Published Ahead of Print on September 27, 2017 as 10.1212/WNL.0000000000004613
EDITORIAL
Oral antidiabetic drugs and dementia risk Does treatment matter?
Anne Fink, MSc Britta Haenisch, PhD
Correspondence to A. Fink: [email protected] Neurology® 2017;89:1–2
As the population ages, dementia grows as a public health problem. The rising life expectancy and the aging of the so-called baby boomer cohort translate to a substantial number of people reaching ages of high risk for age-related conditions like dementia. As a major cause of disability and dependency in elderly people, dementia puts social and economic burden on patients and their families and affects health care systems worldwide. In the absence of a cure, primary prevention will have the largest effect on the reduction of dementia occurrence.1 Thus, public health research should focus on the identification of modifiable risk factors for dementia. Diabetes mellitus is an established risk factor for dementia. Patients with diabetes have an increased risk for any dementia, Alzheimer disease, and vascular dementia.2 The exact mechanisms of cognitive impairment in diabetic patients remain unknown. The main contributors to diabetes-associated cognitive decline include hyperglycemia, decreased insulin secretion, obesity, increased oxidative stress, and inflammation.3 Diabetes not only promotes neurodegeneration but also induces cerebrovascular pathologies such as stroke, which in turn are further risk factors for dementia.4 Furthermore, patients with diabetes often have other comorbidities such as high blood pressure and cardiovascular disease that may contribute to the development of dementia. About 12%–14% of US adults have diabetes.5 An effective treatment could prevent harmful effects of diabetes on cognition. Several studies have examined the association of different antidiabetic medications and cognitive function. Results from epidemiologic studies conflict. Some found protective effects of oral antidiabetic medications such as metformin on dementia risk; others detected deleterious effects.6,7 In this issue of Neurology, Orkaby et al.8 have investigated the use of metformin vs the use of sulfonylureas on the risk of dementia in US veterans aged 65 years and older with diabetes. The retrospective cohort study of 28,640 veterans compares initially dementia-free new users of metformin with new users of sulfonylureas, each as monotherapy for at least 2 years. Metformin and sulfonylureas are the 2 most widely prescribed oral antidiabetic drugs in the United States.9 For
analyses, the national Veterans Administration clinical and administrative databases were linked to Medicare. Cox proportional hazard models with age as analysis time were used to estimate the risk of dementia. The authors developed a propensity score based on 23 variables on demographic information, functional status, and comorbidities, and applied inverse probability of treatment weighting methods to account for confounding by indication. After propensity score inverse probability of treatment weighting adjustments, the authors found a significant difference only in the age group ,75 years. Here, metformin users had a reduced risk of dementia compared to sulfonylurea users (hazard ratio 0.89, 95% confidence interval 0.79–0.99). In further subgroup analyses, metformin users aged ,75 years had decreased dementia risks if they had hemoglobin A1c values $7% and had good renal function. The authors conclude that metformin intake is possibly associated with more neuroprotection than the intake of sulfonylureas. Strengths of this study include the large sample size and the new user design to overcome potential prevalent user bias. However, the fact that the study population is predominantly male limits the generalizability of the results to the total US population. The analysis of claims data also has shortcomings including disease misclassification8 and the absence of information on education, lifestyle, and patients’ adherence to doctors’ recommendation. A healthy user bias whereby patients who adhere to therapy may also use more preventive health services cannot be ruled out. The fact that individuals could use other antidiabetic medications after 2 years of monotherapy may have unclear influence on dementia risk. In addition, the study did not investigate the potential effect of other risk-modifying medications such as anticholinergics or antihypertensive drugs. Nonetheless, the study by Orkaby et al.8 makes an important epidemiologic contribution to the current knowledge about the association between antidiabetic treatment and dementia risk. So far, conclusions and recommendations have had to remain tentative because of the modest and unstable nature of
See page xxx From the German Center for Neurodegenerative Diseases (A.F., B.H.), Bonn; and Rostock Center for the Study of Demographic Change (A.F.), Rostock, Germany. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2017 American Academy of Neurology
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
calculated adjusted protective effect of metformin over sulfonylureas. A recent systematic review analyzed the effect of treatments for type II diabetes on the development of cognitive impairment and dementia on data from 7 randomized controlled trials (RCTs) of 2 or more treatments for type II diabetes and captured cognitive function.10 Those authors did not find evidence that supported any specific treatment strategy for type II diabetes preventing or delaying cognitive impairment.10 However, the systematic review did not include a direct comparison between metformin and sulfonylureas. Prospective longitudinal studies and RCTs on the comparison of metformin vs sulfonylureas and vs other antidiabetic treatments are needed to further examine differences in the effect on cognitive decline. If such studies can establish a protective effect of a certain antidiabetic treatment strategy on cognition, specific and targeted diabetes treatment strategies may prevent subsequent dementia cases in patients with diabetes in the future.
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STUDY FUNDING No targeted funding reported.
9. DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Wu Y-T, Fratiglioni L, Matthews FE, et al. Dementia in western Europe: epidemiological evidence and implications for policy making. Lancet Neurol 2016;15:116–124.
2
Neurology 89
10.
Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 2013;4: 640–650. Gaspar JM, Baptista FI, Macedo MP, Ambrósio AF. Inside the diabetic brain: role of different players involved in cognitive decline. ACS Chem Neurosci 2016;7:131–142. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. J Am Med Assoc 2015; 314:1021–1029. Hsu C-C, Wahlqvist ML, Lee M-S, Tsai H-N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011;24:485–493. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case–control study. J Am Geriatr Soc 2012;60:916–921. Orkaby AR, Cho K, Cormack J, Gagnon DR, Driver JA. Metformin vs sulfonylurea use and risk of dementia in US veterans aged $65 years with diabetes. Neurology 2017;89:xx–xxx. Weng W, Liang Y, Kimball E, et al. Drug usage patterns and treatment costs in newly-diagnosed type 2 diabetes mellitus cases, 2007 vs 2012: findings from a large US healthcare claims database analysis. J Med Econ 2016; 19:655–662. Areosa SA, Vernooij R, González-Colaço HM, Martínez G. Effect of the treatment of type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev 2017;6:CD003804.
October 31, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Oral antidiabetic drugs and dementia risk: Does treatment matter? Anne Fink and Britta Haenisch Neurology published online September 27, 2017 DOI 10.1212/WNL.0000000000004613 This information is current as of September 27, 2017 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2017/09/27/WNL.0000000000 004613.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_dem entia All epidemiology http://www.neurology.org//cgi/collection/all_epidemiology
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2017 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Oral antidiabetic drugs and dementia risk Does treatment matter?
Anne Fink, MSc Britta Haenisch, PhD
Correspondence to A. Fink: [email protected] Neurology® 2017;89:1–2
As the population ages, dementia grows as a public health problem. The rising life expectancy and the aging of the so-called baby boomer cohort translate to a substantial number of people reaching ages of high risk for age-related conditions like dementia. As a major cause of disability and dependency in elderly people, dementia puts social and economic burden on patients and their families and affects health care systems worldwide. In the absence of a cure, primary prevention will have the largest effect on the reduction of dementia occurrence.1 Thus, public health research should focus on the identification of modifiable risk factors for dementia. Diabetes mellitus is an established risk factor for dementia. Patients with diabetes have an increased risk for any dementia, Alzheimer disease, and vascular dementia.2 The exact mechanisms of cognitive impairment in diabetic patients remain unknown. The main contributors to diabetes-associated cognitive decline include hyperglycemia, decreased insulin secretion, obesity, increased oxidative stress, and inflammation.3 Diabetes not only promotes neurodegeneration but also induces cerebrovascular pathologies such as stroke, which in turn are further risk factors for dementia.4 Furthermore, patients with diabetes often have other comorbidities such as high blood pressure and cardiovascular disease that may contribute to the development of dementia. About 12%–14% of US adults have diabetes.5 An effective treatment could prevent harmful effects of diabetes on cognition. Several studies have examined the association of different antidiabetic medications and cognitive function. Results from epidemiologic studies conflict. Some found protective effects of oral antidiabetic medications such as metformin on dementia risk; others detected deleterious effects.6,7 In this issue of Neurology, Orkaby et al.8 have investigated the use of metformin vs the use of sulfonylureas on the risk of dementia in US veterans aged 65 years and older with diabetes. The retrospective cohort study of 28,640 veterans compares initially dementia-free new users of metformin with new users of sulfonylureas, each as monotherapy for at least 2 years. Metformin and sulfonylureas are the 2 most widely prescribed oral antidiabetic drugs in the United States.9 For
analyses, the national Veterans Administration clinical and administrative databases were linked to Medicare. Cox proportional hazard models with age as analysis time were used to estimate the risk of dementia. The authors developed a propensity score based on 23 variables on demographic information, functional status, and comorbidities, and applied inverse probability of treatment weighting methods to account for confounding by indication. After propensity score inverse probability of treatment weighting adjustments, the authors found a significant difference only in the age group ,75 years. Here, metformin users had a reduced risk of dementia compared to sulfonylurea users (hazard ratio 0.89, 95% confidence interval 0.79–0.99). In further subgroup analyses, metformin users aged ,75 years had decreased dementia risks if they had hemoglobin A1c values $7% and had good renal function. The authors conclude that metformin intake is possibly associated with more neuroprotection than the intake of sulfonylureas. Strengths of this study include the large sample size and the new user design to overcome potential prevalent user bias. However, the fact that the study population is predominantly male limits the generalizability of the results to the total US population. The analysis of claims data also has shortcomings including disease misclassification8 and the absence of information on education, lifestyle, and patients’ adherence to doctors’ recommendation. A healthy user bias whereby patients who adhere to therapy may also use more preventive health services cannot be ruled out. The fact that individuals could use other antidiabetic medications after 2 years of monotherapy may have unclear influence on dementia risk. In addition, the study did not investigate the potential effect of other risk-modifying medications such as anticholinergics or antihypertensive drugs. Nonetheless, the study by Orkaby et al.8 makes an important epidemiologic contribution to the current knowledge about the association between antidiabetic treatment and dementia risk. So far, conclusions and recommendations have had to remain tentative because of the modest and unstable nature of
See page xxx From the German Center for Neurodegenerative Diseases (A.F., B.H.), Bonn; and Rostock Center for the Study of Demographic Change (A.F.), Rostock, Germany. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. © 2017 American Academy of Neurology
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
calculated adjusted protective effect of metformin over sulfonylureas. A recent systematic review analyzed the effect of treatments for type II diabetes on the development of cognitive impairment and dementia on data from 7 randomized controlled trials (RCTs) of 2 or more treatments for type II diabetes and captured cognitive function.10 Those authors did not find evidence that supported any specific treatment strategy for type II diabetes preventing or delaying cognitive impairment.10 However, the systematic review did not include a direct comparison between metformin and sulfonylureas. Prospective longitudinal studies and RCTs on the comparison of metformin vs sulfonylureas and vs other antidiabetic treatments are needed to further examine differences in the effect on cognitive decline. If such studies can establish a protective effect of a certain antidiabetic treatment strategy on cognition, specific and targeted diabetes treatment strategies may prevent subsequent dementia cases in patients with diabetes in the future.
2.
3.
4.
5.
6.
7.
8.
STUDY FUNDING No targeted funding reported.
9. DISCLOSURE The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.
REFERENCES 1. Wu Y-T, Fratiglioni L, Matthews FE, et al. Dementia in western Europe: epidemiological evidence and implications for policy making. Lancet Neurol 2016;15:116–124.
2
Neurology 89
10.
Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 2013;4: 640–650. Gaspar JM, Baptista FI, Macedo MP, Ambrósio AF. Inside the diabetic brain: role of different players involved in cognitive decline. ACS Chem Neurosci 2016;7:131–142. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006;5:64–74. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. J Am Med Assoc 2015; 314:1021–1029. Hsu C-C, Wahlqvist ML, Lee M-S, Tsai H-N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis 2011;24:485–493. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case–control study. J Am Geriatr Soc 2012;60:916–921. Orkaby AR, Cho K, Cormack J, Gagnon DR, Driver JA. Metformin vs sulfonylurea use and risk of dementia in US veterans aged $65 years with diabetes. Neurology 2017;89:xx–xxx. Weng W, Liang Y, Kimball E, et al. Drug usage patterns and treatment costs in newly-diagnosed type 2 diabetes mellitus cases, 2007 vs 2012: findings from a large US healthcare claims database analysis. J Med Econ 2016; 19:655–662. Areosa SA, Vernooij R, González-Colaço HM, Martínez G. Effect of the treatment of type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev 2017;6:CD003804.
October 31, 2017
ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Oral antidiabetic drugs and dementia risk: Does treatment matter? Anne Fink and Britta Haenisch Neurology published online September 27, 2017 DOI 10.1212/WNL.0000000000004613 This information is current as of September 27, 2017 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2017/09/27/WNL.0000000000 004613.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): All Cognitive Disorders/Dementia http://www.neurology.org//cgi/collection/all_cognitive_disorders_dem entia All epidemiology http://www.neurology.org//cgi/collection/all_epidemiology
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2017 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
