In the JournalsPerspective

PPIs not linked to cognitive decline in new study of twins

A prospective study of middle-aged and elderly twins in Denmark showed no association between long-term use of proton pump inhibitors and cognitive decline.

These results confirm those from a recent U.S. study that found no association between PPI use and dementia, which the American Gastroenterological Association said “puts these claims to rest.”

“This study is the first to examine the association between long-term PPI use and cognitive decline in a population-based setting,” investigators wrote. “Cognitive scores of more than 7,800 middle-aged and older Danish twins at baseline did not indicate an association with previous PPI use. Follow-up data on more than 4,000 of these twins did not indicate that use of this class of drugs was correlated to cognitive decline. These findings were supported by results of within pairs analyses of twins discordant for cognitive scores (baseline) or cognitive decline (follow-up).”

Prompted by conflicting results from prior studies, investigators evaluated data on middle-aged adults (46-67 years) from the Middle Age Danish Twin study who underwent cognitive assessments over 10 years, and from older adults from the Longitudinal Study of Aging Danish Twins who underwent cognitive assessments over 2 years. Cognitive assessments were performed using a five-component test battery, and PPI use was determined by data from a national prescription registry.

In the middle-aged cohort, PPI use before study enrollment correlated with a “slightly lower” mean cognitive score at baseline, and those who took high levels of PPIs ( 400 defined daily doses) showed a lower adjusted difference in mean cognitive scores than non-users. Those with the highest consumption of PPIs (1600 defined daily doses) showed “slightly less” cognitive decline than non-users.

In the older cohort, those who consumed high levels of PPIs showed higher adjusted cognitive scores than non-users, and a lower adjusted mean difference between baseline and follow-up scores than non-users.

However, none of the differences in cognitive scores between PPI users and non-users reached statistical significance.

“As the cohorts were recruited among Danish twins, we also investigated the association between PPI use and cognition among twin-pairs discordant with regard to cognitive decline — a powerful design to study the effects of non-genetic and non-common environment exposures,” the researchers wrote.

PPI exposure showed no correlation with differences in cognitive scores among twin pairs.

In a post hoc analysis, the investigators also found no association between H2RA use and cognitive decline.

“The magnitude of estimates did not indicate any important association with cognitive function as measured through the composite score, and none of our adjusted estimates reported a statistically significant effect in the longitudinal analyses,” they wrote. “In addition, there did not seem to be a clear dose-response effect in any analyses. Overall, the results of this study do not indicate that long-term PPI use correlates with risk for cognitive decline.” – by Adam Leitenberger

Disclosures: Wod reports no relevant financial disclosures. Please see the full study for a list of all other authors’ disclosures.

A prospective study of middle-aged and elderly twins in Denmark showed no association between long-term use of proton pump inhibitors and cognitive decline.

These results confirm those from a recent U.S. study that found no association between PPI use and dementia, which the American Gastroenterological Association said “puts these claims to rest.”

“This study is the first to examine the association between long-term PPI use and cognitive decline in a population-based setting,” investigators wrote. “Cognitive scores of more than 7,800 middle-aged and older Danish twins at baseline did not indicate an association with previous PPI use. Follow-up data on more than 4,000 of these twins did not indicate that use of this class of drugs was correlated to cognitive decline. These findings were supported by results of within pairs analyses of twins discordant for cognitive scores (baseline) or cognitive decline (follow-up).”

Prompted by conflicting results from prior studies, investigators evaluated data on middle-aged adults (46-67 years) from the Middle Age Danish Twin study who underwent cognitive assessments over 10 years, and from older adults from the Longitudinal Study of Aging Danish Twins who underwent cognitive assessments over 2 years. Cognitive assessments were performed using a five-component test battery, and PPI use was determined by data from a national prescription registry.

In the middle-aged cohort, PPI use before study enrollment correlated with a “slightly lower” mean cognitive score at baseline, and those who took high levels of PPIs ( 400 defined daily doses) showed a lower adjusted difference in mean cognitive scores than non-users. Those with the highest consumption of PPIs (1600 defined daily doses) showed “slightly less” cognitive decline than non-users.

In the older cohort, those who consumed high levels of PPIs showed higher adjusted cognitive scores than non-users, and a lower adjusted mean difference between baseline and follow-up scores than non-users.

However, none of the differences in cognitive scores between PPI users and non-users reached statistical significance.

“As the cohorts were recruited among Danish twins, we also investigated the association between PPI use and cognition among twin-pairs discordant with regard to cognitive decline — a powerful design to study the effects of non-genetic and non-common environment exposures,” the researchers wrote.

PPI exposure showed no correlation with differences in cognitive scores among twin pairs.

In a post hoc analysis, the investigators also found no association between H2RA use and cognitive decline.

“The magnitude of estimates did not indicate any important association with cognitive function as measured through the composite score, and none of our adjusted estimates reported a statistically significant effect in the longitudinal analyses,” they wrote. “In addition, there did not seem to be a clear dose-response effect in any analyses. Overall, the results of this study do not indicate that long-term PPI use correlates with risk for cognitive decline.” – by Adam Leitenberger

Disclosures: Wod reports no relevant financial disclosures. Please see the full study for a list of all other authors’ disclosures.

    Perspective
    David A. Leiman

    David A. Leiman

    There is increasing interest in understanding the potential risks associated with PPI use by providers and patients. The recent study by Wod et al. adds important new evidence to this discussion. Among the several concerns cited about PPI use is dementia, which might be mediated via reduced vitamin B12 absorption or beta-amyloid deposition. Some of the epidemiological studies about this topic have received substantial media attention despite their methodological flaws and overall the data are conflicting.

    The current study helps clarify the nature of this association. It has several substantial strengths. First, the use of twin cohorts reduces potential genetic and life-exposure confounders. Classification of PPI use was based on nationwide prescription registries, which is nearly comprehensive and allowed for a dose response analysis. Also, cognitive function measurement was standardized and performed longitudinally among two cohorts at middle age and late life, with median baseline ages of 56.6 and 75.4 years, respectively. Both individual and within-twin pair analyses were conducted at baseline (n = 7,878) and after 2 or10 years (n = 4,821) of follow-up, depending on the cohort.

    The authors ultimately performed multiple evaluations to test the association between PPI use and dementia and concluded PPI exposure is neither associated with baseline cognitive score nor long-term decline. These data provide compelling evidence that using PPI carries minimal risk, at least regarding dementia. For practicing clinicians, this comports with national society best practice recommendations to continue using PPIs in the appropriate patient and clinical scenario, even when this means long-term treatment. Ultimately, these are powerful data to share with patients to help provide reassurance about the safety of such a widely prescribed and effective medication.

    • David A. Leiman, MD, MSHP
    • Assistant Professor of Medicine Division of Gastroenterology Duke University Medical Center Duke Clinical Research Institute

    Disclosures: Leiman reports no relevant financial disclosures.