#387 Side effects of long-term PPI use: Leaving a bad taste in your mouth?
CLINICAL QUESTION
What are the side effects of long-term proton pump inhibitor (PPI) use?
BOTTOM LINE
Best evidence from large, randomized, placebo-controlled trials suggest PPIs do not increase the risk of cardiovascular disease, fractures, or pneumonia. Observational studies suggest PPIs may be associated with vitamin B12 and magnesium deficiency.
Reading Tools for Practice Article can earn you MainPro+ Credits
Join NowAlready a CFPCLearn Member? Log in
EVIDENCE
- Focusing on large randomized controlled trials (RCTs) and systematic reviews of observational studies where RCT outcomes not unavailable.
- RCTs:
- 17,598 patients with cardiovascular disease, randomized to pantoprazole or placebo.1 At ~3 years, no statistical difference between PPI or placebo, including:
- All-cause mortality, cardiovascular disease, fractures, pneumonia, clostridium difficile infection, chronic kidney disease, dementia, or gastrointestinal malignancies.
- 3761 patients with cardiovascular disease on aspirin, randomized to clopidogrel plus omeprazole or clopidogrel plus placebo.2 Trial ended prematurely when sponsor declared bankruptcy. Outcomes at 180 days:
- All-cause mortality, cardiovascular events, fractures and pneumonia: No difference.
- Upper gastrointestinal events (examples: bleeding, ulcer): 1.1% omeprazole versus 2.9% placebo, statistically different.
- 17,598 patients with cardiovascular disease, randomized to pantoprazole or placebo.1 At ~3 years, no statistical difference between PPI or placebo, including:
- Observational studies:
- Observational studies of the above outcomes have inconsistent findings.3-6
- Best systematic reviews of observational studies on vitamin B12 and magnesium deficiency (no RCT evidence available):
- Vitamin B12 deficiency: increased risk in case-controlled and cohorts.7
- Largest, high quality North American case-control study:8 Vitamin B12 deficient patients more likely to be on PPIs, Odds Ratio (OR): 1.65, statistically different.
- Hypomagnesiemia: Increased risk, OR: 1.71, statistically different.9
- Vitamin B12 deficiency: increased risk in case-controlled and cohorts.7
- Limitations: Observational studies cannot determine causation. Other patient factors may explain associations.
CONTEXT
- Patients on PPIs should have indication reviewed periodically.10
- Many patients with gastroesophageal reflux disease (GERD) use PPIs, including as needed.11
- Lowering dose or discontinuation could be considered for some; tapering may help.12,13
- Continuing PPIs may be appropriate in patients with:14
- Barrett’s or eosinophilic esophagus,
- Erosive esophagitis or GERD related complications (example: stricture), or
- Previous gastrointestinal bleed or ulcer where gastroprotection is needed.
- All PPIs have similar efficacy: Cost and individual response should guide prescribing.15
- Overall, vitamin B12 deficiency occurs in ~5% of patients >60 years.16
- If PPI association is true, the new risk of vitamin B12 deficiency would be ~8%.
Latest Tools for Practice
#392 Mission Slimpossible, Part 3: Tirzepatide for weight loss
Is tirzepatide effective for weight loss?
#391 Trying Tongue-Tie Treatment: Does Frenotomy Fix Feeding Frustrations?
Does surgical frenotomy in infants with ankyloglossia (tongue-tie) improve mother or infant breastfeeding outcomes?
#390 Use the soft touch for buckle fractures?
Is rigid immobilization needed in buckle fractures?
consider B12 levels if on PPI long term
Review B 12 levels annually and supplement as necessary.
very useful
I AGREE USEFUL TO MY PRACTICE
weak data, not terrible SE
To follow up on B12, is it really necessary to check levels if the patient is asymptomatic? Is supplementation useful in the asymptomatic patient? Not clear
I review B12 levels yearly in patients on long term PPI
Posted on behalf of the authors: In the tool, we do not explicitly state that practitioners should check VB12 levels – but leave up to practitioners. Consideration of testing would depend on the clinical circumstance (patient age, other comorbidities, length of PPI use…) and whether or not they have any clinical outcomes of B12 deficiency (for example: anemia, peripheral symptoms or cognitive changes).
Whether treating VB12 deficiency patients depends on clinical circumstances – symptomatic or not, lab values and other clinical clues.
reassuring
I have had a few cases of low B12 in patients on long term PPIs … hard to know if causal, but certainly worth considering based on this.
Confusing data as this goes somewhat against the Choosing Wisely campaign
Periodically check B12 and magnesium levels in patients on chronic PPI use.
good info
GOOD TO KNOW
I can see this, similarly, magnesium levels have tended to normalize after D/C PPI’s and return to low levels once started
wondered it is worth to check the intrinsic factor and parietal cell antibodies in patients on long term ppi , and if came back positive then consider alternative to treat dyspepsia as those are very high risk to develop b12 deficiency