More Good News for PPIs: NO Increased Risk of Dementia

From ACG SmartBrief (thanks to Ben Gold for this):

A study published in The American Journal of Gastroenterology found no link between the use of proton-pump inhibitors and increased dementia risk. The study, led by Muhammad Ali Khan, MD, examined 11 studies with a combined 642,949 participants, and researchers said “PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.”

The American Journal of Gastroenterology: January 2, 2020 – Volume Publish Ahead of Print – Issue – p doi: 10.14309/ajg.0000000000000500



Long-term use of proton pump inhibitors (PPIs) has been associated with a wide variety of potentially serious adverse effects including a possible increased risk of dementia. Studies evaluating this association have reached divergent conclusions. We aimed to evaluate this proposed association further and to assess the quality of the evidence in its support.


We searched MEDLINE, EMBASE, ISI Web of Science, and Cochrane databases for studies examining a link between PPI use and dementia, up to February 2019. Studies reporting summary results as hazard ratio (HR) or odds ratio (OR) were pooled using the DerSimonian and Laird random-effects model for meta-analyses. Methodological quality of individual observational studies was assessed using the Newcastle-Ottawa scale and the overall quality of evidence rated as per the GRADE approach.


We identified and included 11 observational studies comprising 642,949 subjects; 64% were women. Most studies were short-term ranging from 5 to 10 years. There were 158,954 PPI users and 483,995 nonusers. For studies summarizing data as adjusted HR, pooled HR for all causes of dementia was 1.10 (0.88–1.37); for Alzheimer dementia only, it was 1.06 (0.72–1.55). For studies summarizing data as adjusted OR, pooled OR for all causes of dementia was 1.03 (0.84–1.25) and for Alzheimer dementia only 0.96 (0.82–1.11). Per Newcastle-Ottawa scale assessment, 10 studies were of high quality and 1 was of moderate quality. By applying GRADE methodology, quality of evidence for both outcomes was very low.


We found no evidence to support the proposed association between PPI use and an increased risk of dementia. PPI use among patients who have a valid indication for it, should not be curtailed because of concerns about dementia risk.

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NY Times:Supplements Don’t Help Dementia

It is tiresome how many products are marketed with baseless claims of preventing dementia.  Some pushback:

NY Times: Supplements Won’t Prevent Dementia. But These Steps Might.

An excerpt:

The Food and Drug Administration estimates that 80 percent of older adults rely on dietary supplements, many purporting to prevent or treat Alzheimer’s and other forms of dementia…

Vitamins, various antioxidants, concoctions derived from animals and plants — “we see plenty of ads on TV, but we have no evidence that any of these things are preventive,” said Dr. Steven DeKosky, a neurologist and deputy director of the McKnight Brain Institute at the University of Florida.

Dr. DeKosky led a federally supported study of Ginkgo biloba extract, for instance, following more than 3,000 people for seven years to see if it reduced dementia. It didn’t.

Some of the steps that may help according to article:

  • Increased physical activity;

  • Blood pressure management for people with hypertension, particularly in midlife;

  • And cognitive training.

PPIs NOT Linked to Cognitive Decline/Dementia & PPIs NOT Linked to Heart Attacks

In a prospective study (M Wod et al. Clin Gastroenterol Hepatol 2018; 16: 681-89), data on middle-aged (n=2346, 46-67 yrs) and older individuals (n=2475) were collected in the Longitudinal Study of Aging Danish Twins.  This study showed that there was no difference in cognitive decline between PPI users and non-users.

The second study (SN Landi et al. Gastroenterol 2018; 154: 861-73) used a large administrative database and reviewed more than 5 million new  users of prescription PPIs and prescription H2RAs.  The authors found no significant difference in myocardial infarctions (MIs) between PPIs and H2RAs over a 12 month period.

Related blog posts:

Recent Study Did NOT Find Dementia Risk with PPIs

When performing retrospective studies, many times a potential association can be found with medications or diet and specific problems.  When these risks/associations are low (i.e. relative risks <2), often, these findings do not hold up, particularly with prospective studies which are much more able to control for confounding variables.

For proton pump inhibitors (PPIs), many potential complications have been suggested at  low relative risk findings in poorly-controlled studies.  A recent study has contradicted previous findings suggesting that PPIs increase the risk of dementia.

Goldstein FC, et al. J Am Geriatr Soc. 2017;doi:10.1111/jgs.14956. (Thanks to Ben Gold for this reference)

A link and an excerpt from a summary of this study from Healio Gastroenterology:

Link: Study finds no link between PPIs, dementia, Alzheimer’s risk


They evaluated 10,486 volunteers within the NIH-supported Alzheimer’s Disease Centers who were aged 50 years and older and had either normal cognition or mild cognitive impairment at baseline. Participants underwent neuropsychological evaluations and self-reported PPI use at two to six annual visits between 2005 and 2015.

Overall, 884 reported they were taking PPIs at every visit, 1,925 reported they took PPIs intermittently, and 7,677 never reported taking PPIs.

Those who reported continuous PPI use showed a lower risk for cognitive function decline compared with those who never reported using PPIs (HR = 0.78; 95% CI, 0.66-0.93) as well as a lower risk for developing mild cognitive impairment or Alzheimer’s disease (HR = 0.82; 95% CI, 0.69-0.98).

Those who reported using PPIs intermittently also showed a lower risk for cognitive function decline (HR = 0.84; 95% CI, 0.76–0.93) and for developing mild cognitive impairment or Alzheimer’s disease (HR = 0.82; 95% CI, 0.74–0.91).

My take: This study provides reassurance that PPIs are unlikely to result in cognitive decline. Particularly when a study suggests a low risk of an association, further studies are needed to clarify the true risks.

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More advice on Proton Pump Inhibitors

L Laine, A Nagar. Am J Gastroenterol 2016; 111: 913-15.

This reference explains how these clinicians discuss the long-term use of proton-pump inhibitors with their adult patients.  Thanks to Ben Gold for this reference.  Here are a couple pointers:

  • “The recent studies about CKD (chronic kidney disease) and dementia, similar to many prior studies assessing PPI risk, are retrospective observational studies…This results in differences between PPI users and non-users in factors that may impact study outcomes and confound results.”
  • Gastroesophageal reflux disease: The authors suggest that PPIs for GERD can be stopped >2 weeks after symptoms resolve.  For infrequent symptoms, H2RAs, lifestyle modifications and intermittent PPIs often suffice.
  • Barrett’s esophagus: “observational sutdies suggest that PPIs may decrease progression to neoplastic Barrett’s esophagus”

WHAT WE TELL PATIENTS: “Because of inherent risk of bias and low effect sizes we cannot conclude that associations of PPIs and adverse outcomes such as dementia and CKD in recent observational studies are vailid…Nevertheless, we cannot conclude that risks do not exist…we need to ensure that benefits outweigh potential risk.  If PPIs are indicated, using the lowest effective dose and, if possible, intermittent rather than daily therapy..should decrease the risk of potential side effects.”

On the same topic, Paul Moayyedi (in Gastroenterology and Endoscopy News, August 2016): “Every study has shown that sicker patients tend to be prescribed PPIs…Sick patients tend to develop other illnesses so PPIs will be associated with about any disease you can imagine in a database.”  As such, he asserts that weak associations (OR <2) are usually due to cofounding factors.  “The only benefit [these studies]..have is that it is another opportunity to discuss with the patients about stopping their PPI therapy, as there are a significant proportion…on these drugs unnecessarily.”

purple flowers

Piling on PPIs -Now Concerns about Dementia

A recent study (see abstract below -from Mike Hart) indicates the possibility that proton pump inhibitors (PPIs) could increase the risk of dementia to a small degree.  Despite the big numbers, this study cannot adequately control for numerous factors that could influence these results.  As is often said, association does not prove causation.  Nevertheless, this study is another reminder to use PPIs when indicated and to use them for the appropriate length of therapy.

Here’s NBC News Narrative: Popular Heartburn Drugs Linked to Dementia


Association of Proton Pump Inhibitors With Risk of Dementia: A Pharmacoepidemiological Claims Data Analysis

Willy Gomm, PhD1; Klaus von Holt, MD, PhD1; Friederike Thomé, MSc1; Karl Broich, MD2; Wolfgang Maier, MD1,3; Anne Fink, MSc1,4; Gabriele Doblhammer, PhD1,4,5,6; Britta Haenisch, PhD1

JAMA Neurol
. Published online February 15, 2016. doi:10.1001/jamaneurol.2015.4791

Importance  Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline.

Objective  To examine the association between the use of PPIs and the risk of incident dementia in the elderly.

Design, Setting, and Participants  We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015.

Exposures  Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole.

Main Outcomes and Measures  The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy.

Results  A total of 73 679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70 729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001).

Conclusions and Relevance  The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail.

Related blog post: Proton Pump Inhibitors Webinar

Unrelated article (from Ben Gold): J Molina-Infante et al. Am J Gastroenterol 2015; 110: 1567-1575.  This study examined 75 patients (mean age 38 years) with proton-pump inhibitor responsive esophageal eosinophilia (PPI-REE).  55 (73%) had long-term sustained histologic remission with low-dose PPI therapy (20 mg once or twice daily). In addition, the article noted that 9 of 10 relapsers with distal eosinophilia were noted to have a CYP2C19 rapid metabolizer genotype and regained histologic remission with dose intensification.

Briefly noted: AI Sharara et al. Clin Gastroenterol Hepatol 2016; 14: 317-21.  Among 414 who met inclusion criteria (at least 6 months of PPI usage and at least 1 serum magnesium level), 57 (13.8%) had at least 1 low serum magnesium –44 of these patients had recognizable causes (eg. diuretics, chronic diarrhea).  Of the remainder who continued with PPI therapy, the level was normal at final measurement and only mildly low levels were noted previously.  Thus, in patients without other reasons for low magnesium, the authors found that use of a PPI does not appear to be associated with hypomagnesemia.