Is Your PPI Prescription Doing More Harm Than Good?

Proton Pump Inhibitors (PPIs) are among the most frequently prescribed medications worldwide. Their indications are well-known: gastroesophageal reflux disease (GERD), peptic ulcer disease, Helicobacter pylori eradication, and prevention of gastrointestinal bleeding in high-risk patients. With familiar names like omeprazole, pantoprazole, esomeprazole, and lansoprazole, they appear in both prescriptions and over-the-counter products—used often, questioned rarely.

But should they be questioned more often?

Over the past decade, the assumption that PPIs are "safe enough to ignore" has come under scrutiny. This article revisits what we know, what we’ve learned, and what doctors must start doing differently.

How PPIs Work: A Quick Recap

PPIs function by irreversibly inhibiting the H⁺/K⁺ ATPase enzyme system in gastric parietal cells, dramatically reducing acid production. This acid suppression makes them the first-line treatment in many acid-related disorders.

Common indications include:

• GERD and erosive esophagitis
  
  
• H. pylori eradication regimens
  
  
• Peptic ulcer disease
  
  
• Zollinger-Ellison syndrome
  
  
• NSAID-induced ulcer prophylaxis
  
  
• Stress ulcer prevention in critically ill patients
  

Their mechanism is elegant, and their clinical efficacy is rarely in dispute. But it’s not the drugs—it’s the way we use them, particularly the prolonged, often unnecessary use, that causes concern.

The Rise of Long-Term Use and Overprescription

Although PPIs were originally intended for short-term therapy—typically 4 to 8 weeks—many patients continue using them for years.

Some patterns seen in clinical practice:

• Patients remain on PPIs without reassessment
  
  
• PPIs are prescribed “just in case” in older or polymedicated individuals
  
  
• Many patients self-medicate using OTC formulations
  
  
• Clinical inertia keeps patients on therapy indefinitely
  

A 2020 systematic review reported that more than 50% of chronic PPI use lacked a clear indication. That’s not just a statistic—it’s a red flag.

Potential Harms of Long-Term PPI Use: Evidence-Based Risks

When used appropriately, PPIs are effective and well-tolerated. But prolonged use—especially without an indication—carries real, measurable risks. Some of these are backed by solid evidence; others are observational but consistently reported.

Here’s what clinicians should understand:

Nutritional Deficiencies

• Vitamin B12 malabsorption: Gastric acid is essential to liberate B12 from food. Long-term PPI use interferes with this process, especially in elderly patients.
  
  
• Hypomagnesemia: This may develop with long-term use and, in rare cases, result in seizures or cardiac arrhythmias.
  
  
• Iron absorption: Less gastric acid may impair iron solubility, though the clinical relevance remains debated.
  
  
• Calcium malabsorption: PPIs may reduce calcium absorption, raising concerns about increased fracture risk—particularly in the hip, spine, and wrist.
  

Increased Risk of Infections

• Clostridioides difficile infection (CDI): Suppressed gastric acid allows for overgrowth and survival of pathogenic bacteria.
  
  
• Community-acquired pneumonia (CAP): Several studies show a modest but statistically significant increase in pneumonia incidence, particularly in the first month of therapy.
  
  
• Small intestinal bacterial overgrowth (SIBO): Acid suppression facilitates abnormal bacterial colonization in the small intestine.
  

Kidney Injury and Disease

• Acute interstitial nephritis (AIN): An underdiagnosed but documented complication, often presenting with subtle symptoms.
  
  
• Chronic kidney disease (CKD): Multiple observational studies suggest a correlation between chronic PPI use and incident CKD, even progression to end-stage renal disease. Though causality isn’t firmly established, the consistency of findings is concerning.
  

Cognitive Decline and Dementia

Some observational studies suggest a potential link between long-term PPI use and cognitive impairment. One hypothesis involves disrupted amyloid metabolism due to chronic acid suppression. However, the current evidence remains inconclusive and insufficient to warrant definitive clinical recommendations.

Cardiovascular Risks

• Increased risk of myocardial infarction and stroke: Especially noted when PPIs are used concomitantly with clopidogrel, due to CYP2C19 inhibition which may reduce antiplatelet effectiveness.
  
  
• Endothelial dysfunction: Experimental studies propose that PPIs may impair nitric oxide pathways, contributing to vascular stiffness. Human data, however, remain limited.
  

Rebound Acid Hypersecretion

When patients stop PPIs suddenly, the resultant hypergastrinemia can cause excessive acid secretion, worsening symptoms temporarily. This "rebound" reinforces the idea that they "still need" the PPI—creating a cycle of dependence, particularly for patients self-medicating.

Who Is Most at Risk?

Not all patients on PPIs are equally vulnerable. Certain populations are at higher risk for complications:

• Elderly individuals
  
  
• Patients with polypharmacy
  
  
• Those with comorbid conditions such as CKD, osteoporosis, or heart failure
  
  
• Long-term NSAID or antiplatelet users
  
  
• Individuals on high-dose or long-duration PPIs (typically >8 weeks)
  

Do the Benefits Ever Outweigh These Risks?

Yes—and decisively so in some clinical contexts. In patients at high risk of gastrointestinal bleeding or those with specific acid hypersecretory conditions, PPI therapy remains lifesaving and essential.

Examples include:

• Barrett’s esophagus
  
  
• GI bleeding prevention in patients on dual antiplatelet therapy
  
  
• Zollinger-Ellison syndrome
  
  
• NSAID-induced ulcers in the elderly
  
  
• Severe erosive esophagitis confirmed by endoscopy
  

The concern is not with PPIs themselves—but with inappropriate, prolonged use that lacks ongoing justification.

Strategies for Safer Use: What Doctors Can Do

Here’s how clinicians can ensure rational PPI prescribing:

• Clarify the indication at initiation. Don’t prescribe “just in case.”
  
  
• Set a stop date: Communicate and document expected treatment duration.
  
  
• Use the lowest effective dose to control symptoms or heal mucosa.
  
  
• Reassess regularly, especially at follow-up visits for chronic users.
  
  
• Step down to H2 receptor antagonists when appropriate.
  
  
• Educate patients on the risks of long-term, unsupervised OTC use.
  
  
• Deprescribe when no current indication exists—using tapering strategies if needed to prevent rebound.
  

Alternatives to Long-Term PPI Use

Not every reflux or dyspeptic symptom requires long-term acid suppression. In many cases, conservative measures and safer alternatives can be effective:

• Lifestyle changes: weight reduction, avoiding late meals, smoking cessation, elevation of head during sleep
  
  
• On-demand PPI use: for patients with episodic symptoms
  
  
• H2 blockers: suitable for mild to moderate symptoms and as maintenance
  
  
• Surgery: in carefully selected cases with refractory GERD (e.g., Nissen fundoplication)
  

Conclusion: Not Harmless, Not Harmful—Just Misused

PPIs have transformed gastroenterology and remain a cornerstone of acid suppression therapy. But their overuse—often casual and unchecked—has created a quiet epidemic of unnecessary exposure to potential harm.

The myth that PPIs are universally harmless is outdated.

The solution is not to abandon PPIs, but to use them with clarity, caution, and clinical purpose:

• Start with clear rationale
  
  
• Reassess periodically
  
  
• Educate the patient
  
  
• Deprescribe when appropriate
  

When prescribed correctly, PPIs do far more good than harm. But when used reflexively or indefinitely, they may do the opposite. It’s time to reframe the way we think about this “harmless” class of drugs—and bring intention back to acid suppression.