v21.i22.6817 | quote = Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridioides difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. | doi-access = free }}</ref><ref name="SIFO">{{cite journal | vauthors = Erdogan A, Rao SS | title = Small intestinal fungal overgrowth | journal = Current Gastroenterology Reports | volume = 17 | issue = 4 | pages = 16 | date = April 2015 | pmid = 25786900 | doi = 10.1007/s11894-015-0436-2 | quote = Small intestinal fungal overgrowth (SIFO) is characterized by the presence of excessive number of fungal organisms in the small intestine associated with gastrointestinal (GI) symptoms. Candidiasis is known to cause GI symptoms particularly in immunocompromised patients or those receiving steroids or antibiotics. However, only recently, there is emerging literature that an overgrowth of fungus in the small intestine of non-immunocompromised subjects may cause unexplained GI symptoms. Two recent studies showed that 26% (24/94) and 25.3% (38/150) of a series of patients with unexplained GI symptoms had SIFO. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear but small intestinal dysmotility and use of proton pump inhibitors has been implicated. However, further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth, both in healthy subjects and in patients with otherwise unexplained GI symptoms. | s2cid = 3098136 }}</ref>

In [[Cirrhosis|cirrhotic patients]], large volume of ascites and reduced esophageal motility by varices can provoke [[Gastroesophageal reflux disease|GERD]].<ref>{{cite journal | vauthors = Li B, Zhang B, Ma JW, Li P, Li L, Song YM, Ding HG | title = High prevalence of reflux esophagitis among upper endoscopies in Chinese patients with chronic liver diseases | journal = BMC Gastroenterology | volume = 10 | issue = 1 | pages = 54 | date = June 2010 | pmid = 20525368 | pmc = 2889852 | doi = 10.1186/1471-230X-10-54 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Passaretti S, Mazzotti G, de Franchis R, Cipolla M, Testoni PA, Tittobello A | title = Esophageal motility in cirrhotics with and without esophageal varices | journal = Scandinavian Journal of Gastroenterology | volume = 24 | issue = 3 | pages = 334–8 | date = April 1989 | pmid = 2734592 | doi = 10.3109/00365528909093056 }}</ref><ref>{{cite journal | vauthors = Reilly JJ, Schade RR, Van Thiel DS | title = Esophageal function after injection sclerotherapy: pathogenesis of esophageal stricture | journal = American Journal of Surgery | volume = 147 | issue = 1 | pages = 85–8 | date = January 1984 | pmid = 6606991 | doi = 10.1016/0002-9610(84)90039-4 }}</ref> Acidic irritation, in return, may induce the rupture of varices.<ref>{{cite journal | vauthors = Lo GH, Perng DS, Chang CY, Tai CM, Wang HM, Lin HC | title = Controlled trial of ligation plus vasoconstrictor versus proton pump inhibitor in the control of acute esophageal variceal bleeding | journal = Journal of Gastroenterology and Hepatology | volume = 28 | issue = 4 | pages = 684–9 | date = April 2013 | pmid = 23278466 | doi = 10.1111/jgh.12107 | s2cid = 5205186 }}</ref> Therefore, PPIs are often routinely prescribed for cirrhotic patients to treat GERD and prevent variceal bleeding. However, it has been recently shown that long term use of PPIs in patients with [[cirrhosis]] increases the risk of SBP and is associated with the development of clinical decompensation and liver-related death during long-term follow-up.<ref>{{cite journal | vauthors = Janka T, Tornai T, Borbély B, Tornai D, Altorjay I, Papp M, Vitális Z | title = Deleterious effect of proton pump inhibitors on the disease course of cirrhosis | language = en-US | journal = European Journal of Gastroenterology & Hepatology | volume = 32 | issue = 2 | pages = 257–264 | date = February 2020 | pmid = 31464790 | doi = 10.1097/MEG.0000000000001499 | doi-access = free }}</ref>

There is evidence that PPI use alters the composition of the bacterial populations inhabiting the [[Gastrointestinal tract|gut]], the [[gut microbiota]].<ref>{{cite journal | vauthors = Jackson MA, Goodrich JK, Maxan ME, Freedberg DE, Abrams JA, Poole AC, Sutter JL, Welter D, Ley RE, Bell JT, Spector TD, Steves CJ | title = Proton pump inhibitors alter the composition of the gut microbiota | journal = Gut | volume = 65 | issue = 5 | pages = 749–756 | date = May 2016 | pmid = 26719299 | pmc = 4853574 | doi = 10.1136/gutjnl-2015-310861 }}</ref> Although the mechanisms by which PPIs cause these changes are yet to be determined, they may have a role in the increased risk of bacterial infections with PPI use.<ref name=":1" /> These infections can include ''Helicobacter pylori'' due to this species not favouring an acid environment, leading to an increased risk of ulcers and gastric cancer risk in genetically susceptible patients.<ref name=":1">{{cite journal | vauthors = Hagiwara T, Mukaisho K, Nakayama T, Hattori T, Sugihara H | title = Proton pump inhibitors and helicobacter pylori-associated pathogenesis | journal = Asian Pacific Journal of Cancer Prevention | volume = 16 | issue = 4 | pages = 1315–1319 | year = 2015 | pmid = 25743791 | doi = 10.7314/APJCP.2015.16.4.1315 | doi-access = free }}</ref>

PPI use in people who have received attempted ''H. pylori'' eradication may also be associated with an increased risk of gastric cancer.<ref name="pmid29089382">{{cite journal | vauthors = Cheung KS, Chan EW, Wong AY, Chen L, Wong IC, Leung WK | title = Long-term proton pump inhibitors and risk of gastric cancer development after treatment for ''Helicobacter pylori'': a population-based study | journal = Gut | volume = 67 | issue = 1 | pages = 28–35 | date = January 2018 | pmid = 29089382 | doi = 10.1136/gutjnl-2017-314605 | doi-access = free }}</ref> The validity and robustness of this finding, with the lack of causality, have led to this association being questioned.<ref name="PMID31294357">{{cite journal | vauthors = Leontiadis GI, Veldhuyzen Van Zanten S, Hookey L, Armstrong D, Jones N, Moayyedi P | title = Canadian Association of Gastroenterology Statement on the Putative Link Between Proton Pump Inhibitor Treatment and Gastric Cancer after ''Helicobacter pylori'' Eradication | journal = Journal of the Canadian Association of Gastroenterology | volume = 1 | issue = 4 | pages = 155–158 | date = December 2018 | pmid = 31294357 | pmc = 6542241 | doi = 10.1093/jcag/gwy040 }}</ref>  It is recommended that long-term PPIs should be used judiciously after considering individual's risk–benefit profile, particularly among those with history of ''H. pylori'' infection, and that further, well-designed, prospective studies are needed.<ref>{{cite journal | vauthors = Cheung KS, Leung WK | title = Long-term use of proton-pump inhibitors and risk of gastric cancer: a review of the current evidence | journal = Therapeutic Advances in Gastroenterology | volume = 12 | pages = 1756284819834511 | date = January 2019 | pmid = 30886648 | pmc = 6415482 | doi = 10.1177/1756284819834511 | doi-access = free }}</ref>

Long-term use of PPIs is associated with the development of benign [[polyp (medicine)|polyp]]s from [[fundic gland]]s (which is distinct from [[fundic gland polyposis]]); these polyps do not cause cancer and resolve when PPIs are discontinued.<ref name="Corleto2014" /> There is concern that use of PPIs may mask [[gastric]] cancers or other serious gastric problems.<ref name="Corleto2014" />

PPI use has also been associated with the development of [[microscopic colitis]].<ref name="pmid22704658">{{cite journal | vauthors = Münch A, Aust D, Bohr J, Bonderup O, Fernández Bañares F, Hjortswang H, Madisch A, Munck LK, Ström M, Tysk C, Miehlke S | title = Microscopic colitis: Current status, present and future challenges: statements of the European Microscopic Colitis Group | journal = Journal of Crohn's & Colitis | volume = 6 | issue = 9 | pages = 932–45 | date = October 2012 | pmid = 22704658 | doi = 10.1016/j.crohns.2012.05.014 | doi-access = free }}</ref>

=== Cardiovascular ===
Associations of PPI use and cardiovascular events have also been widely studied but clear conclusions have not been made as these relative risks are confounded by other factors.<ref name="pmid23425521">{{cite journal | vauthors = Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW, Huber K, Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atar D, Pathak A, Kjeldsen K, Storey RF | title = Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy | journal = European Heart Journal | volume = 34 | issue = 23 | pages = 1708–13, 1713a-1713b | date = June 2013 | pmid = 23425521 | doi = 10.1093/eurheartj/eht042 | doi-access = free }}</ref><ref name="pmid25587094">{{cite journal | vauthors = Melloni C, Washam JB, Jones WS, Halim SA, Hasselblad V, Mayer SB, Heidenfelder BL, Dolor RJ | title = Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review | journal = Circulation: Cardiovascular Quality and Outcomes | volume = 8 | issue = 1 | pages = 47–55 | date = January 2015 | pmid = 25587094 | pmc = 6143138 | doi = 10.1161/CIRCOUTCOMES.114.001177 }}</ref> PPIs are commonly used in people with cardiovascular disease for gastric protection when [[aspirin]] is given for its antiplatelet actions.<ref name="pmid23425521" /><ref name="pmid21047145">{{cite journal | vauthors = Kwok CS, Nijjar RS, Loke YK | title = Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis | journal = Drug Safety | volume = 34 | issue = 1 | pages = 47–57 | date = January 2011 | pmid = 21047145 | doi = 10.2165/11584750-000000000-00000 | s2cid = 21231797 }}</ref> An interaction between PPIs and the metabolism of the platelet inhibitor [[clopidogrel]] is known and this drug is also often used in people with cardiac disease.<ref name="pmid22851683">{{cite journal | vauthors = Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW | title = Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review | journal = Heart | volume = 99 | issue = 8 | pages = 520–7 | date = April 2013 | pmid = 22851683 | doi = 10.1136/heartjnl-2012-302371 | s2cid = 23689175 }}</ref><ref name="pmid26196021">{{cite journal | vauthors = Cardoso RN, Benjo AM, DiNicolantonio JJ, Garcia DC, Macedo FY, El-Hayek G, Nadkarni GN, Gili S, Iannaccone M, Konstantinidis I, Reilly JP | title = Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis | journal = Open Heart | volume = 2 | issue = 1 | pages = e000248 | year = 2015 | pmid = 26196021 | pmc = 4488889 | doi = 10.1136/openhrt-2015-000248 }}</ref><ref name="doi/10.1136/bmj.l1580">{{cite journal | vauthors = Xie Y, Bowe B, Yan Y, Xian H, Li T, [[Ziyad Al-Aly|Al-Aly Z]] | title = Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study | journal = BMJ | volume = 365 | pages = l1580 | date = May 2019 | pmid = 31147311 | pmc = 6538974 | doi = 10.1136/bmj.l1580 | url = https://medicine.wustl.edu/news/popular-heartburn-drugs-linked-to-fatal-heart-disease-chronic-kidney-disease-stomach-cancer/ | quote = Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use.  | publisher = Washington University School of Medicine }}</ref> There are associations with an increased risk of stroke, but this appears to be more likely to occur in people who already have an elevated risk.<ref>{{cite journal | vauthors = Yang M, He Q, Gao F, Nirantharakumar K, Veenith T, Qin X, Page AT, Wong MC, Huang J, Kuo ZC, Xia B, Zhang C, He Y, Meng W, Yuan J, Pan Y | title = Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials | journal = BMC Medicine | volume = 19 | issue = 1 | pages = 316 | date = December 2021 | pmid = 34856983 | doi = 10.1186/s12916-021-02180-5 | publisher = Springer Science and Business Media LLC | pmc = 8641218 | s2cid = 244803096 | doi-access = free }}</ref>

One suggested mechanism for cardiovascular effects is because PPIs bind and inhibit [[dimethylargininase]], the enzyme that degrades [[asymmetric dimethylarginine]] (ADMA), resulting in higher ADMA levels and a decrease in bioavailable [[nitric oxide]].<ref name="pmid24780466">{{cite journal | vauthors = Schepers E, Speer T, Bode-Böger SM, Fliser D, Kielstein JT | title = Dimethylarginines ADMA and SDMA: the real water-soluble small toxins? | journal = Seminars in Nephrology | volume = 34 | issue = 2 | pages = 97–105 | date = March 2014 | pmid = 24780466 | doi = 10.1016/j.semnephrol.2014.02.003 | url = https://biblio.ugent.be/publication/5866529/file/5866574 | quote = It also seems to be the pathophysiological link between the use of proton pump inhibitors and increased cardiovascular event rate because these medications bind and inhibit DDAH, the enzyme that degrades ADMA, which results in higher ADMA levels and a decrease in bioavailable NO. }}</ref>

=== Cancer ===

A 2022 umbrella review of 21 meta-analyses shows an association between proton-pump inhibitor use and an increased risk of four types of cancer.<ref>{{cite journal |title=Proton Pump Inhibitors and Cancer Risk: An Umbrella Review and Meta-analysis of Observational Studies |year=2022 |doi=10.1097/COC.0000000000000949|pmid=36255347 |last1=Zhang |first1=M. L. |last2=Fan |first2=Y. X. |last3=Meng |first3=R. |last4=Cai |first4=W. K. |last5=Yin |first5=S. J. |last6=Zhou |first6=T. |last7=Huang |first7=Y. H. |last8=Wang |first8=P. |last9=Jiang |first9=F. F. |last10=Yang |first10=M. |last11=He |first11=G. H. |journal=American Journal of Clinical Oncology |volume=45 |issue=11 |pages=475–485 |s2cid=252970194 }}</ref>

=== Other ===
Associations have been shown between PPI use and an increased risk of pneumonia, particularly in the 30 days after starting therapy, where it was found to be 50% higher in community use.<ref name="pmid26042842">{{cite journal | vauthors = Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA | title = Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis | journal = PLOS ONE | volume = 10 | issue = 6 | pages = e0128004 | year = 2015 | pmid = 26042842 | pmc = 4456166 | doi = 10.1371/journal.pone.0128004 | bibcode = 2015PLoSO..1028004L | doi-access = free }}</ref><ref name=pmid21173070>{{cite journal | vauthors = Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS | title = Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis | journal = CMAJ | volume = 183 | issue = 3 | pages = 310–9 | date = February 2011 | pmid = 21173070 | pmc = 3042441 | doi = 10.1503/cmaj.092129 }}</ref> Other very weak associations of PPI use have been found, such as with [[chronic kidney disease]],<ref>{{cite journal |doi = 10.1016/j.cegh.2017.12.008|title = Proton pump inhibitors use and risk of chronic kidney disease: Evidence-based meta-analysis of observational studies|journal = Clinical Epidemiology and Global Health|volume = 7|pages = 46–52|year = 2019| vauthors = Hussain S, Singh A, Habib A, Najmi AK |doi-access = free}}</ref><ref>{{cite journal | vauthors = Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J, Grams ME | title = Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease | journal = JAMA Internal Medicine | volume = 176 | issue = 2 | pages = 238–46 | date = February 2016 | pmid = 26752337 | pmc = 4772730 | doi = 10.1001/jamainternmed.2015.7193 | publisher = American Medical Association (AMA) }}</ref><ref>{{cite journal | vauthors = Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z | title = Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury | journal = Kidney International | volume = 91 | issue = 6 | pages = 1482–1494 | date = June 2017 | pmid = 28237709 | doi = 10.1016/j.kint.2016.12.021 | publisher = Elsevier BV | doi-access = free }}</ref><ref name="doi/10.1136/bmj.l1580" /><ref>{{cite journal | vauthors = Moledina DG, Perazella MA | title = Proton Pump Inhibitors and CKD | journal = Journal of the American Society of Nephrology | volume = 27 | issue = 10 | pages = 2926–2928 | date = October 2016 | pmid = 27080978 | pmc = 5042680 | doi = 10.1681/asn.2016020192 | publisher = American Society of Nephrology (ASN) }}</ref><ref>{{cite journal | vauthors = Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z | title = Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD | journal = Journal of the American Society of Nephrology | volume = 27 | issue = 10 | pages = 3153–3163 | date = October 2016 | pmid = 27080976 | pmc = 5042677 | doi = 10.1681/asn.2015121377 | publisher = American Society of Nephrology (ASN) }}</ref> [[dementia]]<ref>Salman Hussain, Ambrish Singh et al. No association between proton pump inhibitors use and risk of dementia: Evidence from a meta-analysis. J Gastroenterol Hepatol. https://doi.org/10.1111/jgh.14789</ref><ref name="pmid28257716"/><ref name="pmid28130652">{{cite journal | vauthors = Schnoll-Sussman F, Katz PO | title = Clinical Implications of Emerging Data on the Safety of Proton Pump Inhibitors | journal = Current Treatment Options in Gastroenterology | volume = 15 | issue = 1 | pages = 1–9 | date = March 2017 | pmid = 28130652 | doi = 10.1007/s11938-017-0115-5 | quote = The methodology of these studies allows us to find an association with these events but does not provide us with sufficient evidence to determine causality. In general, the findings of the available studies do not fit with our clinical experience nor is the magnitude of the association sufficient to result in a major change in our practice. Nevertheless, the recent literature has resulted in our careful reevaluation of PPI use across both FDA indications and in general. | s2cid = 24718665 }}</ref> and [[Hepatocellular carcinoma]] (HCC).<ref>{{cite journal | vauthors = Singh A, Hussain S, Jha R, Jayraj AS, Klugar M, Antony B | title = Proton pump inhibitor use and the risk of hepatocellular carcinoma: A systematic review of pharmacoepidemiological data | journal = Journal of Evidence-Based Medicine | volume = 14 | issue = 4 | pages = 278–280 | date = December 2021 | pmid = 34643998 | doi = 10.1111/jebm.12456 | s2cid = 238746424 | url = | issn = }}</ref>

As of 2016, results were derived from observational studies, it remained uncertain whether such associations were causal relationships.<ref name="pmid28257716"/><ref name="pmid28528705"/><ref name="pmid27006255">{{cite journal | vauthors = Kia L, Kahrilas PJ | title = Therapy: Risks associated with chronic PPI use - signal or noise? | journal = Nature Reviews. Gastroenterology & Hepatology | volume = 13 | issue = 5 | pages = 253–4 | date = May 2016 | pmid = 27006255 | doi = 10.1038/nrgastro.2016.44 | s2cid = 19207074 | url = https://zenodo.org/record/895402 }}</ref>