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

Risks of Prolonged Proton Pump Inhibitor (PPI) Use

Prolonged PPI use is associated with several significant adverse effects including Clostridium difficile infection, hypomagnesemia, bone loss/fractures, vitamin B12 deficiency, iron deficiency, and potential kidney disease, warranting regular review of ongoing indications and consideration of de-prescribing when appropriate. 1

Key Risks of Long-term PPI Use

Established Risks

• Gastrointestinal infections:

  • Increased risk of Clostridium difficile infection 1
  • Higher susceptibility to bacterial gastroenteritis 1

• Nutritional deficiencies:

  • Hypomagnesemia: 71% higher risk with prolonged use 1
  • Vitamin B12 deficiency: Particularly with higher doses (>1.5 pills/day) and use ≥2 years 1
  • Iron deficiency: Dose-dependent association after ≥1 year of continuous use 1
  • Calcium absorption issues: May contribute to bone health concerns 1

• Bone health concerns:

  • 20% greater risk of hip fracture compared to non-users 1
  • Increased risk of clinical spine and wrist fractures in women 1
  • Risk appears higher with longer duration and higher doses 2, 3

Potential Risks with Emerging Evidence

• Kidney disease: Consistent association with adverse kidney events, especially in elderly patients with pre-existing kidney disease 4
• Rebound acid hypersecretion: Increased gastric acid production above pre-treatment levels upon abrupt discontinuation 4
• Pill burden and medication costs: Additional burden to patients 1

Appropriate Use and Monitoring

Definite Indications for Long-term Use

1. Barrett's esophagus
2. Clinically significant (LA Classification grade C/D) erosive esophagitis
3. Gastroprotection in high-risk users of ASA/NSAIDs
4. Secondary prevention of gastric/duodenal ulcers 1, 5

Conditional Indications for Long-term Use

1. PPI-responsive endoscopy-negative reflux disease with recurrence on cessation
2. Esophageal strictures from GERD (peptic strictures) 1, 5

Inappropriate for Long-term Use

1. Symptoms of nonerosive reflux disease with no sustained response to high-dose therapy
2. Empiric treatment of laryngopharyngeal symptoms
3. Uninvestigated GERD/dyspepsia 1

Recommendations for Clinical Practice

Assessment and De-prescribing Algorithm

1. Regular review of ongoing indications:

   • Document clear indication for continued use
   • If no ongoing indication exists, consider de-prescribing 1

2. Step-down approach:

   • For patients on twice-daily dosing, consider step down to once-daily 1
   • Use the lowest effective dose for the shortest duration possible 4

3. Patient selection for continued therapy:

   • Continue PPI: Patients with complicated GERD (severe erosive esophagitis, esophageal ulcer, peptic stricture) 1
   • Consider de-prescribing: All patients without a definitive indication for chronic PPI use 1

Monitoring Recommendations

• Regular assessment of ongoing need for PPI therapy 1
• Monitor for deficiencies in high-risk patients:
  • Magnesium levels, particularly in elderly patients 1
  • Vitamin B12 and iron status with prolonged use 1
• Bone health: Consider bone density monitoring in elderly patients on long-term therapy 2, 3

Clinical Pitfalls to Avoid

1. Inappropriate continuation: Continuing PPIs without clear ongoing indication 1
2. Excessive dosing: Using higher doses than necessary (>1.5 pills/day) 1
3. Ignoring risk factors: Failing to consider patient-specific risk factors (age, kidney function, concurrent medications) 4
4. Abrupt discontinuation: May cause rebound acid hypersecretion; consider gradual tapering 4
5. Overlooking monitoring: Not regularly assessing for potential adverse effects in long-term users 1

While the evidence for many adverse effects comes from observational studies with inherent limitations, the consistent associations across multiple studies warrant a cautious approach to long-term PPI therapy, with regular reassessment of the risk-benefit balance for each patient.