Clinical Review

Review of the Long-Term Effects of Proton Pump Inhibitors

Fed Pract. 2017 February;34(2):19-23

References

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Dementia

In 2040, it is estimated that more than 80 million people will have from dementia.²⁹ This is expected to become a large fiscal burden on the health care system. In 2010, about $604 billion was spent on therapy for dementia worldwide.³⁰ Although no cure for dementia exists, it is more feasible than in previous years to prevent its occurrence. However, many medications, including PPIs, are associated with the development of dementia; therefore, it is important to minimize their use when possible.

As noted earlier vitamin B₁₂ deficiency may lead to cognitive decline. Due to the malabsorption of vitamin B₁₂that results from PPI use, it is hypothesized that PPIs may be associated with incidence of dementia. Badiola and colleagues discovered that in the brains of mice given a PPI, levels of β-amyloid increased significantly affecting enzymes responsible for cognition.³¹ In a February 2016, JAMA article, researchers conducted a prospective cohort study evaluating 73,679 patients aged ≥75 years with no dementia at baseline. They went on to assess regular use of a PPI, defined as at least 1 PPI prescription every 3 months, and the incidence of dementia. Patients with regular use of a PPI (≥ 1 PPI prescription every 3 months) had a 44% increase risk of incident dementia (HR, 1.44; 95% CI, 1.36-1.52; P < .001).³ Therefore, it is theorized that avoiding PPI use in the elderly may prevent the development of dementia.

Chronic Kidney Disease

The prevalence of CKD has drastically increased in recent decades. It is estimated that up to 13% of people in the U.S. are affected by CKD.³² Some studies suggest that dosing errors occur at much higher rates in patients with declined glomerular filtration rate (GFR).³³ The correct utilization use of medications becomes especially pertinent to this population. Several studies have already linked PPI use to acute interstitial nephritis (AIN) and acute kidney injury (AKI).^34-36

Lazarus and colleagues evaluated the association between PPI use and the incidence of CKD. Their analysis was performed in a long-term running population-based cohort and replicated in a separate health care system. In the running cohort, patients receiving a PPI had a 1.45-fold greater chance of developing CKD (95% CI, 1.11-1.90; P = .006). In that same cohort, patients on a PPI had a 1.72-fold increase risk of AKI (95% CI, 1.28-2.30; P < .001).⁴ Similar outcomes were seen in the replicated cohort. However, the replicated cohort did observe that twice daily dosing of a PPI (adjusted HR, 1.46; CI, 1.28-1.67; P < .001) had a stronger association with CKD than once- daily dosing (adjusted HR, 1.15; 95% CI, 1.09-1.21; P < .001). H₂RAs exhibited no association with CKD in the running cohort (HR, 1.15; 97% CI, 0.98-1.36; P = .10) or the replication cohort (HR, 0.93; 95% CI, 0.88-0.99; P = .03).⁴

Clinical PPI Recommendations

There are several FDA-approved and unapproved indications that warrant PPI therapy. Proton pump inhibitor indications include gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), Helicobacter pylori, and ulcers associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

GERD Recommendations

Optimal dosing and duration is important with all medications to maximize efficacy and minimize toxicity. In the case of PPIs, dosing and duration are of particularly concern due to the aforementioned AEs. Table illustrates manufacturer-recommended dosing and duration for the most commonly prescribed PPIs. Although these dosing regimens are based on clinical studies, PPIs are commonly prescribed at higher doses and for longer durations. By extending the duration of therapy, the risk of potential long-term AEs increases dramatically. If durations are limited to the recommended window, risk of AEs can be reduced.

Alternative Therapies

There are several strategies that exist to limit the use of PPIs, including lifestyle modifications to prevent GERD, supplementation of an alternative agent to prevent high doses of the PPI, or discontinuing PPI therapy all together. Lifestyle modifications provide additional benefit as monotherapy or to supplement a pharmacologic regimen.

The American Journal of Gastroenterology promoted lifestyle modifications that include:

Weight loss for patients with GERD who are overweight and had a recent weight gain;
Elevation of the head of the bed (if nighttime symptoms present);
Elimination of dietary triggers;
Fatty foods, caffeine, chocolate, spicy food, food with high fat content, carbonated beverages, and peppermint;
Avoiding tight fitting garments to prevent increase in gastric pressure;
Promote salivation through oral lozenges or chewing gum to neutralize refluxed acid;
Avoidance of tobacco and alcohol; and
Abdominal breathing exercise to strengthen the barrier of the lower esophageal sphincter.³⁷