What are the potential side effects of long-term proton pump inhibitor (PPI) use in adults with a history of gastrointestinal issues such as gastroesophageal reflux disease (GERD) or peptic ulcer disease?

Side Effects of Long-Term PPI Use

While long-term PPI therapy is associated with several potential adverse effects, the most important clinical principle is that patients with valid indications (erosive esophagitis, Barrett's esophagus, history of GI bleeding, high-risk NSAID users) should continue therapy, as the proven benefits far outweigh the largely unproven or overstated risks. 1

Evidence Quality: Critical Context

The American Gastroenterological Association emphasizes that all studies reporting serious adverse events with PPIs have been observational and cannot establish causality, while randomized controlled trials comparing PPIs with placebo have consistently shown no higher rate of adverse events. 1 Many reported associations lack plausible mechanisms and are likely explained by residual confounding and analytic biases. 1

Established Adverse Effects with Higher Probability of Causality

Gastrointestinal Infections

• Increased susceptibility to Clostridium difficile colitis and bacterial gastroenteritis due to reduced gastric acid barrier, though the magnitude of absolute risk remains slight. 1
• Meta-analyses demonstrate increased risk of C. difficile infection (OR 1.26,95% CI 1.12-1.39). 1
• PPIs increase risk of community-acquired pneumonia with dose-dependent association, showing 67% higher odds in long-term users (OR=1.67; 95% CI: 1.04-2.67). 1

Rebound Acid Hypersecretion

• Common physiologic phenomenon occurring after discontinuation of long-term PPI therapy, lasting 2-6 months, resulting from hypergastrinemia-induced parietal cell proliferation during PPI therapy. 1
• Patients should be warned about potential transient upper GI symptoms when stopping PPIs. 1

Hypomagnesemia

• Both symptomatic and asymptomatic hypomagnesemia reported in patients treated with PPIs for at least 3 months, most commonly after 1 year of therapy. 1
• Meta-analysis shows 71% higher risk of hypomagnesemia with PPI use (adjusted OR: 1.71; 95% CI: 1.33,2.19). 1
• The FDA includes precautionary notices regarding this risk. 1
• Clinicians should monitor magnesium levels in high-risk patients on long-term therapy, particularly those with concurrent diuretic use or other risk factors. 2

Associations with Weaker or Conflicting Evidence

Micronutrient Deficiencies

Vitamin B12:

• Large RCTs have not shown significant differences in serum B12 levels at 5 years, though these studies had methodological limitations. 1
• Routine supplementation beyond the Recommended Dietary Allowance (RDA) is not recommended. 3

Iron Deficiency:

• Dose-dependent associations exist between continuous PPI use and iron deficiency, particularly after ≥1 year of use. 1
• Reduced gastric acid impairs absorption of non-heme iron. 1

Bone Health and Fractures

• Observational studies suggest 20-42% higher risk of hip fracture with PPI use (RR: 1.20; 95% CI: 1.14,1.28). 1
• However, large RCTs including the COMPASS trial found no differences in fracture rates between PPI and placebo groups. 1
• The association appears strongest in patients with pre-existing risk factors (diabetes, CKD, arthritis) and ≥2 years of use. 1
• Routine bone density screening is not recommended solely due to PPI use, though screening elderly patients for osteoporosis irrespective of PPI use remains good medical practice. 1

Cancer Risk

• No causal relationship established in RCTs regarding PPI use and cancer risk. 1
• Japanese population-based data suggest possible association with gastric cancer, though rates are similar between PPIs and H2-receptor antagonists. 1

Enterochromaffin-Like (ECL) Cell Hyperplasia

• Demonstrated in up to 50% of patients receiving PPIs for >2.5 years, though considered a benign histologic change. 1
• Five-year RCT comparing vonoprazan and lansoprazole found infrequent and comparable proportions developing ECL hyperplasia. 1

Cardiovascular Risk

• Long-term PPI use has been associated with increased cardiovascular risk in some observational studies, but these associations have not been confirmed in randomized controlled trials. 1

Critical Management Algorithm

Patients Who Should NEVER Discontinue PPIs:

• Barrett's esophagus 1, 3
• Severe erosive esophagitis (Los Angeles grade C/D) 1
• History of esophageal ulcer or peptic stricture 1
• History of upper GI bleeding, especially with ongoing anticoagulant/antiplatelet therapy 1
• High-risk NSAID/aspirin users requiring gastroprotection 1
• Secondary prevention of gastric/duodenal ulcers 1
• Eosinophilic esophagitis with PPI response 1
• Idiopathic pulmonary fibrosis 1

Candidates for De-prescribing:

• All patients without definitive indication for chronic PPI should be considered for trial of de-prescribing. 1
• Non-erosive reflux disease 1
• Mild erosive esophagitis 1
• Patients on twice-daily dosing should be stepped down to once-daily PPI. 1

Step-Wise De-prescribing Approach:

1. Step down from twice-daily to once-daily dosing 1
2. Taper to lowest effective dose 1
3. Consider conversion to on-demand therapy (only for non-erosive disease) 1
4. Warn patients about rebound acid hypersecretion lasting 2-6 months 1

Monitoring Recommendations

The American Gastroenterological Association recommends NOT routinely monitoring:

• Bone mineral density 1, 3
• Serum creatinine 1
• Magnesium levels (except in high-risk patients) 1, 3
• Vitamin B12 1, 3
• Calcium supplementation beyond RDA 3

Exception: Consider magnesium monitoring in patients with risk factors (concurrent diuretic use, elderly, multiple comorbidities). 2

Common Pitfalls to Avoid

• Discontinuing PPIs in patients with definite indications based on concerns about unproven risks may lead to recurrent symptoms and serious complications, including upper GI bleeding. 1
• Do not substitute H2-receptor antagonists for maintenance therapy in patients with erosive disease, as they are significantly less effective. 4
• Do not use on-demand or intermittent PPI therapy for patients with documented erosive disease, as this leads to high recurrence rates. 4
• Up to 70% of PPI use may be inappropriate, highlighting the need for periodic reassessment of indication. 1
• The indication for long-term PPI therapy should be clearly documented in the medical record. 4

Practical Safety Approach

Do not discontinue PPIs solely due to concern about potential adverse events when a valid indication exists. 1 The lowest effective dose should be used, and appropriateness should be reevaluated within 12 months after initiation in patients with unproven GERD. 5 Primary care providers should be primarily responsible for reviewing ongoing indications and identifying candidates for de-prescribing. 1