Featured Highlight: Is There an Association Between Proton Pump Inhibitor Use and Dementia?

F e a t u r e d H i g h l i g h t

Is There an Association Between Proton Pump Inhibitor Use and Dementia?

Authors

Pamela L. Griffin, PharmD*, PGY-1 Pharmacy Practice Resident, Banner Boswell Medical Center, 10401 W Thunderbird Blvd., Sun City, AZ 85351; and Steven MacKay, PharmD, BCPS, BCGP, Clinical Pharmacist, Banner Boswell Medical Center, 10401 W Thunderbird Blvd., Sun City, AZ 85351 Corresponding Author* Conflicts of interest: None

ABSTRACT Proton pump inhibitor use is a common therapy for patients experiencing gastroesophageal reflux disease and peptic ulcer disease. As it is easily accessible and widely utilized it is important to examine the long term effects of its use. While several important side effects of long term use have been well established, two epidemiologic studies in Germany point towards an association between long-term proton pump inhibitor use and the development of any dementia. There is a high burden of care and decline in quality of life experienced by patients with dementia and Alzheimer’s disease, and the availability of effective therapy for its treatment is limited. The prevention of dementia by limiting unnecessary factors that increase risk of its development is imperative.

In direct contrast to the results of the German studies, more recent evidence from several other countries call this association into question. Additional studies in Finland and the United States have been conducted in an attempt to validate the findings of the German epidemiologic studies. The study out of Finland examined the association of proton pump inhibitor use and clinically verified Alzheimer’s disease, while the study from the United States evaluated any dementia or Alzheimer’s disease. These studies did not result in a statistically significant association between proton pump inhibitor use and the development of dementia. The strengths and weaknesses of each study need to be weighed to determine if an association exists. This will ensure the best clinical decisions are made for patients taking into account potential risks and benefits.

INTRODUCTION Proton pump inhibitors (PPIs) are used to treat a variety of conditions involving the detrimental effects of increased acid production in the gastrointestinal (GI) system. These conditions include stress ulcer prophylaxis, gastroesophageal reflux disease (GERD), and peptic ulcer disease.1-3 Initially, this medication class was deemed very safe with relatively few side effects. Over time, however, it was noted these drugs, especially with longterm use, were not without potential risks. Consequences of long-term use have now been well established and

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include increased risk for developing vitamin B12 deficiency, pneumonia, Clostridium difficile infection, bone fracture, and chronic kidney disease.4-8 More recently, several studies have reported an association between PPI use and development of dementia and/or Alzheimer’s disease.9 Due to the severe impact these disease states have not only on the patients, their family, as well as caregivers, it is vital to look at the current body of evidence to determine if there is enough evidence to establish a legitimate correlation between PPI use and risk of dementia and what its clinical relevance may be.

DISCUSSION Vitamin B12 deficiency has been regarded as a risk factor in the development of dementia, as well as a side effect associated with longterm PPI use.4 In 2014, a German epidemiological study assessed the association between PPI use among elderly patients and incidence of dementia.9 The researchers looked at 3,327 primary care patients age 75 and older over a period of up to six years. They determined the association between PPI use and any dementia was statistically significant [HR 1.38, 95% CI 1.04-1.83; p=0.02]. The study also concluded PPI use increased the risk of developing AD [HR 1.44, 95% CI 1.012.06; p=0.03].9 Information regarding drug use pattern of intermittent versus regular PPI use was limited until the third follow-up visit. A subsequent study by the same group of investigators evaluated claims data from the largest German health insurer.10 This study, published in 2016, included 73,679 patients among which 2,950, or 4%, had history of PPI use. The results of this study showed a statistically significant association between PPI use and incidence of dementia even after adjusting for potential confounding factors [HR 1.44, CI 95% 1.36-1.52; p < 0.001]. Interestingly, the hazard ratio was higher for those of male gender compared to females at 1.52 for males compared to 1.42 for females.10 Certain risk factors for dementia, including ApoE4 allele carriers and lower educational level, could not be adjusted for due to lack of information in the claims database. Additionally, the investigators were unable to differentiate between types of dementia, as many of the diagnoses were coded as unspecified or mixed dementia.

A second potential mechanism for the increase in cognitive decline caused by PPI use was evaluated in mice and cellular models.11 Alzheimer’s disease is associated with elevated levels of amyloid-β plaques and intracellular neurofibrillary tangles in the brain.12 Badiola et al. examined the effect lansoprazole has on amyloid-β production and suggested that PPIs negatively impact the metabolic pathway for amyloid-β degradation and increase its production.11 The results of the two German studies and this proposed mechanism prompted other researchers to validate the results in several other countries.

A longitudinal observational study evaluated the risk associated with PPI use and the development or worsening of mild cognitive impairment (MCI), dementia, and AD among 10,486 patients that had normal cognition or MCI at baseline.13 The results

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showed that continuous use of PPI was associated with lower risk of decline in cognitive function [HR 0.78, CI 95% 0.66-0.93; p=0.005], and lower risk of conversion to MCI or AD [HR 0.82, CI 95% 0.69-0.98; p=0.03].13 These findings failed to validate the results from the German studies. However, study limitations included reliance on self-reported PPI use and researchers had no access to dispensing data. A nationwide nested case-control study conducted in Finland not only compared the risk of AD among PPI users and non-users, but also evaluated a dose-response relationship and evaluated specific PPI use and its association with AD risk.14 From 2005–2011 over 70,000 patients in the community setting with a diagnosis of AD were matched with up to four non-AD patients for comparison. Cumulative and average daily PPI dose was evaluated and adjusted for confounding variables. Unique to this study was the use of lag windows which would account for the long latency period it takes AD to develop as well as for “reverse causality.” This means data for the analysis would not include PPI use in the preceding three- or five-years before AD diagnosis. The data was evaluated with no lag window, as well as lag windows of three and five years. The results showed only a slight increase risk of AD among PPI users with no lag taken into account, a three-year lag window, and a five-year lag window. The adjusted odds ratios for any use of PPIs before AD diagnosis were 1.02, 1.03, and 1.05 respectively.14 The confidence intervals however, did include one in the no lag and threeyear lag analysis. Furthermore, there was no dose-response relationship noted between PPI dose and AD diagnosis. The findings of this study failed to show an association between PPI use and AD.

A prospective population-based cohort study looked at 3,484 patients age 65 and older within the Kaiser Permanente Washington system.15 These patients had no dementia diagnosed at study entry and were screened every two years for dementia symptoms. PPI exposure was evaluated by total standardized daily dose and duration of use then compared to time to dementia or AD. Average followup was 7.5 years and determined PPI exposure was not associated with risk of dementia (p=0.66) or AD (p=0.77).15 The investigators of this study were unable to show an association between dementia and duration of PPI use. Although this study did not evaluate a dose-response relationship, the exposure time evaluated exceeded that of the German studies, which is a more accurate reflection of the duration of time it takes to develop diseases like AD.

CONCLUSION With conflicting data, it is currently unclear how long-term PPI use affects an individual’s risk of developing dementia, especially AD. The two large German studies that were able to show an association between PPI use and risk of dementia were not designed to delineate by type of dementia nor show a dose-response relationship. There have been two proposed mechanisms whereby PPI use may increase the risk of dementia: induced vitamin B12 deficiency, and the possibility of increased formation of amyloid-β plaques. Though amyloid-β

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plaques are pathological markers found in AD, they have not been related to other forms of dementia. As more recent studies publish data that fail to show an association with PPI use and dementia, the need to discontinue every patient at low risk for dementia to prevent its progression may be unnecessary. However, the risks and benefits of therapy should be weighed carefully in light of the current conflicting body of evidence and their use should be judicious and only for patients that clinically warrant longterm therapy. n

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