A recent study adds to the ongoing discussion about proton pump inhibitors and cognition, after an analysis of 5 700 older adults suggested that cumulative use of PPIs – the drugs used to help control acid reflux and other gastrointestinal disorders – might raise the risk of dementia.
Over a median follow-up of 5.5 years, people in the Atherosclerosis Risk in Communities (ARIC) cohort who used prescribed PPIs for more than 4.4 years had a higher risk of dementia (adjusted HR 1.3, 95% CI 1.0-1.8) than those reporting no PPI use, said Dr Kamakshi Lakshminarayan of the University of Minnesota and co-authors.
Associations were not significant for fewer years of PPI use, the researchers wrote in Neurology.
Long-term use of PPIs has been linked in previous studies to a higher risk of stroke, bone fractures, and chronic kidney disease, the researchers noted. Reports over the years have shown mixed data about PPIs and cognition, however.
In 2016, a prospective study in Germany found a relationship between PPI use and dementia in adults aged 75 and older.
More recently, reports MedPage Today, an analysis of data from the ASPREE trial led by Dr Andrew Chan of Harvard Medical School and Massachusetts General Hospital reported that PPIs were not linked to increased risks of dementia or cognitive decline in people 65 and older.
“I would be cautious about the study’s conclusions that PPI use is associated with risk of dementia,” Chan said. “Importantly, most of their analyses do not support a link. They find an association only in a small subgroup of individuals without a clear linear relationship between duration of use and risk.”
The finding from the ARIC cohort could be due to confounding by other factors associated with the use of these drugs, Chan told MedPage Today.
“Taken together with evidence from our recent study that did not find an association in a separate cohort, I think most patients can be reassured that PPI use is not associated with dementia.”
Lakshminarayan and co-authors studied 5 712 people who were dementia-free at baseline, defined as visit five (2011-2013) in the ongoing ARIC study. Mean baseline age was 75; 22% of participants were black, and 58% were female.
During in-person ARIC study visits, participants were asked to bring all over-the-counter and prescription medications used during the preceding two weeks. PPI use also was ascertained through annual phone calls.
Cumulative PPI use included use from ARIC visit one through visit five. Findings were adjusted for demographics, comorbid conditions, and other medication use.
The researchers divided participants into four groups: those not using PPIs, those using them for up to 2.8 years, those using them for 2.8 to 4.4 years, and those using them for more than 4.4 years. Over-the-counter medications not prescribed by a doctor were excluded.
In total, 1 490 participants used PPIs. Minimum cumulative PPI use was 112 days, and maximum use was 20.3 years. Median use was 3.8 years, and mean use was 4.4 years.
Over a median of 5.5 years, 585 people – roughly 10% of the baseline population – developed dementia. Participants using PPIs at ARIC visit five did not have a higher risk of developing dementia than those not using PPIs (adjusted HR 1.1, 95% CI 0.9-1.3).
Only those participants who used PPIs for more than 4.4 cumulative years before visit five had a higher risk.
In a secondary analysis, Lakshminarayan and co-authors examined the relationship between PPIs and dementia with histamine-2 receptor antagonists (H2RAs) as an active comparator. Results were similar to those of the main analyses: more than 4.4 cumulative years of exposure to PPIs was associated with greater dementia risk compared with H2RAs, but there was no association with use for shorter durations or current use.
The researchers attempted to adjust for anticholinergic medication use due to reported associations between those drugs and cognitive impairment, but were not able to due to small cell size.
However, less than 2% of the total sample used anticholinergics at visit five, they noted. Despite adjusting for many other variables, residual confounding may have influenced results, they acknowledged.
Study details
Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study
Carin Northuis, Elizabeth Bell, Pamela Lutsey, Kristen George, Rebecca Gottesman, Tom Mosley, Eric Whitsel, Kamakshi Lakshminarayan.
Published in Neurology on 9 August 2023
Abstract
Background
Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study.
Methods
These analyses used participants from a community-based cohort (ARIC) from the time of enrolment (1987-89) through 2017. PPI use was assessed via visual medication inventory at clinic Visits 1 (1987-89) to 5 (2011-13) and reported annually in study phone calls (2006-2011). The present study uses ARIC Visit 5 as baseline, since this was the first visit in which PPI use was common. PPI use was examined two ways: current use at Visit 5 and duration of use prior to Visit 5 (Visit 1 to 2011, exposure categories: 0 days, 1 day – 2.8yrs, 2.8-4.4yrs, >4.4yrs). The outcome was incident dementia after visit 5. Cox Proportional Hazard models were used, adjusted for demographics, co-morbid conditions, and other medication use.
Results
A total of 5 712 dementia-free participants at visit 5 (mean age 75.4±5.1 years; 22% black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. Minimum cumulative PPI use was 112 days and maximum use was 20.3 years. There were 585 cases of incident dementia over median follow up time. Participants using PPIs at Visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (Hazard Ratio (HR): 1.1 [95% Confidence Interval (CI): 0.9-1.3]). Those who used PPIs for >4.4 cumulative years prior to Visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95%CI: 1.0-1.8]) than those reporting no use. Associations were not significant for lesser amounts of PPI use.
Discussion
Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia.
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