Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts

Galit Weinstein, Kendra L. Davis-Plourde, Sarah Conner, Jayandra J. Himali, Alexa S. Beiser, Anne Lee, Andreea M. Rawlings, Sanaz Sedaghat, Jie Ding, Erin Moshier, Cornelia M. Van Duijn, Michal S. Beeri, Elizabeth Selvin, M. Arfan Ikram, Lenore J. Launer, Mary N. Haan, Sudha Seshadri

Research output: Contribution to journalArticle

Abstract

Objective To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties. Research design and methods Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis. Results After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014 ±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was lifestyle change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity. Conclusions Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.

Original languageEnglish (US)
Article numbere0212293
JournalPloS one
Volume14
Issue number2
DOIs
StatePublished - Feb 1 2019

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metformin
sulfonylureas
dementia
Metformin
Alzheimer disease
Dementia
Brain
Alzheimer Disease
Cohort Studies
insulin
Insulin
brain
Medical problems
diabetes
glycemic control
cognition
Magnetic resonance imaging
Cognition
Linear Models
Aging of materials

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease : Pooled analysis from 5 cohorts. / Weinstein, Galit; Davis-Plourde, Kendra L.; Conner, Sarah; Himali, Jayandra J.; Beiser, Alexa S.; Lee, Anne; Rawlings, Andreea M.; Sedaghat, Sanaz; Ding, Jie; Moshier, Erin; Van Duijn, Cornelia M.; Beeri, Michal S.; Selvin, Elizabeth; Arfan Ikram, M.; Launer, Lenore J.; Haan, Mary N.; Seshadri, Sudha.

In: PloS one, Vol. 14, No. 2, e0212293, 01.02.2019.

Research output: Contribution to journalArticle

Weinstein, G, Davis-Plourde, KL, Conner, S, Himali, JJ, Beiser, AS, Lee, A, Rawlings, AM, Sedaghat, S, Ding, J, Moshier, E, Van Duijn, CM, Beeri, MS, Selvin, E, Arfan Ikram, M, Launer, LJ, Haan, MN & Seshadri, S 2019, 'Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts', PloS one, vol. 14, no. 2, e0212293. https://doi.org/10.1371/journal.pone.0212293
Weinstein, Galit ; Davis-Plourde, Kendra L. ; Conner, Sarah ; Himali, Jayandra J. ; Beiser, Alexa S. ; Lee, Anne ; Rawlings, Andreea M. ; Sedaghat, Sanaz ; Ding, Jie ; Moshier, Erin ; Van Duijn, Cornelia M. ; Beeri, Michal S. ; Selvin, Elizabeth ; Arfan Ikram, M. ; Launer, Lenore J. ; Haan, Mary N. ; Seshadri, Sudha. / Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease : Pooled analysis from 5 cohorts. In: PloS one. 2019 ; Vol. 14, No. 2.
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abstract = "Objective To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties. Research design and methods Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis. Results After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95{\%} CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014 ±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was lifestyle change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity. Conclusions Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.",
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AU - Weinstein, Galit

AU - Davis-Plourde, Kendra L.

AU - Conner, Sarah

AU - Himali, Jayandra J.

AU - Beiser, Alexa S.

AU - Lee, Anne

AU - Rawlings, Andreea M.

AU - Sedaghat, Sanaz

AU - Ding, Jie

AU - Moshier, Erin

AU - Van Duijn, Cornelia M.

AU - Beeri, Michal S.

AU - Selvin, Elizabeth

AU - Arfan Ikram, M.

AU - Launer, Lenore J.

AU - Haan, Mary N.

AU - Seshadri, Sudha

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N2 - Objective To determine whether classes of diabetes medications are associated with cognitive health and dementia risk, above and beyond their glycemic control properties. Research design and methods Findings were pooled from 5 population-based cohorts: the Framingham Heart Study, the Rotterdam Study, the Atherosclerosis Risk in Communities (ARIC) Study, the Aging Gene-Environment Susceptibility-Reykjavik Study (AGES) and the Sacramento Area Latino Study on Aging (SALSA). Differences between users and non-users of insulin, metformin and sulfonylurea were assessed in each cohort for cognitive and brain MRI measures using linear regression models, and cognitive decline and dementia/AD risk using mixed effect models and Cox regression analyses, respectively. Findings were then pooled using meta-analytic techniques, including 3,590 individuals with diabetes for the prospective analysis. Results After adjusting for potential confounders including indices of glycemic control, insulin use was associated with increased risk of new-onset dementia (pooled HR (95% CI) = 1.58 (1.18, 2.12);p = 0.002) and with a greater decline in global cognitive function (β = -0.014 ±0.007;p = 0.045). The associations with incident dementia remained similar after further adjustment for renal function and excluding persons with diabetes whose treatment was lifestyle change only. Insulin use was not related to cognitive function nor to brain MRI measures. No significant associations were found between metformin or sulfonylurea use and outcomes of brain function and structure. There was no evidence of significant between-study heterogeneity. Conclusions Despite its advantages in controlling glycemic dysregulation and preventing complications, insulin treatment may be associated with increased adverse cognitive outcomes possibly due to a greater risk of hypoglycemia.

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