This is very interesting work, and the apparent role of PPIs in dementia is worthy of further investigation. We have studied [18F]lansoprazole and its derivatives as high-affinity PET radiotracers for tau neurofibriliary tangles (see Fawaz et al., 2014). However, we know that while derivatives have proven useful for imaging tau, at radiotracer doses in rats, monkeys, and humans, lansoprazole does not cross the blood-brain barrier (BBB) to enter the CNS because it is a P-glycoprotein (Pgp) substrate/inhibitor (see Pauli-Magnus et al., 2001). P-glycoprotein helps maintain the integrity of the BBB by pumping molecules that enter endothelial cells back into the blood. At the higher doses used for routine PPI therapy, lansoprazole could block Pgp activity. Since Pgp deficiency at the BBB is thought to increase amyloid-β deposition (see Cirrito et al., 2005), the proposed link between lansoprazole and dementia could be increased accumulation of amyloid as a result of Pgp inhibition. It remains to be determined whether all Pgp inhibitors and/or PPIs are correlated with increased dementia and if this is a medical class side effect, or whether it is specific to the PPIs tested in the present work. Either way, further clinical studies investigating the preliminary findings that connect PPIs to dementia are warranted.
References:
Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, Sherman P, Quesada CA, Hockley BG, Kilbourn MR, Albin RL, Frey KA, Scott PJ.
High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.
ACS Chem Neurosci. 2014 Aug 20;5(8):718-30. Epub 2014 Jun 16
PubMed.
Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF.
Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein.
Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):551-7.
PubMed.
Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM.
P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model.
J Clin Invest. 2005 Nov;115(11):3285-90.
PubMed.
This study by Gomm et al. examined a very large sample of nearly 74,000 patients in a large German administrative claims database and found higher risk of dementia among those with regular proton-pump inhibitor (PPI) use than in those not using PPIs at all over a period of up to seven years. The database study results confirm previous analyses in a smaller, complementary, clinic-based study with more direct and detailed observations. Given the numbers of older adults on long-term PPI therapy (2-3 percent in the United States as suggested by Kuller’s commentary), understanding any cognitive risks involved is critical.
That being said, the study has some limitations worth pointing out: 1) The authors assessed associations between PPI use and a coded billing claim of dementia, not a clinical diagnosis of dementia. Much dementia is clinically unrecognized, or at least uncoded, and there are likely false positives as well. 2) A second issue is that PPIs may be more often used long-term to treat gastrointestinal complications from NSAID use in secondary prevention for cardiovascular disease. Because cardiovascular risk factors and cardiovascular disease increase risk for dementia, this means that long-term PPI use probably occurs more frequently among patients with higher underlying risk for dementia. The authors attempt to counter this issue by adjusting for ischemic heart disease and stroke diagnoses, but the related diagnostic codes likely also involve some misclassification, so confounding of this sort may only be partially resolved. 3) The analyses excluded participants based on their entire PPI use trajectory over many years, specifically dropping those with intermittent use throughout follow-up, which relies on very strong assumptions about how confounding factors are related to prior PPI use. Some of these issues might be resolved in large cohort studies that have both clinically validated dementia diagnoses and linkable prescription dispensing claims. Using such data, more sophisticated modelling approaches could be used to appropriately censor patients when they stop taking PPIs regularly.
The study's findings (along with the earlier clinical study) are certainly concerning. Whether or not the methodological limitations are first-, second-, or third-order issues remains to be resolved. Hopefully, other investigators will work to confirm these findings in other databases with appropriate study designs and analytic tools.
Comments
The University of Michigan
This is very interesting work, and the apparent role of PPIs in dementia is worthy of further investigation. We have studied [18F]lansoprazole and its derivatives as high-affinity PET radiotracers for tau neurofibriliary tangles (see Fawaz et al., 2014). However, we know that while derivatives have proven useful for imaging tau, at radiotracer doses in rats, monkeys, and humans, lansoprazole does not cross the blood-brain barrier (BBB) to enter the CNS because it is a P-glycoprotein (Pgp) substrate/inhibitor (see Pauli-Magnus et al., 2001). P-glycoprotein helps maintain the integrity of the BBB by pumping molecules that enter endothelial cells back into the blood. At the higher doses used for routine PPI therapy, lansoprazole could block Pgp activity. Since Pgp deficiency at the BBB is thought to increase amyloid-β deposition (see Cirrito et al., 2005), the proposed link between lansoprazole and dementia could be increased accumulation of amyloid as a result of Pgp inhibition. It remains to be determined whether all Pgp inhibitors and/or PPIs are correlated with increased dementia and if this is a medical class side effect, or whether it is specific to the PPIs tested in the present work. Either way, further clinical studies investigating the preliminary findings that connect PPIs to dementia are warranted.
References:
Fawaz MV, Brooks AF, Rodnick ME, Carpenter GM, Shao X, Desmond TJ, Sherman P, Quesada CA, Hockley BG, Kilbourn MR, Albin RL, Frey KA, Scott PJ. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection. ACS Chem Neurosci. 2014 Aug 20;5(8):718-30. Epub 2014 Jun 16 PubMed.
Pauli-Magnus C, Rekersbrink S, Klotz U, Fromm MF. Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. Naunyn Schmiedebergs Arch Pharmacol. 2001 Dec;364(6):551-7. PubMed.
Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB, Jiang H, Prior JL, Sagare A, Bales KR, Paul SM, Zlokovic BV, Piwnica-Worms D, Holtzman DM. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. J Clin Invest. 2005 Nov;115(11):3285-90. PubMed.
View all comments by Peter ScottThis study by Gomm et al. examined a very large sample of nearly 74,000 patients in a large German administrative claims database and found higher risk of dementia among those with regular proton-pump inhibitor (PPI) use than in those not using PPIs at all over a period of up to seven years. The database study results confirm previous analyses in a smaller, complementary, clinic-based study with more direct and detailed observations. Given the numbers of older adults on long-term PPI therapy (2-3 percent in the United States as suggested by Kuller’s commentary), understanding any cognitive risks involved is critical.
That being said, the study has some limitations worth pointing out: 1) The authors assessed associations between PPI use and a coded billing claim of dementia, not a clinical diagnosis of dementia. Much dementia is clinically unrecognized, or at least uncoded, and there are likely false positives as well. 2) A second issue is that PPIs may be more often used long-term to treat gastrointestinal complications from NSAID use in secondary prevention for cardiovascular disease. Because cardiovascular risk factors and cardiovascular disease increase risk for dementia, this means that long-term PPI use probably occurs more frequently among patients with higher underlying risk for dementia. The authors attempt to counter this issue by adjusting for ischemic heart disease and stroke diagnoses, but the related diagnostic codes likely also involve some misclassification, so confounding of this sort may only be partially resolved. 3) The analyses excluded participants based on their entire PPI use trajectory over many years, specifically dropping those with intermittent use throughout follow-up, which relies on very strong assumptions about how confounding factors are related to prior PPI use. Some of these issues might be resolved in large cohort studies that have both clinically validated dementia diagnoses and linkable prescription dispensing claims. Using such data, more sophisticated modelling approaches could be used to appropriately censor patients when they stop taking PPIs regularly.
The study's findings (along with the earlier clinical study) are certainly concerning. Whether or not the methodological limitations are first-, second-, or third-order issues remains to be resolved. Hopefully, other investigators will work to confirm these findings in other databases with appropriate study designs and analytic tools.
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