What are the long-term side effects of Proton Pump Inhibitors (PPI)?

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Last updated: April 16, 2025 • View editorial policy

From the Guidelines

Long-term use of proton pump inhibitors (PPIs) can potentially cause several concerning side effects, including increased susceptibility to certain infections, nutrient deficiencies, and increased risk of bone fractures, and therefore, patients taking PPIs long-term should consider periodic attempts at dose reduction under medical supervision, use the lowest effective dose, and have regular monitoring for nutrient deficiencies and kidney function. The most significant long-term risks of PPI use include:

  • Increased susceptibility to certain infections (particularly Clostridium difficile and pneumonia) 1
  • Nutrient deficiencies (especially vitamin B12, magnesium, calcium, and iron) 1
  • Increased risk of bone fractures, chronic kidney disease, and dementia 1
  • Microscopic colitis, small intestinal bacterial overgrowth, and fundic gland polyps in the stomach 1
  • Interactions with the absorption of certain drugs like clopidogrel, reducing their effectiveness 1 The risk of these side effects generally increases with longer duration of use, particularly beyond 1-2 years 1. Despite these concerns, for many patients with severe acid-related conditions like GERD, Barrett's esophagus, or peptic ulcers, the benefits of PPIs often outweigh the risks 2. It is essential to weigh the benefits and harms of PPI use and consider de-prescribing in patients without a strong indication for use 3, 4, 5, 6. Regular review of the ongoing indications for PPI use and documentation of that indication is crucial to determine whether a PPI’s potential benefits outweigh the potential harms 3. 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 5.

From the Research

Long-term Side Effects of PPI

The long-term use of Proton Pump Inhibitors (PPIs) has been associated with several potential side effects, including:

  • Osteoporosis-related fractures 7, 8, 9, 10
  • Intestinal infections, such as Clostridium difficile 7, 9, 11
  • Poor absorption of vitamins and minerals, including vitamin B12, magnesium, and iron 7, 10, 11
  • Dementia 7, 11
  • Kidney disease, particularly in the elderly with long-term PPI use and pre-existing kidney disease 7, 10, 11
  • Increased risk of community-acquired pneumonia, hip fracture, and colorectal cancer 9
  • Acid rebound, which occurs when PPIs are abruptly discontinued, leading to increased gastric acid production above pre-PPI treatment levels 7
  • Bone fracture, acute and chronic kidney disease, gastrointestinal infections, deficiencies in vitamin B12 and magnesium, and coronavirus disease 2019 and respiratory infections 10

Risk Factors and Considerations

The risk of these side effects may be increased in certain populations, such as:

  • The elderly 7, 10, 11
  • Those with pre-existing kidney disease 7, 10, 11
  • Those taking PPIs for extended periods of time 7, 8, 9, 10, 11
  • Those taking PPIs at high doses or for inappropriate indications 8, 11

Clinical Management and Recommendations

To mitigate the risk of these side effects, it is recommended to:

  • Use PPIs at the lowest effective dose and for the shortest possible duration 7, 8, 10
  • Monitor patients for signs of adverse effects, particularly in high-risk populations 10
  • Consider alternative treatments or de-escalation strategies in patients with safety concerns 10

References

Research

SAFETY OF LONG-TERM PROTON PUMP INHIBITORS: FACTS AND MYTHS.

Arquivos de gastroenterologia, 2022

Research

Proton pump inhibitors: Understanding the associated risks and benefits of long-term use.

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2023

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.