What are the risks associated with long-term treatment with Proton Pump Inhibitors (PPIs)?

From the Guidelines

Long-term treatment with Proton Pump Inhibitors (PPIs) carries significant risks, including rebound acid hypersecretion, bone fractures, vitamin B12 deficiency, increased susceptibility to infections, kidney problems, and potential cognitive decline, emphasizing the need for cautious use and regular reassessment of therapy. The most recent and highest quality study, published in 2022 in the journal Gastroenterology 1, highlights the risk of rebound acid hypersecretion upon discontinuation of long-term PPI therapy, which can lead to transient upper GI symptoms. This phenomenon occurs due to the increased parietal cell mass and subsequent acid-generating potential unleashed when PPIs are discontinued.

Key risks associated with long-term PPI use include:

• Bone fractures, particularly hip, wrist, and spine fractures, due to decreased calcium absorption
• Vitamin B12 deficiency, as stomach acid is necessary for B12 absorption
• Increased susceptibility to infections, such as Clostridium difficile and pneumonia
• Kidney problems, including acute interstitial nephritis and chronic kidney disease
• Potential cognitive decline, although the connection remains controversial
• Hypomagnesemia (low magnesium levels), leading to muscle cramps, arrhythmias, and seizures

According to the 2022 study in Gastroenterology 1, the emerging literature has identified several adverse effects potentially linked to PPIs, including chronic kidney disease, fracture, dementia, and COVID-19. However, it is essential to note that these associations are based on observational studies and do not establish causality. Randomized controlled trials comparing PPIs with placebo have not shown a higher rate of adverse events among PPI users 1.

To minimize risks, PPIs should be used at the lowest effective dose for the shortest necessary duration, with periodic reassessment of the need for continued therapy. The primary care provider should be responsible for reviewing the presence of ongoing indications for PPI use and identifying candidates for de-prescribing, as suggested in the 2022 study in Gastroenterology 1. Regular review of PPI therapy is crucial to ensure that the potential benefits outweigh the potential harms and to minimize the risk of adverse effects.

From the FDA Drug Label

Omeprazole delayed-release capsules can cause serious side effects, including: • A type of kidney problem (tubulointerstitial nephritis). • Diarrhea. • Bone fractures. • Certain types of lupus erythematosus.

Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

The risks associated with long-term treatment with Proton Pump Inhibitors (PPIs) like omeprazole include:

• Kidney problems: Long-term use of PPIs may increase the risk of kidney problems, such as tubulointerstitial nephritis.
• Diarrhea: PPIs may increase the risk of severe diarrhea, which can be caused by an infection (Clostridium difficile) in the intestines.
• Bone fractures: Long-term use of PPIs, especially at high doses, may increase the risk of fractures of the hip, wrist, or spine.
• Lupus erythematosus: PPIs may increase the risk of certain types of lupus erythematosus, an autoimmune disorder.
• Vitamin B-12 deficiency: Long-term use of acid-suppressing medications, including PPIs, may lead to malabsorption of cyanocobalamin (vitamin B-12) 2, 2.

From the Research

Risks Associated with Long-Term Treatment with Proton Pump Inhibitors (PPIs)

• The long-term use of PPIs has been associated with several risks, including:
  • Osteoporosis-related fractures 3
  • Intestinal infections, such as Clostridium difficile 3, 4
  • Poor absorption of vitamins and minerals, including vitamin B12, magnesium, and iron 3, 4, 5
  • Increased risk of kidney disease, particularly in the elderly with pre-existing kidney disease 3, 4
  • Potential increased risk of dementia, pneumonia, myocardial infarction, and stroke 3
  • Acid rebound, which can occur with abrupt discontinuation of PPIs 3
• The American Gastroenterological Association has provided best practice advice for the use of PPIs, including:
  • Using the lowest effective dose and periodically reevaluating the dose 6
  • Not routinely using probiotics to prevent infection or raising intake of calcium, vitamin B12, or magnesium beyond the Recommended Dietary Allowance (RDA) 6
  • Not routinely screening or monitoring bone mineral density, serum creatinine, magnesium, or vitamin B12 in long-term PPI users 6

Specific Risks and Considerations

• Gastric cancer: There is no clear association between PPI use and an increased risk of gastric cancer 3, 5
• Bone fracture: Increased risk of bone fracture has been consistently reported, particularly in studies involving low-quality data 3, 4
• Kidney disease: Long-term PPI use may be associated with an increased risk of adverse kidney events, particularly in the elderly with pre-existing kidney disease 3, 4
• Gastrointestinal infections: PPIs may increase the risk of enteric infections, including Clostridium difficile 3, 4

Clinical Implications

• Clinicians should be aware of the potential risks associated with long-term PPI use and consider these risks when prescribing PPIs 4
• Higher-quality data is needed to better understand PPI-associated risks and to inform clinical decision-making 4