What are the risks of long-term proton pump inhibitor (PPI) therapy in a patient with a history of gastroesophageal reflux disease (GERD) symptoms?

Risks of Long-Term PPI Therapy

Long-term PPI therapy is generally safe when appropriately indicated, with most reported serious adverse events lacking causal evidence from randomized controlled trials, though established risks include increased susceptibility to enteric infections, rebound acid hypersecretion upon discontinuation, and potential micronutrient deficiencies with prolonged use. 1, 2

Evidence Quality: Critical Context

The American Gastroenterological Association emphasizes that all studies reporting associations between PPIs and serious adverse events have been observational and cannot establish causality, while randomized controlled trials comparing PPIs with placebo have consistently shown no higher rate of adverse events among PPI users. 2 Many reported associations lack plausible mechanisms and are likely explained by residual confounding and analytic biases. 2

Established Risks with Higher Probability of Causality

Infectious Complications

• Clostridium difficile infection risk is increased with PPI use (OR 1.26,95% CI 1.12-1.39), representing the most well-established infectious complication. 2, 3
• Enteric infections and gastroenteritis occur more frequently due to reduced gastric acid barrier, though the magnitude of absolute risk remains slight. 2
• Community-acquired pneumonia shows dose-dependent association, with 67% higher odds (OR=1.67; 95% CI: 1.04-2.67) in long-term users, though hospital-acquired pneumonia risk is not increased. 1, 2, 4

Rebound Acid Hypersecretion

• Occurs commonly after discontinuation of long-term PPI therapy, lasting 2-6 months, resulting from hypergastrinemia-induced parietal cell proliferation during treatment. 2
• Patients should be warned about potential transient upper GI symptoms when stopping PPIs to prevent unnecessary reinstitution of therapy. 2

Acute Kidney Injury

• Acute tubulointerstitial nephritis may occur at any point during PPI therapy, with patients presenting with varying signs from symptomatic hypersensitivity to non-specific decreased renal function. 3
• Discontinue PPIs immediately if acute TIN is suspected. 3

Associations with Weaker or Conflicting Evidence

Bone Health and Fractures

• Observational studies suggest 42% higher odds of hip fracture (OR=1.42; 95% CI: 1.33-1.53) and 20% greater risk (RR: 1.20; 95% CI: 1.14,1.28) with long-term use. 1, 2, 4
• However, large randomized controlled trials including the COMPASS trial found no differences in fracture rates between PPI and placebo groups. 2
• The FDA includes precautionary notices regarding fracture risk, particularly with high-dose (multiple daily doses) and long-term therapy (≥1 year). 3
• Association appears strongest in patients with pre-existing risk factors (diabetes, CKD, arthritis) and ≥2 years of use. 2

Micronutrient Deficiencies

• Vitamin B12 deficiency: Large RCTs have not shown significant differences in serum B12 levels at 5 years, though these studies had methodological limitations. 2 Daily treatment longer than 3 years may lead to malabsorption caused by hypo- or achlorhydria. 3
• Iron deficiency: Dose-dependent associations exist with continuous PPI use, particularly after ≥1 year, as reduced gastric acid impairs non-heme iron absorption. 2
• Hypomagnesemia: Meta-analysis shows 71% higher risk (adjusted OR: 1.71; 95% CI: 1.33,2.19), typically occurring after at least 3 months of use, most commonly after 1 year. 2, 3

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. 2

Cancer Risk

• No causal relationship established in RCTs regarding PPI use and cancer risk. 2
• Observational data suggest 55% higher odds of colorectal cancer (OR=1.55; 95% CI: 0.88-2.73), though confidence intervals cross unity. 4
• Japanese population-based data suggest possible association with gastric cancer, though rates are similar between PPIs and H2-receptor antagonists. 2

Enterochromaffin-Like Cell Hyperplasia

• Demonstrated in up to 50% of patients receiving PPIs for >2.5 years, though considered a benign histologic change. 2
• Five-year RCT comparing vonoprazan and lansoprazole found infrequent and comparable proportions developing ECL hyperplasia. 2

Cutaneous and Systemic Lupus Erythematosus

• CLE and SLE have been reported with PPI use, occurring as new onset or exacerbation of existing autoimmune disease. 3
• Most common form is subacute CLE (SCLE), occurring within weeks to years after continuous therapy. 3
• Discontinue PPIs if signs or symptoms consistent with CLE or SLE develop; most patients improve within 4-12 weeks after discontinuation. 3

Critical Management Algorithm

Step 1: Determine if Definitive Indication Exists

Patients who should NOT discontinue PPIs: 1, 5

• Barrett's esophagus (any length)
• Severe erosive esophagitis (LA Classification grade C/D)
• History of esophageal ulcer or peptic stricture
• High-risk NSAID/aspirin users requiring gastroprotection
• Secondary prevention of gastric/duodenal peptic ulcers
• Zollinger-Ellison syndrome
• Idiopathic pulmonary fibrosis

Step 2: Identify Candidates for De-prescribing

All patients without definitive indication for chronic PPI should be considered for trial of de-prescribing, including: 1, 5

• Non-erosive reflux disease (NERD) with resolved symptoms
• Mild erosive esophagitis (LA grade A/B) with healed mucosa
• PPI-responsive symptoms with no endoscopic findings
• Patients on twice-daily dosing who can be stepped down to once-daily

Step 3: De-prescribing Strategy

• First: Step down from twice-daily to once-daily dosing if applicable. 1, 5
• Second: Taper to lowest effective dose that controls symptoms. 1, 5
• Third: Consider conversion to on-demand therapy for patients with NERD or mild disease. 5, 6
• Monitor: Assess for symptom recurrence; if symptoms return, resume previous effective dose and consider objective testing (ambulatory pH/impedance monitoring). 5, 7

Step 4: Monitoring Recommendations

The 2008 American Gastroenterological Association guideline found insufficient evidence to mandate: 1

• Routine bone density studies
• Calcium supplementation beyond RDA
• H. pylori screening
• Routine monitoring of serum creatinine, magnesium, or vitamin B12

However, it is good medical practice to screen and treat elderly patients for osteoporosis irrespective of PPI use. 2

Common Pitfalls to Avoid

• Do not discontinue PPIs in patients with valid indications based on concerns about unproven risks, as this may lead to recurrent symptoms and serious complications including upper GI bleeding. 2
• Up to 15% of PPI users are on higher-than-standard doses without clear evidence of benefit, and higher doses have been more strongly associated with complications including community-acquired pneumonia, hip fracture, and C. difficile infection. 1
• Double-dose PPIs (standard dose twice daily or double-strength dose once daily) have not been studied in any RCT and are not FDA-approved. 1
• On-demand therapy cannot be recommended for patients with known history of erosive esophagitis, as recurrence rates of erosive disease are high compared with continuous therapy. 1
• Most patients with GERD have non-erosive disease (only 30-40% have erosive esophagitis), making many candidates for de-escalation strategies. 1

Key Takeaway for Clinical Practice

The main identifiable risk associated with reducing or discontinuing PPI therapy in appropriate candidates is increased symptom burden, not progression to serious complications. 1 There are no high-quality data suggesting that continuous antisecretory therapy alters the natural history of reflux disease other than reducing the already low incidence of peptic stricture. 1 Therefore, primary care providers should be primarily responsible for reviewing ongoing indications for PPI use and identifying candidates for de-prescribing. 1