Proton Pump Inhibitors 2.0

November 26, 2010

By Mary C. Whitman, MD

Faculty Peer Reviewed

Proton pump inhibitors (PPIs) are generally considered “safe” medications[1] and are prescribed to over 100 million patients per year for a variety of indications, often for long durations.[2] Recently, new data has emerged that suggests that we should be more judicious in prescribing PPIs.

In a recent development, the FDA announced that it will require new labeling of PPIs indicating that their use at high dosage and for prolonged durations is associated with an increased risk of fracture.[3] This change was prompted, in part, by a recent study[4] that showed an increased risk of hip fractures among at-risk patients, who took PPIs for at least 2 years.  The study was a case-control, retrospective study of 33,752 patients with hip fracture and 130,471 matched controls in the Kaiser Permanente system.  Among patients who had used PPIs for two or more years, there was a 30% increased risk of hip fracture compared to non-users (OR 1.30).  Interestingly, the authors also indentified an increased risk of hip fracture among patients with two or more years use of H2-receptor antagonists (OR 1.18).

The association between PPIs and hip fractures was positively correlated with the dosage of PPI received, but not the duration.  The risk was greatest among current PPI users, and decreased with a longer interval since the last PPI prescription. The increased risk of hip fracture with PPI use was only present among patients with at least one other risk factor for hip fracture.  Of note, however, 73% of persons 50 or older had at least one additional risk factor, and of the patients with 2 or more years of PPI use, 94.4% had at least one other risk factor. Thus, among patients with risk factors for hip fracture (which includes a majority of older adults), practitioners should re-evaluate the risk-benefit ratio for PPIs before writing that prescription.

Confounding any effort to draw back on PPI use is the possibility that their administration may be “addictive”.  In a randomized, double-blind study, normal asymptomatic volunteers, chosen for their lack of prior heartburn or dyspeptic symptoms, who were treated with 8 weeks of esomeprazole developed mild-moderate acid-related symptoms during the withdrawal period.[5] These findings have important implications for patients treated empirically with PPIs for symptoms such as cough.  If the PPI does not lead to resolution of symptoms, the patient may find themselves with reflux symptoms when the PPIs are withdrawn. Thus, we may be creating new patients who require PPIs simply by virtue of their short-term administration.

These findings also suggest that patients who appropriately receive PPIs for acid-peptic symptoms may find it difficult to withdraw the medications when clinically indicated.  In fact, it is this exact population, patients started empirically on PPIs by their primary care providers for dyspeptic symptoms, that the same authors studied next. At the recent AGA meeting, they reported that when patients who had been on long-term PPIs without an endoscopic indication were asked to discontinue the medication, only 14% were able to do so without recurrence of symptoms.[6]

An additional issue associated with the use of PPIs is the effect of genetic polymorphisms in the CYP2C19 enzyme, that metabolizes these drugs in the liver, on treatment efficacy.  This enzyme is quite polymorphic; multiple mutations are seen in this enzyme, which lead to three clinical phenotypes: poor metabolizers, intermediate metabolizers, and extensive metabolizers.  Systemic exposure to the PPIs is 5-12 times higher in poor metabolizers as compared to extensive metabolizers, such that poor metabolizers have significantly higher pH in the stomach (greater medication efficacy) in response to equivalent doses than extensive metabolizers.[7] The frequency of the different phenotypes varies among different populations. While only 3-5% of Caucasians and African-Americans are poor metabolizers, 12-100% of Asian populations can be characterized as such.[8] These differences affect treatment success, including relapse of GERD[9] and H. pylori eradication with standard triple-therapy[10].

In one study, differences between metabolizer groups were not seen with rabeprazole (Aciphex), suggesting that especially in the Caucasian and African-American populations, which have large proportions of extensive metabolizers, using rabeprazole might decrease rates of treatment failure. Another, more complicated, option would be to change the dosing parameters depending on PPI chosen and metabolism phenotype. In one study, 40mg daily of esomeprazole was not sufficient to achieve therapeutic levels of acid suppression in extensive metabolizers, but breaking the dose into 20mg twice a day or 10mg four times a day led to effective control of acid secretion for all 3 phenotypes.[11] One caveat, however, is that most of the studies of genetic polymorphisms have been conducted in Asian populations, who have much higher proportions of poor metabolizers, and are therefore more responsive to PPIs.  Although most American and European studies of the efficacy of PPIs likely included patients who were mostly extensive metabolizers, they have still shown significant benefits of PPIs.

In conclusion, PPIs can be very beneficial medications, but they are over-prescribed, often empirically, and patients often remain on them for prolonged periods of time. Long-term use is not benign, being associated with an increased risk of hip fractures in the elderly. Given this risk, perhaps patients on PPIs should be reevaluated for possible discontinuation of this medication.  This may prove to be difficult given the risk of rebound acid hypersecretion, resulting in acid-peptic symptoms, even in patients who were previously asymptomatic. In addition, genetic differences in P450 enzymes affect patients’ ability to metabolize PPIs. While it is probably not cost-effective to genotype patients before starting a PPI, switching medications or increasing the number of doses per day may be necessary in patients who are extensive metabolizers. In light of the above, as well as the recent negative publicity about the possible interactions between Plavix (clopidogrel) and PPIs, it may be time for a reassessment of the indications for PPI, and more judicious prescribing practices for patients with documented reflux in whom those lifestyle changes and use of weaker antacids are unsuccessful.

Dr. Whitman was a former resident at NYU Langone Medical Center, and is currently an opthalmology resident at Columbia Presbyterian.

Peer reviewed by: Michael Poles, MD  is a section editor, Clinical Correlations

Image Courtesy of Wikimedia Commons


[1] Thomson AB, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World J Gastroenterol. 2010. 16(19):2323-30.

[2] Katz MH. Failing the Acid Test: Benefits of Proton Pump Inhibitors May not justify the risks for many users. Arch Intern Med. 2010;170(9):747-748.


[4] Corley DA, Kubo A, Zhao W, Quesenberry C. Proton Pump Inhibitors and Histamine-2 Receptor Antagonists are Associated with Hip Fractures Among At-Risk Patients. Gastrolenterology 2010. March. Epub ahead of print.

[5] Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal. Gastroenterology. 2009 Jul;137(1):80-87.

[6]Reimer C, Bytzer P. Discontinuation of Long-term Proton Pump Inhibitor therapy in primary care patients a randomized, placebo-controlled trial in patients with symptom relapse. Gastroenterology. 138(5) Supplement 1 Page S-483.

[7] Klotz U, Schwab M, Treiber G. CYP2C19 Polymorphism and Proton Pump Inhibitors. Pharmacology & Toxicology. 2004 95:2-8.

[8] Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacology. 2001. 52(4):349-355.

[9] Saitoh T, Otsuka H, Kawasaki T, Endo H, Iga D, Tomimatsu M, Fukushima Y, Katsube T,  Ogawa K, Otsuka K. Influences of CYP2C19 polymorphism on recurrence of reflux esophagitis during proton pump inhibitor maintenance therapy.. Hepatogastroenterology. 2009 May-Jun;56(91-92):703-6.

[10] Zhao F, Wang J, Yang Y, Wang X, Shi R, Xu Z, Huang Z, Zhang G. Effect if CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis. Helicobacter. 2008 Dec;13(6):532-41.

[11] Lou HY, Chang CC, Sheu MT, Chen YC, Ho HO. Optimal dose regimens of espmeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism. Eur J Clin Pharmacol. 2009. Jan;65(1):55-64.