March/April 2024

March/April 2024 Issue

Proton Pump Inhibitors
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 17 No. 2 P. 16

Short-term use of proton pump inhibitors is generally safe, but long-term use comes with risks, including dementia.

Proton pump inhibitors (PPIs) are a class of drugs that effectively reduce gastric acid production and are used to treat gastrointestinal (GI) disorders such as gastroesophageal reflux disease, peptic ulcer disease, and many other acid-related GI disorders. PPIs are among the most widely prescribed medications in the world, with more than 15 million people in the United States receiving prescriptions each year and millions more who purchase them over the counter (OTC), often outside of the care of a physician.1

While the short-term use of PPIs is generally very safe, long-term use is associated with risks, including vitamin and mineral deficiencies, kidney disease, increased infections, osteoporosis and fractures, hypergastrinemia, cardiovascular disease, cancers, and dementia. A recent study adds to the findings of previous research indicating a possible association between long-term PPI use and increased dementia risk, finding a 33% higher dementia risk when PPI use stretched beyond four years.2 While these studies don’t prove that PPI use directly causes dementia, they do suggest the need for increased awareness about potential risks. Health care providers should counsel patients on the appropriate use of this class of medications and the increased potential for risks with long-term use.

Dementia
As the population rapidly ages, the number of persons with dementia and the cost to care for these persons is quickly growing. As of 2023, about 6.7 million people, or one in nine Americans aged 65 and older, are living with dementia.3 And by 2050, without medical breakthroughs to cure or treat dementia, the number of people with dementia is expected to double to 12.7 million, with associated costs increasing to $1.5 trillion per year.3 In addition to the cost associated with dementia, the disorder has significant implications for the quality of life for both patients and their families and caregivers. As there is no cure for dementia and treatments are limited, it’s essential to identify and minimize potential risk factors for dementia.

PPI Availability
PPIs available by prescription in the United States include omeprazole (Prilosec, Zegerid), pantoprazole (Protonix), lansoprazole (Prevacid), rabeprazole (Aciphex), esomeprazole (Nexium), and dexlansoprazole (Dexilant). Many of these PPIs are also available OTC, which has further increased their accessibility and potential for misuse.

PPI Mechanism of Action
PPIs effectively inhibit gastric acid production through irreversible binding to the gastric parietal cell H+/K+ ATPase pump (the “proton pump”). While other drugs, such as H2 receptor blockers (eg, famotidine), can also reduce acid secretion in the stomach, PPIs are the most potent acid-reduction drugs available.

PPI Misuse
PPIs provide a valuable and much-needed option for the prevention or treatment of certain GI disorders, including duodenal and gastric ulcers, gastroesophageal reflux disease, NSAID-induced gastroduodenal ulcers, acid hypersecretory conditions such as Zollinger-Ellison syndrome, H. pylori (when used in combination with antibiotics), stress ulcers in critically ill patients, and many other indications. However, along with their proven efficacy and long perceived tolerability and safety, the use of PPIs has increased exponentially over the past 30 years, leading to extensive inappropriate overuse.4

A significant and common problem contributing to PPI overuse is their utilization beyond the recommended duration of therapy. Per consensus guidelines, PPI use beyond eight weeks’ duration is typically only appropriate for a few indications, including a history of prior GI bleed, Barrett’s esophagus, Los Angeles grade D esophagitis, ongoing NSAID use, dual-antiplatelet therapy in patients with previous upper GI bleed and other risk factors, and active hypersecretory conditions.4

The inappropriate use of PPIs is a concern that’s been reported across health care settings. For instance, PPIs are commonly overused in hospitalized patients with low risk for GI bleeding, with the issue compounded as the drugs frequently are not discontinued at the time of discharge.5 In the community setting, providers often prescribe PPIs for every GI complaint when other medications, such as antacids or H2 blockers, may be more appropriate, and then fail to reevaluate the patient for the continued need, leading to indefinite PPI use. An additional contributor to misuse is that patients may use OTC PPIs—which are only indicated to treat frequent heartburn—beyond the product labeling recommendation to limit their use to 14 days and not more than three times per year without consulting a prescriber.

Unintended Consequences of Long-Term PPI Use
As noted, the short-term use of PPIs is safe; however, long-term use can have unintended consequences, including the following.

Infections
PPIs significantly reduce gastric acid production, thereby increasing gastric pH, which can lead to small intestinal bacterial overgrowth and impaired immune response.6 This can increase the risk for infectious complications such as pneumonia and C. difficile. Furthermore, persons using PPIs twice daily are at an increased risk of COVID-19 infection.7

Micronutrient Deficiencies
Small intestinal bacterial overgrowth can also cause malabsorption of many micronutrients, including vitamin B12, vitamin C, magnesium, iron, and calcium. The resulting deficiencies can be especially concerning in older adults, who are already at a high risk for nutritional deficiencies. These deficiencies can contribute to osteoporosis and fracture risk, anemia, cardiovascular disease, renal concerns, and neurological issues.

Renal Issues
Studies have found a connection between PPIs and the onset of renal diseases like acute interstitial nephritis, acute kidney injury, chronic kidney disease, and end-stage renal disease.8 It’s hypothesized that PPIs or their metabolites can accumulate in the table-interstitium, triggering a cell-mediated immune response, which could lead to acute kidney injury and progress to chronic kidney disease and end-stage renal disease.9 Long-term use of PPIs is also associated with hypomagnesemia, which could cause endothelial cell dysfunction, accelerated endothelial senescence, enhanced oxidative stress, hyperinflammation, and vascular senescence and subsequent progression of kidney disease.10

PPI-Associated Dementia Risk
Studies evaluating the link between PPI use and dementia have produced mixed findings. While many studies have shown an association between PPI use and dementia, other studies have shown either no increased risk or decreased risk of dementia. Keep in mind when reviewing these studies that most have a low level of clinical evidence, and many are observational studies, which carry an inherent risk of bias and confounding due to unrecognized risk factors or unrecorded risk factors such as existing vitamin B12 deficiency, depression, or socioeconomic factors. As such, current studies showing an association between PPI use and dementia do not prove that these drugs cause dementia. Large clinical trials are needed to establish a direct causative effect. However, these studies also shouldn’t be disregarded, as they may provide valuable insight into potential risk factors associated with the long-term use and misuse of PPIs, which could be modified for many patients through improved prescribing and medication use practices.

Atherosclerosis Risk in Communities Study
A recent observational study published in Neurology found a 33% higher dementia risk when PPI use stretched beyond four years.2 One of the study’s objectives was to examine the impact of cumulative PPI use and the risk of incident dementia in the Atherosclerosis Risk in Communities Study.2 Researchers analyzed participants enrolled in the community-based cohort from the time of enrollment (1987–1989) through 2017. Participants’ PPI use was assessed through visual medication inventory at clinic visits #1 (1987–1989) to #5 (2011–2013) and reported annually in study phone calls (2006–2011). The researchers note that they used visit five as their baseline since this was the first visit in which PPI use was common. A total of 5,712 dementia-free participants at visit five (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in the analysis, with a median follow-up time of 5.5 years. There were 585 cases of incident dementia identified during follow-up. Study participants who used PPIs for greater than 4.4 cumulative years before visit five were at 33% higher risk of developing dementia during follow-up than were those reporting no use. Associations were not significant for lesser durations of PPI use.

A Systematic Review
A recent systematic review evaluated studies published between January 2015 and May 2022 examined the risk of dementia or Alzheimer’s disease associated with PPI use.11 The review included 17 studies, as follows:

• Two were cross-sectional studies.
• One was a case-control study.
• Twelve were cohort studies.
• Two were randomized controlled trials.

The review found that PPI use was associated with an increased risk of dementia in six studies. The review found no association between PPI use and the risk of dementia in eight studies, and two studies showed a decreased risk of dementia with PPI use. In another study, there was no association between PPI use and Alzheimer’s disease, but the same study showed that PPI use is associated with an increased risk of non-Alzheimer’s dementia. The researchers noted that the studies included in the review used large sample sizes combined from different populations worldwide. However, the studies showed conflicting results, indicating the impact of PPI use on cognition is still in dispute.

Possible Mechanisms for PPI Dementia Link
Several mechanisms have been proposed as to how the long-term use of PPIs may increase dementia risk, including vitamin B12 deficiency, the facilitation of oxidative stress and neurotoxicity in the brain, and reduced levels of acetylcholine.

Vitamin B12 Deficiency
The long-term use of PPIs can result in B12 insufficiency, which has been proposed as a potential mechanism for cognitive decline and neurological effects associated with long-term PPI use.12 Vitamin B12 is an essential vitamin required for neurological health, and vitamin B12 deficiency can have severe consequences for cognitive health, as it may cause neurological degeneration, demyelination of the spinal cord, and irreversible dementia if left untreated for a long time. Some of the symptoms of vitamin B12 deficiency that may affect cognition include memory loss, concentration problems, verbal fluency difficulties, mood changes, agitation, weight loss, fatigue, weakness, constipation, poor balance, tingling or numbness in hands or feet, and sore mouth.

Blood-Brain Barrier Penetration
The ability of PPIs to cross the blood-brain barrier could result in direct neurological effects on the brain. Studies have shown that at least some of the PPIs (eg, omeprazole and lansoprazole) can cross the blood-brain barrier, which also explains the potential for some of the neurological adverse reactions seen with PPI use, including migraine, peripheral neuropathies, and impairment of hearing, vision, and memory.13

Amyloid Beta Peptide and Tau Protein
Alzheimer’s disease, the most common type of dementia, is characterized by the extracellular accumulation of amyloid beta peptide (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein. These plaques and tau protein lead to oxidative stress and inflammatory damage in the brain and subsequent cognitive decline.14

Once through the blood-brain barrier, PPIs may interact with microglia (neuronal support cells), which rely on acid-producing organelles to degrade unwanted proteins.15 As a result, there may be a reduced ability to eliminate the neurofibrillary tangles consisting of tau protein that contributes to dementia. PPIs have also been shown to increase Aβ levels in mice. As such, PPIs may facilitate tau and Aβ-induced neurotoxicity, which may increase Alzheimer’s disease progression and cognitive decline.15

Reduced Acetylcholine
Another possible mechanism by which PPIs affect cognition is through the reduction of the neurotransmitter acetylcholine. Alzheimer’s disease is associated with the loss of cholinergic neurons that produce the neurotransmitter acetylcholine. A recent study showed that PPIs potently and selectively inhibit the enzyme responsible for biosynthesis of the neurotransmitter acetylcholine (choline-acetyltransferase) and thereby may inhibit neuronal signaling in the brain.16

Improving PPI Use
It’s essential to differentiate between appropriate use and inappropriate long-term PPI use. For patients with appropriate indications for the use of PPIs, the risks are unlikely to outweigh the benefits.

However, for patients who are receiving PPIs without proper indication and for inappropriate duration, the concerns should be weighed carefully and should include taking steps to minimize their inappropriate use. Patients should be counseled on the benefits and risks associated with PPIs when used long-term and to use the lowest effective dose. Consideration should be given to alternative treatments, such as antacids or H2 blockers for those patients with less severe GI symptoms. Providers should also evaluate PPI use regularly and discontinue when no longer appropriate. For those patients who require long-term PPI use, consideration should be given to monitoring vitamin and mineral levels, bone density, and kidney function.

— Mark D. Coggins, PharmD, BCGP, FASCP, is a long term care expert and corporate pharmacy consultant for Touchstone-Communities, a leading provider of senior care that includes skilled nursing care, memory care, and rehabilitation for older adults throughout Texas. He’s a past director of the American Society of Consultant Pharmacists and was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the Excellence in Geriatric Pharmacy Practice Award.

References
1. Sauerwein K. Heartburn drugs linked to fatal heart and kidney disease, stomach cancer. Washington University School of Medicine in St. Louis website. https://medicine.wustl.edu/news/popular-heartburn-drugs-linked-to-fatal-heart-disease-chronic-kidney-disease-stomach-cancer/. Published May 30, 2019.

2. Northuis CA, Bell EJ, Lutsey PL, et al. Cumulative use of proton pump inhibitors and risk of dementia: the Atherosclerosis Risk in Communities Study. Neurology. 2023;101(18):e1771-e1778.

3. Alzheimer’s disease facts and figures. Alzheimer’s Association website. https://www.alz.org/alzheimers-dementia/facts-figures

4. Boster J, Lowry LE, Bezzant ML, Kuiper B, Surry L. Reducing the jnappropriate use of proton pump inhibitors in an internal medicine residency clinic. Cureus. 2020;12(1):e6609.

5. Ladd AM, Panagopoulos G, Cohen J, Mar N, Graham R. Potential costs of inappropriate use of proton pump inhibitors. Am J Med Sci. 2014;347(6):446-451.

6. Kiecka A, Szczepanik M. Proton pump inhibitor-induced gut dysbiosis and immunomodulation: current knowledge and potential restoration by probiotics. Pharmacol Rep. 2023;75(4):791-804.

7. Almario CV, Chey WD, Spiegel BMR. Increased risk of COVID-19 among users of proton pump inhibitors. Am J Gastroenterol. 2020;115(10):1707-1715.

8. Al-Aly Z, Maddukuri G, Xie Y. Proton pump inhibitors and the kidney: implications of current evidence for clinical practice and when and how to deprescribe. Am J Kidney Dis. 2020;75(4):497-507.

9. Maideen NMP. Adverse effects associated with long-term use of roton pump inhibitors. Chonnam Med J. 2023;59(2):115-127.

10. Nochaiwong S, Ruengorn C, Awiphan R, et al. The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant. 2018;33(2):331-342.

11. Gao X, Shao ZY, Grysman N, Grossberg GT. Proton pump inhibitor use and risk of dementia in older adults: a systematic review. touchREVIEWS in Neurology. 2023;19(1). https://touchneurology.com/alzheimers-disease-dementia/journal-articles/proton-pump-inhibitor-use-and-risk-of-dementia-in-older-adults-a-systematic-review/

12. Vogiatzoglou A, Smith AD, Nurk E, et al. Cognitive function in an elderly population: interaction between vitamin B12 status, depression, and apolipoprotein E ε4: the Hordaland Homocysteine Study. Psychosom Med. 2013;75(1):20-29.

13. Ortiz-Guerrero G, Amador-Muñoz D, Calderón-Ospina CA, López-Fuentes D, Nava Mesa MO. Proton pump inhibitors and dementia: physiopathological mechanisms and clinical consequences. Neural Plast. 2018;2018:5257285.

14. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362(4):329-344.

15. Ortiz-Guerrero G, Amador-Muñoz D, Calderón-Ospina CA, López-Fuentes D, Nava Mesa MO. Proton pump inhibitors and dementia: physiopathological mechanisms and clinical consequences. Neural Plast. 2018;2018:5257285.

16. Kumar R, Kumar A, Nordberg A, Långström B, Darreh-Shori T. Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme—a plausible missing link for their association with incidence of dementia. Alzheimers Dement. 2020;16(7):1031-1042.