Proton pump inhibitors: a mixed bag

Last week I wrote that proton pump inhibitors and H2 blockers are two mainstays of medical treatment for gastroesophageal reflux disease. Since GERD affects so many people, these are two of the most widely prescribed classes of medications. Here, I will focus on PPIs, for which more than 113 million prescriptions are written every year in the U.S. (JW Gen Med. Jun. 8, 2011).

PPIs include Nexium (esomeprazole), Prilosec (omeprazole), Protonix (pantoprazole) and Prevacid (lansoprazole) Many come in two forms — over-the-counter and prescription strength. PPIs have demonstrated efficacy for short-term use in the treatment of H. pylori-induced (bacteria overgrowth in the gut) peptic ulcers, GERD symptoms and complication prevention, and gastric ulcer prophylaxis associated with NSAID use (aspirin, ibuprofen, etc.) as well as upper gastrointestinal bleeds.

However, they are often used long-term as maintenance therapy for GERD. PPIs used to be considered to have mild side effects. Unfortunately, recent evidence is showing that this may not be true. Most of the data in the package inserts is based on short-term studies lasting weeks, not years. The landmark study supporting long-term use approval was only one year, not ten years. Maintenance therapy usually continues over multiple years.

The side effects that have occurred after years of use are increased risk of bone fractures and calcium malabsorption; Clostridium difficile, a bacterial infection in the intestines; potential B12 deficiencies and weight gain (World J Gastroenterol. 2009;15(38):4794–4798).

Fracture risks

There has been a debate about whether PPIs contribute to fracture risk. The Nurses’ Health Study, a prospective (forward-looking) study involving approximately 80,000 postmenopausal women, showed a 40 percent overall increased risk of hip fracture in long-term users (more than two years duration) compared to nonusers (BMJ 2012;344:e372). Risk was especially high in women who also smoked or had a history of smoking, with a 50 percent increased risk. Those who never smoked did not experience significant increased fracture risk. The reason for the increased risk may be due partially to malabsorption of calcium, since stomach acid is needed to effectively metabolize calcium.

In the Women’s Health Initiative, a prospective study that followed 130,000 postmenopausal women between the ages of 50 and 79, hip fracture risk did not increase among PPI users, but the risks for wrist, forearm and spine were significantly increased (Arch Intern Med. 2010;170(9):765-771). The study duration was approximately eight years.

Bacterial infection
The FDA warned that patients who use PPIs may be at increased risk of a bacterial infection called C. difficile. This is a serious infection that occurs in the intestines and requires treatment with antibiotics. Unfortunately, it only responds to a few antibiotics and that number is dwindling.

In the FDA’s meta-analysis, 23 of 28 studies showed increased risk of infection. Patients need to contact their physicians if they develop diarrhea when taking PPIs and the diarrhea doesn’t improve (www.FDA.gov/safety/medwatch/safetyinformation). In one study, there was a 96 percent increased risk of C. difficile with PPIs, compared to a 40 percent increased risk with H2 blockers (Am J Gastroenterol. 2007;102(9):2047-2056).

B12 deficiencies

Suppressing hydrochloric acid produced in the stomach may result in malabsorption issues if turned off for long periods of time. In a study where PPIs were associated with B12 malabsorption, it usually took at least three years duration to cause this effect. B12 was not absorbed properly from food, but the PPIs did not affect B12 levels from supplementation (Linus Pauling Institute; lpi.oregonstate.edu). Therefore, if you are taking a PPI chronically, it is worth getting your B12 and methylmalonic acid (a metabolite of B12) levels checked and discussing possible supplementation with your physician if you have a deficiency (Aliment Pharmacol Ther. 2000;14(6):651-668).

Package insert of the PPIs

Interestingly, the package inserts of PPIs recommend the lowest dose possible for maintenance therapy. While prescription PPIs warn that fractures of the wrist, back and hip may occur, suggesting that it may be appropriate to use vitamin D and calcium supplementation to reduce fracture risk, OTC PPIs are not required to include the fracture risk warning.

The problem with PPIs is that patients taking the medications for more than a year are mostly unwitting participants in long-term, anecdotal, postmarketing study on efficacy and tolerability.

My recommendations would be to use PPIs for the short term, except with careful monitoring by your physician.  If you choose medications for GERD management, H2 blockers might be a better choice, since they only partially block acid. Lifestyle modifications may also be appropriate in some of the disorders, with or without PPIs. Consult your physician before stopping PPIs since there may be rebound hyperacidity (high acid produced) if they are stopped abruptly.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.