PPIs Not Linked to Cognitive Decline, Study Finds

Bridget M. Kuehn

July 25, 2017

Proton pump inhibitor (PPI) use was not associated with an increased risk for cognitive decline in an analysis of data from the Nurses' Health Study II.

Although the results provide reassuring data from a large prospective study, they are unlikely to completely resolve safety concerns about long-term use of PPIs.

Paul Lochhead, PhD, from Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues published their findings online July 20 in Gastroenterology.

Several previous studies have found a link between long-term use of PPIs and dementia, including a 2016 analysis of a German health insurers' database, which found a 44% increased risk of developing dementia among those individuals who took PPIs ( JAMA Neurology. 2016;73:410-416). And some animal studies have proposed a potential mechanism that might explain this association ( PloS One. 2013;8:e58837).

In addition, these widely used medications have been linked to community-acquired pneumonia, hip fracture, nutrient deficiencies, chronic kidney disease, and Clostridium difficile–associated diarrhea in observational studies.

This widely used class of drugs effectively treats acid-related gastrointestinal disorders, including gastroesophageal reflux disease, but evidence of potential adverse events has led to concern among some patients and physicians.

"One of the most common questions gastroenterologists receive from their patients is whether PPIs are safe to use, based on the troubling headlines linking PPIs to everything from hip fracture, to dementia, to death," coauthor Andrew T. Chan, MD, director of the gastroenterology training program at Massachusetts General Hospital, said in a news release. "Our new research should provide some reassurance to individuals who require these highly effective medications for long-term treatment."

The study analyzed data on 13,864 women from the Nurses Health Study, a massive nationally representative study that has followed more than 100,000 US nurses for almost 3 decades. The researchers determined use of PPIs  on the basis of participant questionnaires. They assessed cognitive function with an online battery of neuropsychological tests the women completed at home; the tests take about 15 to 20 minutes to complete. The women were between the age 50 and 70 years at the time they completed the cognitive tests. Deficits in the cognitive skills assessed by the tests have previously been found to be predictors of dementia, the authors write.

A small decline in performance on tests of psychomotor speed and attention was linked to a longer duration of PPI use (−0.06; 95% confidence interval, −0.11 to 0.00; P trend = .03), however, this difference was "attenuated" when the authors adjusted for use of histamine H2 receptor antagonists, which are used to treat ulcers and related conditions.

The results appear to contradict the findings of the German study. The authors write that the German study may have been confounded by differences in education levels or other health-linked characteristics. They also note that dementia is often misdiagnosed and PPIs are frequently inappropriately prescribed.

"Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis," the researchers explain. "This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy."

The study authors do, however, note some weaknesses in their study, and say replication of their findings by other observational studies would be helpful.

"We recognize that our study has some limitations," the authors write. "We cannot exclude the possibility that PPI use was associated with a more modest reduction in cognitive function, and we lacked power to detect it."

Dr Chan reports having served as a consultant for Bayer Healthcare, Pfizer, and Aralez Pharmaceuticals. One coauthor reports receiving consulting fees from AbbVie Inc, Samsung Bioepis, and Takeda Pharmaceuticals. The remaining authors have disclosed no relevant financial relationships.

Gastroenterology. Published online July 20, 2017. Abstract

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