Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia

Marie-Laure Charpignon, Bella Vakulenko-Lagun, Bang Zheng, Colin Magdamo, Bowen Su, Kyle Evans, Steve Rodriguez, Artem Sokolov, Sarah Boswell, Yi-Han Sheu, Melek Somai, Lefkos Middleton, Bradley T. Hyman, Rebecca A. Betensky, Stan N. Finkelstein, Roy E. Welsch, Ioanna Tzoulaki (), Deborah Blacker (), Sudeshna Das () and Mark W. Albers ()
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Marie-Laure Charpignon: Institute for Data, Systems, and Society, Massachusetts Institute of Technology
Bella Vakulenko-Lagun: University of Haifa
Bang Zheng: Ageing Epidemiology Research Unit, School of Public Health, Imperial College London
Colin Magdamo: Massachusetts General Hospital/Harvard Medical School
Bowen Su: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
Kyle Evans: Massachusetts General Hospital/Harvard Medical School
Steve Rodriguez: Massachusetts General Hospital/Harvard Medical School
Artem Sokolov: Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School
Sarah Boswell: Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School
Yi-Han Sheu: Massachusetts General Hospital/Harvard Medical School
Melek Somai: Inception Labs, Collaborative for Health Delivery Sciences, Medical College of Wisconsin
Lefkos Middleton: Ageing Epidemiology Research Unit, School of Public Health, Imperial College London
Bradley T. Hyman: Massachusetts General Hospital/Harvard Medical School
Rebecca A. Betensky: New York University
Stan N. Finkelstein: Institute for Data, Systems, and Society, Massachusetts Institute of Technology
Roy E. Welsch: Institute for Data, Systems, and Society, Massachusetts Institute of Technology
Ioanna Tzoulaki: Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London
Deborah Blacker: Massachusetts General Hospital/Harvard Medical School
Sudeshna Das: Massachusetts General Hospital/Harvard Medical School
Mark W. Albers: Massachusetts General Hospital/Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin’s action in the brain.

Date: 2022
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DOI: 10.1038/s41467-022-35157-w

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