Pharmacology Watch

PPIs, Clostridium difficile, and Bone Fractures

In this issue: New reports about proton pump inhibitors and the effects of gastric suppression, pioglitazone vs vitamin E for non-alcoholic steatohepatitis, metformin and vitamin B12 deficiency, and FDA Actions.

PPIs, C. difficile, and bone fractures

Since H2 antagonists were introduced 30 years ago followed by proton pump inhibitors (PPIs) 20 years ago, there has been speculation whether long-term gastric acid suppression might have adverse effects. Billions of doses later, there is new evidence that chronic PPI use may lead to infections, especially Clostridium difficile infection (CDI), and may also contribute to bone fractures.

In the first of several studies published in the May 10 issue of Archives of Internal Medicine, researchers looked at more than 101,796 discharges from a tertiary care medical center during a five-year period, reviewing the level of acid suppression therapy and its relationship to CDI. As the level of acid suppression increased, the risk of CDI increased from 0.3% in patients not receiving acid suppressive therapy to 0.6% in those receiving H2 antagonists to 0.9% in those receiving daily PPIs and finally 1.4% in those receiving high-dose PPI therapy. After adjustment for a number of factors including comorbid conditions, age, and antibiotic use, the odds ratio for CDI infections were: 1 with no acid suppressing treatment, 1.53 (95% confidence interval [CI], 1.12-2.10) with H2 antagonist, 1.74 (95% CI, 1.39-2.13) with PPIs, and 2.36 (95% CI, 1.12-2.10) with high-dose PPI therapy. The authors conclude that increasing levels of pharmacologic acid suppression are associated with increased risk of nosocomial C. difficile infections, and the risk increases with more aggressive acid suppression (Arch Intern Med 2010;170:784-790).

In a second study from the same journal, researchers from the VA system in Massachusetts performed a retrospective, cohort study of 1166 inpatients and outpatients with CDI to determine if PPI use affected recurrence rates. During treatment for CDI, 45% of patients received a PPI while 55% did not. Recurrent CDI was more common in those exposed to PPIs than in those not exposed (25.2% vs 18.2%). The hazard ratio for recurrent CDI in those exposed to PPIs was 1.42 (95% CI, 1.11-1.82). The risk was higher in patients older than 80 years and in patients exposed to antibiotics not targeted to CDI infections The authors conclude that PPI use during treatment for CDI was associated with a 42% increased risk of recurrence (Arch Intern Med 2010;170:772-778).

It has also been postulated that suppressing gastric acid may affect digestion and absorption of certain nutrients, specifically calcium. Although this has never been definitively proven, multiple studies have shown that chronic PPI use is associated with bone fractures. The most recent study, also published in the May 10 issue of Archives of Internal Medicine, was a prospective analysis of more than 160,000 women enrolled in the Women's Health Initiative study. In more than 1 million person-years of follow-up, there were 1500 hip fractures, 4881 forearm or wrist fractures, 2315 clinical spine fractures, and more than 21,000 total fractures. The multivariate-adjusted hazard ratios for current PPI use was 1 for hip fracture, 1.47 (95% CI, 1.18-1.82) for clinical spine fracture, 1.26 (95% CI, 1.05-1.51) for forearm or wrist fractures, and 1.25 (95% CI, 1.15-1.36) for total fractures. Bone mineral density did not vary between PPI users and non-users. The authors conclude that use of PPIs in women was not associated with hip fractures but was modestly associated with clinical spine, forearm or wrist, and total fractures (Arch Intern Med 2010;170:765-771). This study confirms the findings of several large epidemiological studies that suggest that PPI use is associated with increased osteoporotic fracture risk. On May 25, the FDA issued a warning regarding the possible fracture risk associated with high-dose long-term use of PPIs. The Agency will require labeling changes to describe the possible risk.

As noted in these studies, PPI use is associated with risk of osteoporotic fractures and Clostridium difficile infections. Other studies have linked the PPIs to a higher risk of hospital- and community-acquired pneumonia, as well as enteric infection such as Salmonella and Campylobacter gastroenteritis. In an editorial in the May 10 issue of Archives of Internal Medicine, Mitchell Katz, MD, notes that of the more than 110 million prescriptions for proton pump inhibitors filled each year, many are for inappropriate indications, making PPIs one of the most overprescribed medication classes in the world. He suggests that "for most patients the adverse effects of PPIs outweigh the benefits" and urges physicians to offer other treatments for dyspepsia, prescribe shorter courses, and consider a trial of discontinuing PPIs in patients who are asymptomatic (Arch Intern Med 2010;170:747-748).

Pioglitazone vs vitamin E for NASH

Non-alcoholic steatohepatitis (NASH) is a common liver disease that is difficult to treat and often progresses to cirrhosis. A new study compares the thiazolidinedione pioglitazone (30 mg daily) to vitamin E (800 IU daily) in a placebo-controlled trial for 96 weeks in 247 nondiabetic NASH patients. The primary outcomes were standardized scores for steatosis, lobar inflammation, hepatocellular ballooning, and fibrosis as determined by liver biopsy. Vitamin E therapy was associated with a significant improvement in non-alcoholic steatohepatitis (43% vs 19%; P = 0.001), but pioglitazone did not show statistical improvement (34% vs 19%; P = 0.04). Serum transaminases improved with both treatments, and both reduced hepatic steatosis and lobular inflammation, but neither improved fibrosis. Pioglitazone caused significant weight gain compared to vitamin E or placebo. The authors conclude that vitamin E was superior to placebo for the treatment of NASH in adults without diabetes (N Engl J Med2010;362:1675-1685).

Metformin and vitamin B12 deficiency

Monitor your patients on metformin for vitamin B12 deficiency. This is the message of a recent study from the Netherlands. The study enrolled 390 patients with type 2 diabetes on insulin and initiated metformin 850 mg three times a day or placebo for an average of 4.3 years. Metformin treatment was associated with a mean decrease in vitamin B12 concentrations of 19% (P < 0.001) and an increase in homocysteine concentrations of 5% (P = 0.091). Longer-term treatment with metformin was associated with larger declines in vitamin B12 levels. The authors conclude that metformin likely causes malabsorption of vitamin B12 and recommends routine monitoring of vitamin B12 levels in patients who are treated with metformin (BMJ 2010;340:c2181).

FDA actions

The FDA has approved a new formulation of oxycodone (OxyContin®) that is designed to discourage chewing, crushing, or dissolving the drug. The FDA admits, however, that although the new formulation reduces the risk of snorting or injecting the drug, it can still be abused by simply ingesting larger doses than recommended. Vocal critics have called for oxycodone's withdrawal from the market due to an explosion in abuse of the drug nationwide and calls this new formulation "too little too late."

The FDA has recommended resuming use of Rotarix® rotavirus vaccine and to continue using RotaTeq® rotavirus vaccine. Rotarix was found to have elements of the porcine circovirus 1 (PCV1) in March, which resulted in an advisory to clinicians to stop using the vaccine. Subsequently, DNA from PCV1 and PCV2 was discovered in the RotaTeq vaccine. The FDA now says that there is no evidence that PCV causes illness or infection in humans while the benefits of the vaccine are substantial.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: