Proton pump inhibitor drugs could increase the risk of developing dementia

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Millions of people around the world use proton pump inhibitors for conditions like heartburn, gastritis and stomach ulcers. Researchers at Karolinska Institutet in Sweden now report that the long-term use of these drugs could increase the risk of developing dementia. Their results are published in the journal Alzheimer’s & Dementia.

“We’ve been able to show that proton pump inhibitors affect the synthesis of the neurotransmitter acetylcholine, which plays a significant part in conditions such as Alzheimer’s disease,” says Taher Darreh-Shori, senior researcher at the Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.

“Since there’s no effective treatment for the disease, it’s important to avoid risk factors. We therefore want to draw attention to this so that the drugs aren’t used needlessly for a long time.”

Proton pump inhibitors (PPIs) work by blocking the pumps that transport acidic hydrogen ions from the cells that form the mucosa. When the pumps are out of action, there is a reduction in acid, and ultimately, the corrosive damage it does to tissue.

Population studies have previously shown higher rates of dementia in people using PPIs, but the connection was unclear until now.

First, the researchers used 3-D computer simulations to examine how six PPI variants based on different active substances interacted with an enzyme called choline acetyletransferase, the function of which is to synthesize the neurotransmitter acetylcholine.

As a neurotransmitter, acetylcholine is needed for passing signals among nerve cells, but this only works if enough of the substance is produced. The simulations showed that all the tested drugs were able to bind with the enzyme.

The researchers then analyzed the effect of this binding. They found that all the drugs inhibited the enzyme, resulting in a reduced production of acetylcholine, where the stronger the binding, the stronger the inhibitory effect.

Drugs based on the active substances omeprazole, esomeprazole, tenatoprazole and rabeprazole had the greatest affinity and were therefore the strongest inhibitors of the enzyme, while the variants pantoprazole and lansoprazole were the weakest (see illustration).

Proton pump inhibitors’ effect on the enzyme that synthesizes the neurotransmitter acetylcholine. Credit: Taher Darreh-Shori

Complementary studies are now needed to examine whether these laboratory observations represent what occurs in the body. However, Darreh-Shori is already advising against the overuse of PPIs.

“Special care should be taken with the more elderly patients and those already diagnosed with dementia,” he says. “The same also applies to patients with muscle weakness diseases such as ALS, as acetylcholine is an essential motor neurotransmitter.

In such cases, doctors should use the drugs that have the weakest effect and prescribe them at lowest dose and for as short a time as possible.”

“I would, however, like to stress that the correct use of the drugs is safe also in the elderly, as long as the drugs are used for a limited time and when they’re really needed, as our nervous system is pretty flexible when it comes to tolerating short-term impact,” he adds.


A number of risk factors have been described as being associated with dementia including low educational attainment, midlife obesity, hypertension, diabetes mellitus, smoking and physical inactivity [4, 5]. In two pharmacoepidemiological cohort studies, the use of proton‐pump inhibitors (PPIs) was shown to constitute another risk factor for dementia [6, 7], which, however, was in contrast to other studies [8, 9]. Methodological differences between the reported studies have been discussed as contributing to the disparity of the findings, highlighting the insufficient bias limitation in studies reporting an association between PPI use and dementia [10].

Proton‐pump inhibitors are among the most widely prescribed medications [11] and associated with a number of adverse effects including renal disease, hypomagnesaemia, infections and osteoporotic fractures [12]. With regard to these adverse events, two recent observational cohort studies reported an increased risk of death associated with the use of PPIs [13, 14].

PPIs have also been suggested to have a specific effect on Alzheimer’s disease pathophysiology [15] and, potentially, Alzheimer’s disease progression. Potential biological mechanisms underlying the detrimental effect of PPIs could be related to an impairment of autophagy and lysosomal acidification by inhibition of vacuolar H+ ATPases and were shown to be associated with telomere erosion and the accelerated senescence of endothelial cells [16].

The use of PPIs might thus represent a frequent and modifiable risk factor in dementia patients with the need to better understand their impact on disease course and survival. For this purpose, we used a large national Austrian prescription database to assess the impact of the cumulative PPI exposure on survival in patients with dementia and matched controls.

Results

A total of 28 428 individuals with dementia were identified by ADD prescriptions with females constituting 67.8% of the cohort and a median age at the index date of 82.1 years (interquartile range, 76.7–86.6).

There were 14 640 deaths (51.5%) in the dementia cohort during the study period, which resulted in a median survival of 1625 days [95% confidence intervals (CI), 1598–1652]. In the control cohort of 56 856 individuals, 20 484 (36.0%) persons died during the study period and survival was significantly longer compared with dementia patients with a median duration of 3356 days (95% CI, 3312–3400; P < 0.0001) 

(Tables 1 and 2).

Table 1. Characteristics of patients with dementia and controls: a control‐matched cohort study in Austria (January 2005 to June 2016)

 Patients with dementiaControls
TotalPPI userPPI non‐userTotalPPI userPPI non‐user
n28 428 (100%)12 979 (45.7%)15 449 (54.3%)56 856 (100%)21 948 (38.6%)34 908 (61.4%)
Sex (female)19 267 (67.8%)8935 (68.8%)10 332 (66.9%)38 779 (68.2%)15 360 (70.0%)23 419 (67.1%)
Age at index date (years)82.1 (76.7–86.6)82.2 (76.8–86.6)82.1 (76.6–86.6)82.3 (77.2–85.9)82.8 (77.9–86.5)82.0 (76.7–85.6)
Age group (years)
<50142 (0.5%)58 (0.4%)84 (0.5%)105 (0.2%)25 (0.1%)80 (0.2%)
50–59395 (1.4%)186 (1.4%)209 (1.4%)554 (1.0%)168 (0.8%)386 (1.1%)
60–691943 (6.8%)846 (6.5%)1097 (7.1%)3883 (6.8%)1240 (5.6%)2643 (7.6%)
70–798530 (30.0%)3909 (30.1%)4621 (29.9%)16 161 (28.4%)5933 (27.0%)10 228 (29.3%)
80–8914 753 (51.9%)6796 (52.4%)7957 (51.5%)31 324 (55.1%)12 334 (56.2%)18 990 (54.4%)
≥902665 (9.4%)1184 (9.1%)1481 (9.6%)4829 (8.5%)2248 (10.2%)2581 (7.4%)
ATC9.0 (4.0–14.0)13 (9–19)5 (2–9)10.0 (6.0–16.0)13 (8–19)9 (5–14)
ATC groups
≤24662 (16.4%)74 (0.6%)4588 (29.7%)2154 (3.8%)424 (1.9%)1730 (5.0%)
3–77958 (28.0%)2214 (17.1%)5744 (37.2%)16 939 (29.8%)4334 (19.7%)12 605 (36.1%)
8–126859 (24.1%)3646 (28.1%)3213 (20.8%)15 675 (27.6%)5943 (27.1%)9732 (27.9%)
13–174224 (14.9%)2999 (23.1%)1225 (7.9%)10 086 (17.7%)4593 (20.9%)5493 (15.7%)
18–222414 (8.5%)1955 (15.1)459 (3.0)6023 (10.6)3136 (14.3)2887 (8.3)
≥232311 (8.1%)2.091 (16.1%)220 (1.4%)5979 (10.5%)3518 (16.0%)2461 (7.0%)
PPI use (before index date) cDDD173 ± 152145 ± 139
PPI use (after index date) cDDD460 ± 595198 ± 421603 ± 730219 ± 469
NSAID user7862 (27.7%)5569 (42.9%)2293 (14.8%)18 888 (33.2%)10 522 (47.9%)8366 (24.0%)
  • ATC, anatomical therapeutic chemical classification system; cDDD, cumulative defined daily dose; NSAID, non‐steroidal anti‐inflammatory drug; PPI, proton‐pump inhibitor. Data are given as n (%), median (interquartile range) and mean ± SD.

Table 2. Effect of proton‐pump inhibitor (PPI) use on survival in patients with dementia and controls: a multivariate Cox regression analysis for non‐proportional hazards in a control‐matched cohort study in Austria (January 2005 to June 2016)

 Patients with dementiaControls
TotalDeathsAdjusted HR (95% CI) per 100 DDDsTotalDeathsAdjusted HR (95% CI) per 100 DDDs
Overall effect a28 42819 267 (67.8%)1.03 (1.01–1.05)56 85620 484 (36.0%)1.15 (1.05–1.26)
Overall effectb10 5915634 (53.2%)1.07 (1.03–1.12)18 8926436 (34.1%)1.47 (1.31–1.64)
Time‐dependent effect (years after index date)b
010 5911953 (18.4%)1.61 (1.50–1.72)18 8921248 (6.6%)3.45 (3.32–3.58)
186381248 (14.4%)1.22 (1.17–1.28)176441046 (5.9%)2.01 (1.95–2.08)
273901104 (14.9%)1.00 (0.94–1.06)16 5981055 (6.4%)1.38 (1.31–1.45)
35172754 (14.6%)0.94 (0.89–1.00)13 361850 (6.4%)1.27 (1.20–1.33)
42595336 (12.9%)0.98 (0.93–1.03)8761630 (7.2%)1.40 (1.34–1.46)
51095162 (14.8%)1.02 (0.97–1.08)6394436 (6.8%)1.55 (1.48–1.63)
637444 (11.8%)1.03 (0.97–1.09)5507410 (7.4%)1.57 (1.49–1.65)
717415 (8.6%)0.99 (0.91–1.08)4710401 (8.5%)1.47 (1.40–1.54)
88015 (18.8%)0.94 (0.80–1.08)3567301 (8.4%)1.30 (1.20–1.39)
9273 (11.1%)0.87 (0.65–1.10)161542 (2.6%)1.10 (0.95–1.25)
1070 (0.0%)0.80 (0.49–1.12)28917 (5.9%)0.92 (0.70–1.14)
  • CI, confidence intervals; DDD, defined daily dose; HR, hazard ratio. Data are given as n (%) unless otherwise stated.
  • a Including cases and controls with PPI exposure after the index date.
  • b Excluding cases and controls with PPI exposure after the index date.

Proton‐pump inhibitor exposure is associated with an increased risk of death

In the dementia cohort, 12 979 individual cases (45.7%) were exposed to PPIs with at least one prescription and a mean cDDD of 173 ± 152 in the year preceding the index date (Table 1). The use of PPIs prior to the index date was significantly associated with an increased risk of death (adjusted HR per 100 DDDs of PPIs, 1.03; 95% CI, 1.01–1.05; P = 0.0069) (Table 2). In the control cohort, the proportion of individuals exposed to PPIs in the year before the index date was significantly lower (n = 21 948, 38.6% of the total cohort, P < 0.0001, chi‐squared test) with a mean cDDD of 145 ± 139 (Table 1). PPI exposure was significantly associated with an increased risk of death in the control cohort (adjusted HR per 100 DDDs of PPIs, 1.15; 95% CI, 1.05‐1.26; P = 0.0028) (Table 2).

The association between PPI exposure and risk of death was stronger in controls compared with dementia patients (P < 0.0001), but controls exposed to PPIs in the year before the index date also had a higher PPI usage thereafter (mean cDDD of 603 ± 730 in controls and 460 ± 595 in patients with dementia), which could have contributed to the difference. To account for this bias, Cox regression analyses were repeated in patients with dementia and controls without any PPI use after the index date (37.3% of patients with dementia and 33.2% of controls, respectively) (Table 2). PPI exposure was still associated with an increased risk of death in both patients with dementia (adjusted HR per 100 DDDs of PPIs, 1.07; 95% CI, 1.03‐1.12; P = 0.0008) and the control cohort (adjusted HR per 100 DDDs of PPIs, 1.47; 95% CI, 1.31‐1.64; P < 0.0001) with a significantly stronger detrimental effect of PPI exposure on survival in controls compared with dementia patients (P < 0.0001). As further analysis of our model did not fulfill the proportional hazards assumption, we sought to better describe the time at which the effect was strongest. In both patients with dementia and controls, adjusted HRs were highest at the beginning and decreased over time, plateauing at about 2 years after the index date (Fig. 1 and Table 2). Age at the index date and cardiovascular risk [14] were not associated with an excess of mortality upon PPI exposure (data not shown).

image
Figure 1

Survival of patients with dementia and controls in relation to the use of proton‐pump inhibitors (PPIs). (a) Median survival in patients with dementia exposed to PPIs before the index date was 1596 days [95% confidence intervals (CI), 1555–1637] and median survival in dementia patients without PPIs was 1655 days (95% CI, 1619–1691) (P = 0.0011). (b) Median survival in controls exposed to PPIs before the index date was 2921 days (95% CI, 2864–2978) and median survival in controls without PPIs was 3657 days (95% CI, 3647–3667) (P < 0.0001).

Time‐dependent multivariate Cox regression analysis for non‐proportional hazards in relation to 100 defined daily doses (DDDs) of PPIs in patients with dementia (c) and controls (d). HR, hazard ratio.

References


More information: “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,” Rajnish Kumar, Amit Kumar, Agneta Nordberg, Bengt Långström and Taher Darreh-Shori, Alzheimer’s & Dementia, online May 8, 2020, DOI: 10.1002/alz.12113

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