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Long-term use of proton pump inhibitors was significantly associated with later diagnoses of dementia in adults aged 75 years and older in a prospective cohort study of more than 73,000 individuals. The findings were published online Feb. 15 in JAMA Neurology.
Overall, the risk of incident dementia was 44% higher among the 2,950 patients who received regular proton pump inhibitors, compared with 70,729 who didn’t receive PPIs (hazard ratio of 1.44), according to Willy Gomm, Ph.D., of the German Center for Neurodegenerative Diseases in Bonn, and his colleagues.
To assess the potential link between PPIs and dementia, the researchers reviewed data from a German insurance database during 2004-2011. The study population included 73,679 community-dwelling adults aged 75 years and older who were free of dementia at the start of the study (JAMA Neurol. 2016 Feb 15. doi: 10.1001/jamaneurol.2015.4791). The patients taking PPIs were slightly but significantly older than those not taking PPIs and had a higher proportion of women (P less than .001 for both). PPI users were also significantly more likely than nonusers to have a history of depression, stroke, coronary disease, and use of polypharmacy (P less than .001 for each).
The risk of incident dementia decreased with age, from 69% for patients aged 75-79 years to 49% among those 80-84-years and 32% among those aged 85 years and older.
In addition, the risk of dementia was not significantly different based on specific drug in a subgroup analysis of the three most often prescribed PPIs, omeprazole, pantoprazole, and esomeprazole, for which the hazard ratios were 1.51, 1.58, and 2.12, respectively.
“If PPIs have adverse effects, it is important to be aware of them,” Dr. Daniel E. Freedberg of Columbia University, New York, said in an interview. “When PPIs are indicated, the preponderance of data indicate that their benefits outweigh their potential risks,” he added. “Clinicians should reassure patients that this was a single study and that previous studies have reached different conclusions. Clinicians should focus on whether or not PPIs are indicated rather than on PPI side effects.”
Dr. Freedberg also noted several key limitations of the study.
“First, the authors were unable to adjust for crucial variables that might explain a noncausal link between PPIs and dementia. For example, lower socioeconomic status is an established predictor of dementia and may also be associated with PPI use. However, the authors could not capture socioeconomic status.
“Second, patients who use PPIs have more frequent and more intensive health care interactions than patients who do not use PPIs. These patients are thus also more likely to be diagnosed with dementia. This is another source for bias that the authors were not able to capture. Third, clinicians should be aware that this study was designed to compare extremes of PPI use,” Dr. Freedberg emphasized.
In addition, “In the primary analysis, patients were classified as exposed to PPIs only if they received at least one PPI prescription every 3 months for an 18-month period. Patients who used occasional PPIs were excluded from the study,” said Dr. Freedberg.
“The present study can only provide a statistical association between PPI use and risk of dementia,” the researchers noted. “The possible underlying causal biological mechanism has to be explored in future studies,” they wrote.
The researchers had no financial conflicts to disclose.
Challenging research lies ahead
The researchers have provided an important and interesting challenge to evaluate the possible association of the use of PPIs and the risk of dementia.
 |
Dr. Lewis H. Kuller |
Further determinants of whether PPIs are causal for dementia requires validation in large cohorts and probably in well-designed case-control studies with good measures of long-term PPI use, covariates, and especially methods to measure incidence of dementia.
Dr. Lewis H. Kuller is affiliated with the department of epidemiology at the University of Pittsburgh. He made his remarks in an accompanying editorial and had no financial conflicts to disclose.
PPIs and dementia: More of much ado about nothing?
This study has attracted considerable media attention. Unfortunately, this was somewhat unbalanced. One TV news program stated that there was a “44% increased risk of dementia.” Many of our patients would not be able to interpret that appropriately – let alone weigh the potential risks and benefits of PPI treatment.
The 44% increase is derived from the hazard ratio of 1.44 that the investigators reported. However, to quote Dr. David A. Grimes and Dr. Kenneth F. Schulz, “Any claim coming from an observational study is most likely to be wrong. Of the reported associations that are correct, most are exaggerated” (Obstet Gynecol. 2012;120:920-7).
In the German study, the patients who had been taking PPIs were more likely to have prior diagnoses of depression, stroke, and ischemic heart disease than those not on PPIs. They were also much more likely to be on multiple other medicines. These patients may have been more likely to be given a PPI because of their comorbidity. There may, therefore, be an element of channeling bias or confounding by indication to explain the findings.
However, let us assume that there had been a stronger suggestion of a causal association between PPI use and the risk of developing dementia. It would be important to consider what its underlying biological rationale might be. The investigators state that PPI use “has been shown to be potentially involved in cognitive decline.” The evidence offered in support of this claim comes from a case-control study that did not evaluate cognitive function but reported an increased incidence of vitamin B12 deficiency among adults taking PPIs for 2 or more years [very small odds ratio of 1.65 (JAMA 2013;310:2435-42)]. Low B12 levels were linked to “cognitive deficit” in a population-based study from Norway (Psychosom Med. 2013;75:20-9). So, the proposed biological rationale for any association between PPI use and dementia is tenuous at best.
For PPIs, long-term or indefinite use is appropriate for indications such as erosive esophagitis, esophageal stricture, or the prevention of upper GI tract ulcers and ulcer bleeding in patients taking aspirin or NSAIDs. Patients with a valid indication for PPI treatment should continue to receive it for as long as clinically indicated – and at the lowest effective dose. It would be unfortunate if patients with indications for PPI treatment discontinued it on the basis of this study.
Dr. Colin W. Howden, AGAF, is Hyman Professor of Medicine, chief of the division of gastroenterology, University of Tennessee Health Science Center, Memphis. He is a consultant for Takeda, Otsuka, Ironwood, Allergan, Aralez, and Pfizer Consumer Health.
Challenging research lies ahead
The researchers have provided an important and interesting challenge to evaluate the possible association of the use of PPIs and the risk of dementia.
|
Dr. Lewis H. Kuller |
Further determinants of whether PPIs are causal for dementia requires validation in large cohorts and probably in well-designed case-control studies with good measures of long-term PPI use, covariates, and especially methods to measure incidence of dementia.
Dr. Lewis H. Kuller is affiliated with the department of epidemiology at the University of Pittsburgh. He made his remarks in an accompanying editorial and had no financial conflicts to disclose.
PPIs and dementia: More of much ado about nothing?
This study has attracted considerable media attention. Unfortunately, this was somewhat unbalanced. One TV news program stated that there was a “44% increased risk of dementia.” Many of our patients would not be able to interpret that appropriately – let alone weigh the potential risks and benefits of PPI treatment.
The 44% increase is derived from the hazard ratio of 1.44 that the investigators reported. However, to quote Dr. David A. Grimes and Dr. Kenneth F. Schulz, “Any claim coming from an observational study is most likely to be wrong. Of the reported associations that are correct, most are exaggerated” (Obstet Gynecol. 2012;120:920-7).
In the German study, the patients who had been taking PPIs were more likely to have prior diagnoses of depression, stroke, and ischemic heart disease than those not on PPIs. They were also much more likely to be on multiple other medicines. These patients may have been more likely to be given a PPI because of their comorbidity. There may, therefore, be an element of channeling bias or confounding by indication to explain the findings.
However, let us assume that there had been a stronger suggestion of a causal association between PPI use and the risk of developing dementia. It would be important to consider what its underlying biological rationale might be. The investigators state that PPI use “has been shown to be potentially involved in cognitive decline.” The evidence offered in support of this claim comes from a case-control study that did not evaluate cognitive function but reported an increased incidence of vitamin B12 deficiency among adults taking PPIs for 2 or more years [very small odds ratio of 1.65 (JAMA 2013;310:2435-42)]. Low B12 levels were linked to “cognitive deficit” in a population-based study from Norway (Psychosom Med. 2013;75:20-9). So, the proposed biological rationale for any association between PPI use and dementia is tenuous at best.
For PPIs, long-term or indefinite use is appropriate for indications such as erosive esophagitis, esophageal stricture, or the prevention of upper GI tract ulcers and ulcer bleeding in patients taking aspirin or NSAIDs. Patients with a valid indication for PPI treatment should continue to receive it for as long as clinically indicated – and at the lowest effective dose. It would be unfortunate if patients with indications for PPI treatment discontinued it on the basis of this study.
Dr. Colin W. Howden, AGAF, is Hyman Professor of Medicine, chief of the division of gastroenterology, University of Tennessee Health Science Center, Memphis. He is a consultant for Takeda, Otsuka, Ironwood, Allergan, Aralez, and Pfizer Consumer Health.
Challenging research lies ahead
The researchers have provided an important and interesting challenge to evaluate the possible association of the use of PPIs and the risk of dementia.
|
Dr. Lewis H. Kuller |
Further determinants of whether PPIs are causal for dementia requires validation in large cohorts and probably in well-designed case-control studies with good measures of long-term PPI use, covariates, and especially methods to measure incidence of dementia.
Dr. Lewis H. Kuller is affiliated with the department of epidemiology at the University of Pittsburgh. He made his remarks in an accompanying editorial and had no financial conflicts to disclose.
PPIs and dementia: More of much ado about nothing?
This study has attracted considerable media attention. Unfortunately, this was somewhat unbalanced. One TV news program stated that there was a “44% increased risk of dementia.” Many of our patients would not be able to interpret that appropriately – let alone weigh the potential risks and benefits of PPI treatment.
The 44% increase is derived from the hazard ratio of 1.44 that the investigators reported. However, to quote Dr. David A. Grimes and Dr. Kenneth F. Schulz, “Any claim coming from an observational study is most likely to be wrong. Of the reported associations that are correct, most are exaggerated” (Obstet Gynecol. 2012;120:920-7).
In the German study, the patients who had been taking PPIs were more likely to have prior diagnoses of depression, stroke, and ischemic heart disease than those not on PPIs. They were also much more likely to be on multiple other medicines. These patients may have been more likely to be given a PPI because of their comorbidity. There may, therefore, be an element of channeling bias or confounding by indication to explain the findings.
However, let us assume that there had been a stronger suggestion of a causal association between PPI use and the risk of developing dementia. It would be important to consider what its underlying biological rationale might be. The investigators state that PPI use “has been shown to be potentially involved in cognitive decline.” The evidence offered in support of this claim comes from a case-control study that did not evaluate cognitive function but reported an increased incidence of vitamin B12 deficiency among adults taking PPIs for 2 or more years [very small odds ratio of 1.65 (JAMA 2013;310:2435-42)]. Low B12 levels were linked to “cognitive deficit” in a population-based study from Norway (Psychosom Med. 2013;75:20-9). So, the proposed biological rationale for any association between PPI use and dementia is tenuous at best.
For PPIs, long-term or indefinite use is appropriate for indications such as erosive esophagitis, esophageal stricture, or the prevention of upper GI tract ulcers and ulcer bleeding in patients taking aspirin or NSAIDs. Patients with a valid indication for PPI treatment should continue to receive it for as long as clinically indicated – and at the lowest effective dose. It would be unfortunate if patients with indications for PPI treatment discontinued it on the basis of this study.
Dr. Colin W. Howden, AGAF, is Hyman Professor of Medicine, chief of the division of gastroenterology, University of Tennessee Health Science Center, Memphis. He is a consultant for Takeda, Otsuka, Ironwood, Allergan, Aralez, and Pfizer Consumer Health.
Long-term use of proton pump inhibitors was significantly associated with later diagnoses of dementia in adults aged 75 years and older in a prospective cohort study of more than 73,000 individuals. The findings were published online Feb. 15 in JAMA Neurology.
Overall, the risk of incident dementia was 44% higher among the 2,950 patients who received regular proton pump inhibitors, compared with 70,729 who didn’t receive PPIs (hazard ratio of 1.44), according to Willy Gomm, Ph.D., of the German Center for Neurodegenerative Diseases in Bonn, and his colleagues.
To assess the potential link between PPIs and dementia, the researchers reviewed data from a German insurance database during 2004-2011. The study population included 73,679 community-dwelling adults aged 75 years and older who were free of dementia at the start of the study (JAMA Neurol. 2016 Feb 15. doi: 10.1001/jamaneurol.2015.4791). The patients taking PPIs were slightly but significantly older than those not taking PPIs and had a higher proportion of women (P less than .001 for both). PPI users were also significantly more likely than nonusers to have a history of depression, stroke, coronary disease, and use of polypharmacy (P less than .001 for each).
The risk of incident dementia decreased with age, from 69% for patients aged 75-79 years to 49% among those 80-84-years and 32% among those aged 85 years and older.
In addition, the risk of dementia was not significantly different based on specific drug in a subgroup analysis of the three most often prescribed PPIs, omeprazole, pantoprazole, and esomeprazole, for which the hazard ratios were 1.51, 1.58, and 2.12, respectively.
“If PPIs have adverse effects, it is important to be aware of them,” Dr. Daniel E. Freedberg of Columbia University, New York, said in an interview. “When PPIs are indicated, the preponderance of data indicate that their benefits outweigh their potential risks,” he added. “Clinicians should reassure patients that this was a single study and that previous studies have reached different conclusions. Clinicians should focus on whether or not PPIs are indicated rather than on PPI side effects.”
Dr. Freedberg also noted several key limitations of the study.
“First, the authors were unable to adjust for crucial variables that might explain a noncausal link between PPIs and dementia. For example, lower socioeconomic status is an established predictor of dementia and may also be associated with PPI use. However, the authors could not capture socioeconomic status.
“Second, patients who use PPIs have more frequent and more intensive health care interactions than patients who do not use PPIs. These patients are thus also more likely to be diagnosed with dementia. This is another source for bias that the authors were not able to capture. Third, clinicians should be aware that this study was designed to compare extremes of PPI use,” Dr. Freedberg emphasized.
In addition, “In the primary analysis, patients were classified as exposed to PPIs only if they received at least one PPI prescription every 3 months for an 18-month period. Patients who used occasional PPIs were excluded from the study,” said Dr. Freedberg.
“The present study can only provide a statistical association between PPI use and risk of dementia,” the researchers noted. “The possible underlying causal biological mechanism has to be explored in future studies,” they wrote.
The researchers had no financial conflicts to disclose.
Long-term use of proton pump inhibitors was significantly associated with later diagnoses of dementia in adults aged 75 years and older in a prospective cohort study of more than 73,000 individuals. The findings were published online Feb. 15 in JAMA Neurology.
Overall, the risk of incident dementia was 44% higher among the 2,950 patients who received regular proton pump inhibitors, compared with 70,729 who didn’t receive PPIs (hazard ratio of 1.44), according to Willy Gomm, Ph.D., of the German Center for Neurodegenerative Diseases in Bonn, and his colleagues.
To assess the potential link between PPIs and dementia, the researchers reviewed data from a German insurance database during 2004-2011. The study population included 73,679 community-dwelling adults aged 75 years and older who were free of dementia at the start of the study (JAMA Neurol. 2016 Feb 15. doi: 10.1001/jamaneurol.2015.4791). The patients taking PPIs were slightly but significantly older than those not taking PPIs and had a higher proportion of women (P less than .001 for both). PPI users were also significantly more likely than nonusers to have a history of depression, stroke, coronary disease, and use of polypharmacy (P less than .001 for each).
The risk of incident dementia decreased with age, from 69% for patients aged 75-79 years to 49% among those 80-84-years and 32% among those aged 85 years and older.
In addition, the risk of dementia was not significantly different based on specific drug in a subgroup analysis of the three most often prescribed PPIs, omeprazole, pantoprazole, and esomeprazole, for which the hazard ratios were 1.51, 1.58, and 2.12, respectively.
“If PPIs have adverse effects, it is important to be aware of them,” Dr. Daniel E. Freedberg of Columbia University, New York, said in an interview. “When PPIs are indicated, the preponderance of data indicate that their benefits outweigh their potential risks,” he added. “Clinicians should reassure patients that this was a single study and that previous studies have reached different conclusions. Clinicians should focus on whether or not PPIs are indicated rather than on PPI side effects.”
Dr. Freedberg also noted several key limitations of the study.
“First, the authors were unable to adjust for crucial variables that might explain a noncausal link between PPIs and dementia. For example, lower socioeconomic status is an established predictor of dementia and may also be associated with PPI use. However, the authors could not capture socioeconomic status.
“Second, patients who use PPIs have more frequent and more intensive health care interactions than patients who do not use PPIs. These patients are thus also more likely to be diagnosed with dementia. This is another source for bias that the authors were not able to capture. Third, clinicians should be aware that this study was designed to compare extremes of PPI use,” Dr. Freedberg emphasized.
In addition, “In the primary analysis, patients were classified as exposed to PPIs only if they received at least one PPI prescription every 3 months for an 18-month period. Patients who used occasional PPIs were excluded from the study,” said Dr. Freedberg.
“The present study can only provide a statistical association between PPI use and risk of dementia,” the researchers noted. “The possible underlying causal biological mechanism has to be explored in future studies,” they wrote.
The researchers had no financial conflicts to disclose.
FROM JAMA NEUROLOGY
Key clinical point: Proton pump inhibitors may add to the risk of dementia in older adults.
Major finding: The risk of incident dementia was 44% higher in adults who used PPIs long term, compared with those who did not.
Data source: The prospective cohort study included 73,679 adults aged 75 years and older.
Disclosures: The researchers had no financial conflicts to disclose.
