Appropriate Use and Stewardship of Proton-Pump Inhibitors

Dylan Ren, 2020 PharmD Candidate; Erin Gurney, 2020 PharmD Candidate; Jaime R. Hornecker, PharmD, BCPS, CDE, DPLA


US Pharmacist. 2019;44(12):25-31. 

In This Article

Adverse Events of PPIs

As PPI use continues to grow every year, concerns regarding their safety have arisen. Throughout the years, the FDA has published numerous safety statements and recommendations with regards to appropriate PPI use as new data have become available. Although once thought of as safe options, PPI usage in recent years has raised concerns, evidenced by numerous studies and reviews exploring a diverse range of adverse outcomes associated with PPI use. (See Table 2 for a list of PPI-associated adverse events and mechanisms.)


In 2011, the FDA issued a warning that long-term PPI use may lower serum magnesium levels that supplementation alone may not correct unless the PPI was discontinued.[14] When severe, hypomagnesemia may present in the form of muscle weakness, tetany, seizures, cardiac arrhythmias, and hypotension, with the potential to be life-threatening.[15] The risk of hypomagnesemia was further studied by a 2015 systematic review and meta-analysis that included over 100,000 patients and assessed the risk of hypomagnesemia in patients with PPI as compared with non-PPI users. This study ultimately concluded approximately a 40% increased risk of hypomagnesemia with PPI use as compared with non-PPI therapy.[4]


In 2015, the FDA issued a public safety alert in regards to increased Clostridium difficile infections associated with PPI use. This was primarily based upon a 2012 systematic review and meta-analysis study that included over 30 studies and 300,000 patients, which concluded that PPI users had a 74% higher risk of developing a C diff infection, as well as a 2.5-fold higher risk of recurrent infections, as compared with nonusers.[16]

In addition to increased C diff infections, PPI use may also lead to increased rates of pneumonia. A meta-analysis performed in 2011 showed that the risk of community-acquired pneumonia (CAP) was 34% higher in patients on PPIs, which increased with higher dosing.[17] It should be mentioned that this study did not find an increased risk with hospital-acquired pneumonia.

For both C diff and CAP, it is generally hypothesized to be due to decreased gastric acidity caused by long-term PPI use and a subsequent increase in bacterial colonization.[17,18]


Osteoporosis is one of the most common bone-related disorders, with complications that are associated with high morbidity, mortality, and health-care-associated costs.[19] In May of 2010, the FDA issued a public safety statement alert regarding potential increased risk of fractures associated with PPI use.[20] Since then, numerous studies exploring the relationship between PPI use and fracture risk have been examined. A 2016 meta-analysis reviewing over 200,000 fracture cases reported a 26% higher risk of hip fracture, 58% higher risk of spine fracture, and a 33% risk of fracture at any site in individuals who used PPI as compared with those who have not, even at a duration of less than 1 year.[19]

Cardiovascular Disease

Individuals with acute coronary syndrome (ACS) who have undergone percutaneous coronary intervention are commonly prescribed antiplatelet therapy to reduce and prevent further cardiovascular complications. PPIs may be prescribed in conjunction with antiplatelet therapy to reduce risk of gastrointestinal bleeding. In addition, as mentioned, PPIs are used commonly by the general populace as a whole for other acid-related disorders.[24] In 2009, the FDA issued a statement warning against the combination of the antiplatelet agent clopidogrel and PPIs due potential drug interactions between the two.[21] Mechanistically, clopidogrel is metabolized to its active form through the same liver enzymes that metabolize PPIs, raising concern of a potential diminished antiplatelet effect and therefore an increase in cardiovascular events.[15]

Currently, data surrounding the clinical significance of this event are mixed. A 2015 meta-analysis of 31 observational studies found that individuals on PPI therapy and clopidogrel had a 30% increased risk of cardiovascular events as compared to nonusers of PPI therapy.[22] However, the four randomized clinical trials included in the review found there was no increased risk of events identified.[22]

In addition, another 2015 systematic review that explored the use of PPIs and the risk of myocardial infarction found a 16% increased risk associated with use. This was found to be regardless of clopidogrel use and was not seen with H2 blocker therapy.[5]

Other Concerns

There are numerous other concerns associated with PPI use for which the FDA has not released statements. These include issues such as subacute cutaneous lupus, dementia, acute interstitial nephritis, and vitamin B[12] deficiency.[23] Overall, the safety of PPIs remains controversial. As numerous new reports and literature are published, the use of PPIs and safety of PPI therapy should be recommended with hesitancy over other options.