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LeAnn W. O'Neill, PharmD, Benjamin L. Culpepper, PharmD, John A. Galdo, PharmD, BCPS
Disclosures
US Pharmacist. 2013;38(12):38-42.
Abstract and Introduction
Abstract
Proton pump inhibitors (PPIs), available with or without a prescription, are commonly used for the treatment of acid-related
disorders. Despite their ease of availability and common use, PPIs can have severe side effects. The long-term
consequences of chronic PPI use include the potential increased risk of hypocalcemia, hypomagnesemia, Clostridium
difficile infections, and pneumonia. Community pharmacists are poised to provide evidence-based recommendations and
educate patients about the benefits and risks associated with chronic PPI use.
Introduction
Proton pump inhibitor (PPIs) have been on the market since the late 1980s and have replaced the histamine2 receptorantagonists
(H2RAs) as the most potent class of drugs for the treatment of acid-related diseases.[1] Anti-ulcer medications
(therapeutic areas are based on proprietary IMS Health definitions) were the ninth largest class based on prescription
volume in the United States in 2012 and the 11th in sales.[2,3]
Medications in the PPI class are widely available with or without a prescription. Currently, the U.S. market contains six PPIs,
two of which are also available as OTC products ().[4–9] In the early 2000s, the FDA announced the availability of
omeprazole (Prilosec OTC) as the first OTC PPI.[10] It was soon followed by the approval of OTC lansoprazole (Prevacid
24HR).[11]
PPIs are used for the treatment of many gastric conditions including peptic ulcer disease, eradication of Helicobacter pylori
infections, treatment and prevention of nonsteroidal anti-inflammatory drug (NSAID) gastroduodenal ulcer, Zollinger-Ellison
syndrome, and gastroesophageal reflux disease (GERD).[1] Generally, these medications are prescribed because of the low
incidence of side effects and superior efficacy compared to other drugs used to treat the same conditions.[1]
Long-term use of any medication raises safety concerns, especially if that product is available OTC. The American
Gastroenterological Association (AGA) released guidelines on the management of GERD in 2008 that recommended against
routine monitoring for PPIs due to insufficient evidence.[12] However, since then studies have continued to show long-term
consequences from chronic PPI use including malabsorption consequences and infections. Subsequently, in March 2013,
the American College of Gastroenterology (ACG) released guidelines for the diagnosis and treatment of GERD.[13] These
guidelines do provide some insight into monitoring for long-term consequences of chronic PPI use. This article is a review of
the recent literature and guideline recommendations regarding the possible long-term consequences of chronic PPI
pharmacotherapy and opportunities to prevent these complications.
In animal studies, PPIs raised concerns about a potential for hypergastrinemia, but human studies failed to show an
association.[1] Therefore, long-term consequences of chronic PPI use can be grouped into two main categories,
malabsorption and infections.[1] Malabsorption secondary to PPI use affects calcium and magnesium, and the literature
specifies two infections most often associated with PPI use, Clostridium difficile and pneumonia. Unfortunately, a definition in
the literature for "long-term" is lacking; neither the AGA guidelines nor the ACG guidelines define what is considered
long-term. For the rest of this article, the authors use long-term to designate therapy greater than 14 days, the maximum
therapy for the OTC products.[10,11]
Malabsorption
The first potential long-term consequence of chronic PPI use is malabsorption of key minerals in the body, namely calcium
and magnesium. The loss of these minerals could lead to bone fractures or cardiac abnormalities.
Decreased Calcium Absorption (Hypocalcemia)
Long-term PPI use has been associated with an increased risk of osteoporosis and decreased bone mineral density (BMD),
with a 35% increased risk of fractures.[14] Calcium serves an important role in bone health and formation, as it is a key
component of hydroxyapatite (the main structural element of bone). Bone material is a major reservoir for calcium and may
contain greater than 99% of a body's calcium.[15] The hypothesis for the mechanism of PPI-induced bone fractures is that
dietary calcium absorption is dependent upon an acidic environment in the gastrointestinal (GI) tract. Due to the decrease in
acidity from the pharmacologic effect of PPIs, a potential loss of calcium absorption occurs. This reduction in calcium
absorption leads to decreased osteoclastic activity and thus decreases in BMD, thereby increasing fracture risk.[1]
The 2013 ACG guidelines on GERD state that existing osteoporosis is not a contraindication to PPI therapy.[13] Patients with
osteoporosis may remain on PPI therapy unless another risk factor for hip fracture exists.[13] Furthermore, in March 2011,
the FDA modified its osteoporosis and fracture warning. It was concluded that OTC products do not warrant label changes to
include warnings of fracture risk.[16]
However, several studies have demonstrated an association between long-term PPI use and risk of fractures, but they
contain numerous confounders. Common risk factors for fractures such as a sedentary lifestyle and concomitant use of
certain medications (e.g., thiazide diuretics, hormone replacement therapy, corticosteroids) are often observed in patients
who routinely take PPIs.[14] Additionally, patients who take high doses of PPIs are at higher fracture risk versus patients who
take lower OTC doses.[17] Finally, patients who take PPIs for extended periods of time (>1 year) are more likely to
experience a fracture.[18]
An analysis of the data obtained from the Canadian Multicentre Osteoporosis Study revealed that the use of PPIs was
associated with lower BMD, particularly at the hip and femoral neck, when compared to non-PPI use.[19] However, long-term
PPI use was not associated with an accelerated decline in BMD. Targownik et al reported that patients using PPIs did have
lower BMD; however, these patients were significantly older (66.3 vs. 60.9 years; P <.001) and had a higher mean body
mass index (BMI) (28.3 vs. 26.9; P <.001).[19]
Data remain relatively inconclusive and conflicting regarding the magnitude of the PPI and fracture association in the
absence of additional risk factors. According to the 2013 ACG guidelines, there is insufficient evidence to warrant routine
BMD tests, calcium supplementation, or other routine precautions because of PPI use.[13] In contrast, Health Canada issued
an alert in April 2013 stating that patients with existing risk factors for osteoporosis should be monitored closely and should
also receive short-term PPI therapy at the lowest effective dose.[20] This is parallel to current recommendations from the
FDA despite the lack of recommendations from the ACG.[16] If calcium supplementation is indicated, use of calcium citrate is
the preferred calcium supplement in patients taking PPIs, as it can be absorbed in the absence of an acidic environment.[1]
Decreased Magnesium Absorption (Hypomagnesemia)
In March 2011, the FDA released a warning regarding low serum magnesium levels associated with long-term use of
PPIs.[21] An analysis of reports from the FDA's Adverse Event Reporting System (AERS) states that approximately 1% of
patients who experienced an adverse effect while on a PPI experienced hypomagnesemia.[21] The mechanism behind the
changes in absorption is unknown. Symptoms of hypomagnesemia include seizures, arrhythmias, hypotension, and tetany.
Hypomagnesemia is also potentially fatal.[22] Hypomagnesemia related to chronic PPI use was not addressed in the 2013
ACG guidelines.[13]
All PPIs are associated with decreased magnesium absorption.[21] Hypomagnesemia was more common in older patients
taking a PPI (mean age 64.4 years).[21] Mean time to onset of hypomagnesemia was 5.5 years after initiation of therapy.[21]
Similarly, a systematic review of case reports found that patients who presented with hypomagnesemia in association with
PPI use also presented with other electrolyte disturbances, specifically hypokalemia and hypocalcemia.[23]
Hypomagnesemia generally resolved with the discontinuation of the PPI and recurred soon after the PPI was
rechallenged.[24]
Concurrent use of medications that also decrease magnesium increases the risk of significant hypomagnesemia. Danziger
et al reported that patients who take a PPI with a diuretic have nearly a 55% greater risk of hypomagnesemia than patients
who take only a PPI.[22]
An FDA Drug Safety Communication warns of the risks of hypomagnesemia and recommends that providers monitor serum
magnesium levels in patients taking PPIs.[21] The FDA suggests that providers obtain serum magnesium levels prior to
initiation of therapy and periodically thereafter for patients who will continue prolonged treatment and for patients who take
medications that also cause hypo-magnesemia. Patients who present with clinically significant hypomagnesemia may
require discontinuation of PPI therapy, magnesium replacement via oral or IV methods, and treatment with an alternative
class of drugs for GI conditions such as an H2RA.[1]
Infections
In addition to decreased magnesium and calcium absorption, patients on long-term PPIs may be at an increased risk of
infection. The hypothesis for the mechanism of action is that the gastric acid secretions act as a defense mechanism against
enteric bacteria, and the increased gastric pH during PPI use allows for colonization of opportunistic microbes.[1] The 2013
ACG guidelines warned about the risk of increased infections of C difficile and community-acquired pneumonia (CAP).[13]
Clostridium difficile
In a 2005 retrospective study, researchers found that patients who were taking PPIs had a hazard ratio (HR) of 2.9 (95% CI,
2.4–3.4); i.e., patients had a 2.9-fold increase in the risk of acquiring C difficile than patients who were not on a PPI.[25]
Seventy-five percent of the patients with reported cases were over the age of 65 years. Not only does long-term use of PPIs
cause an increased incidence of C difficile, but patients who received a PPI during treatment of C difficile were also 42%
(95% CI, 1.11–1.82) more likely to have a recurrent infection after finishing therapy.[25]
A 2010 study by Linsky et al looked at the association of PPI use and recurrent C difficile. [26] The authors determined
whether or not the patient had an infection with recurrent C difficile, 15 to 90 days after initial C difficile infection, if the patient
received a PPI within 14 days of initial C difficle infection. The HR for patients exposed to PPIs during treatment was 1.42
(95% CI, 1.11–1.82). For patients over the age of 80 years, the HR increases from 1.42 to 1.86 (95% CI, 1.15–3.01).[26]
In 2012, the FDA issued a statement detailing the relationship between C difficile–associated diarrhea (CDAD) with the use
of a PPI.[27] The FDA safety alert warns patients and healthcare professionals to consider CDAD if a patient takes a PPI and
experiences persistent diarrhea.[27] The FDA also recommends that patients be on the lowest dose for the shortest period of
time to treat their current condition.[27] The 2013 ACG guidelines recommend use of PPIs with caution in patients with a risk
of C difficile infections.[13]
Community-Acquired Pneumonia
Patients taking PPIs may potentially be at an increased risk for CAP. However, the degree of association is unclear due to
conflicting data.[28–30] The 2013 ACG guidelines state that short-term PPI use may increase the risk of CAP, but the risk
does not seem to be elevated in long-term use.[13]
A 2012 cohort study by de Jagar et al showed that patients on PPIs were 2.23 times (95% CI, 1.28–3.75) more likely to
develop a CAP infection compared to patients not on PPIs.[31] Unfortunately, the duration of time that patients were
prescribed was not included in the study design.[31] In a meta-analysis completed in 2004, researchers discovered that
patients who were on an acid-suppressing agent, either a PPI or an H2RA, were 4.5 (95% CI, 3.8–5.1) times more likely to
develop pneumonia.[30] Mean duration of use for H2RAs was 2.8 months; for PPIs the mean duration was 5 months.[30]
Conversely, a 2008 study conducted by Sarkar et al showed that current PPI use was not associated with an increased risk
of CAP (odds ratio [OR] 1.02, 95% CI 0.97–1.08).[29] However, the study did observe an increased risk of acquiring an
infection in patients initiated on a PPI within the past 14 days (adjusted OR 3.21, 95% CI 2.46–4.18).[29]
The data support a short-term increase risk of pneumonia infections, but they are conflicting regarding long-term
consequences. Despite the conflicting data, this risk is important to consider, especially because of the new Centers for
Medicare & Medicaid (CMS) regulations on hospital readmissions.[32] Laheij et al determined that the incidence rate of
pneumonia was 2.5 per 100 patient-years for patients on PPIs.[30] With 65.7 million prescriptions of omeprazole alone and
an increased $15,682 cost to Medicare beneficiaries due to pneumonia hospitalizations, the risk of PPI use-associated
infections warrants vigilance and evidence-based medicine on the part of the pharmacist.[33,34]
Conclusion
PPIs are an efficacious and safe drug class. They offer relief to patients in a patient-centered healthcare system.
Unfortunately, these agents do potentially have some long-term consequences from continued use, including malabsorption
issues and increased risk of infections. The pharmacist can be an advocate for the patient in the hospital system or in the
community by understanding these risks and fostering patient-centered care by empowering a well-informed patient in
healthcare decisions.
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