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

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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
Issue number2
StatePublished - Feb 2019
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by a grant from the Alzheimer’s Drug Discovery Foundation (contract number 20150702). Work on the SALSA study for this was supported by NIA AG12975. The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I). Neurocognitive data is collected by U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the NIH (NHLBI, NINDS, NIA and NIDCD), and with previous brain MRI examinations funded by R01-HL70825 from the NHLBI. The authors thank the staff and participants of the ARIC study for their important contributions. Dr. Selvin was supported by NIH/NIDDK grants K24DK106414 and R01DK089174. Dr. Rawlings was supported by NIH/NHLBI grant T32HL007024 during the time of her contributions to this project. The AGES-Reykjavik Study was funded by National Institutes of Health (NIH) (contract N01-AG-12100); the Intramural Research Program of the National Institute on Aging; the Icelandic Heart Association and the Icelandic Parliament. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners, pharmacists and the Erasmus Epidemiology data management team. The Framingham Study received grants from the National Institute on Aging (R01 AG054076, AG016495, AG049505, AG049607, and AG033193), the National Institute of Neurological Disorders and Stroke (NS017950), and the National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-HL081572) and support from the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contracts no. N01-HC-25195 and HHSN268201500001I). The Israel Diabetes and Cognitive Decline study received funding from the National Institute on Aging (R01 AG034087 and R01 AG 051545) and from the LeRoy Schecter Foundation and the Bader Philanthropies.

Publisher Copyright:
© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.


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