U.S. Pharmacist
Long-term Consequences of Chronic Proton
Pump Inhibitor Use
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 receptor-antagonists (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 (Table
1).[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 ofHelicobacter pylori infections, treatment and prevention of nonsteroidal antiinflammatory 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 patientcentered healthcare system. Unfortunately, these agents do potentially have some longterm 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.