What are the long-term risks of prolonged use of Proton Pump Inhibitors (PPIs)?

From the Guidelines

Long-term use of proton pump inhibitors (PPIs) is associated with several potential risks, including decreased absorption of nutrients, increased risk of bone fractures, kidney problems, and certain infections, and therefore, patients should work with their healthcare provider to use the lowest effective dose for the shortest duration necessary. The use of PPIs has been linked to a range of adverse effects, from chronic kidney disease to fracture to dementia and COVID-19, although these associations are based on observational studies and have not been confirmed by randomized controlled trials 1.

Potential Risks of Long-term PPI Use

• Decreased absorption of nutrients such as vitamin B12, magnesium, calcium, and iron, which can lead to deficiencies over time
• Reduced calcium absorption may contribute to an increased risk of bone fractures, particularly in the hip, wrist, and spine
• Long-term PPI use has been associated with a slightly higher risk of kidney problems, including chronic kidney disease and acute kidney injury
• Evidence suggesting an increased risk of certain infections, including Clostridium difficile infections and pneumonia, due to reduced stomach acid allowing more bacteria to survive
• Some studies have linked prolonged PPI use to a small increased risk of dementia, though this connection remains controversial

Recommendations for PPI Use

• Patients taking a PPI should have a regular review of the ongoing indications for use and documentation of that indication, which should be the responsibility of the patient’s primary care provider (PCP) 1
• In patients with a known history of more severe erosive esophagitis or those with GERD-related complications, PPIs should generally not be considered for discontinuation unless the benefits and harms have been weighed and discussed with the patient 1
• If you require long-term acid suppression therapy, work with your healthcare provider to use the lowest effective dose for the shortest duration necessary, consider periodic attempts to reduce or discontinue use, and monitor for potential nutrient deficiencies through regular blood tests.

From the FDA Drug Label

5.4 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer) Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines

5.5 Cutaneous and Systemic Lupus Erythematosus Cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including omeprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease.

5.6 Cyanocobalamin (Vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature.

5.7 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures.

5.11 Fundic Gland Polyps PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year.

The long-term risks of taking proton pump inhibitors (PPIs) for a long period of time include:

• Increased risk of osteoporosis-related fractures of the hip, wrist, or spine, especially with high-dose and long-term therapy 2
• Cutaneous and systemic lupus erythematosus, which can occur as new onset or exacerbation of existing autoimmune disease 2
• Cyanocobalamin (Vitamin B-12) deficiency, which can occur with long-term use of acid-suppressing medications 2 3
• Hypomagnesemia, which can occur with long-term use of PPIs, especially after a year of therapy 3
• Fundic gland polyps, which can occur with long-term use of PPIs, especially beyond one year 3

From the Research

Long-term Risks of Proton Pump Inhibitors

The long-term use of proton pump inhibitors (PPIs) has been associated with several potential risks, including:

• Increased risk of community-acquired pneumonia, but not hospital-acquired pneumonia 4
• Development of fundic gland polyps (FGP), which can regress after stopping PPIs 4
• Mild/modest hypergastrinemia, a physiological response to reduced gastric acid secretion 4
• Potential increased risk of osteoporosis-related fractures, intestinal infections, and poor absorption of vitamins and minerals such as vitamin B12, magnesium, and iron 5
• Reports of dementia, pneumonia, kidney disease, myocardial infarction, and stroke, although the causal association is still subject to validation 5
• Increased risk of acid rebound after abrupt discontinuation of PPIs 5
• Associations with bone fracture, acute and chronic kidney disease, gastrointestinal infections, deficiencies in vitamin B12 and magnesium, and coronavirus disease 2019 and respiratory infections, although mostly reported in low-quality data and subject to bias 6

Specific Risks and Considerations

• The use of PPIs may be associated with an increased risk of adverse kidney events, especially in the elderly, with long-term PPI use and pre-existing kidney disease 5
• The risk of pneumonia was increased 27-39% in short-term use of PPIs in three meta-analyses 7
• C. difficile infections were also associated with the use of PPIs (odds ratio: 2.15; 95% CI: 1.81-2.55; p < 0.00001) 7
• Thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis, and acute interstitial nephritis have also been reported with the use of PPIs 7
• Patients with GERD and acid-related complications should take a PPI for short-term healing, maintenance of healing, and long-term symptom control, while patients with uncomplicated GERD who respond to short-term PPIs should attempt to stop or reduce them 8

Mitigating Adverse Effects

• The key to mitigating adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration 5
• Long-term PPI users should not routinely use probiotics to prevent infection, raise their intake of calcium, vitamin B12, or magnesium beyond the Recommended Dietary Allowance (RDA), or screen or monitor bone mineral density, serum creatinine, magnesium, or vitamin B12 8
• Specific PPI formulations should not be selected based on potential risks 8
• Clinicians may consider greater vigilance with PPI use, but the data does not demonstrate a need for wide adoption of de-escalation strategies solely out of safety concerns 6