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

Autor: Charpignon ML; Institute for Data, Systems, and Society, Massachusetts Institute of Technology, Cambridge, MA, USA., Vakulenko-Lagun B; Department of Statistics, University of Haifa, Mt Carmel, Haifa, Israel., Zheng B; Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK., Magdamo C; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA., Su B; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK., Evans K; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA., Rodriguez S; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA., Sokolov A; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA., Boswell S; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA., Sheu YH; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA., Somai M; Inception Labs, Collaborative for Health Delivery Sciences, Medical College of Wisconsin, Wauwatosa, WI, USA., Middleton L; Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK.; Public Health Directorate, Imperial College London NHS Healthcare Trust, London, UK., Hyman BT; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA., Betensky RA; Department of Biostatistics, School of Global Public Health, New York University, New York, NY, USA., Finkelstein SN; Institute for Data, Systems, and Society, Massachusetts Institute of Technology, Cambridge, MA, USA.; Division of Clinical Informatics, Beth Israel Deaconess Medical Center, Boston, MA, USA., Welsch RE; Institute for Data, Systems, and Society, Massachusetts Institute of Technology, Cambridge, MA, USA.; Sloan School of Management, Massachusetts Institute of Technology, Cambridge, MA, USA., Tzoulaki I; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. i.tzoulaki@imperial.ac.uk.; Dementia Research Institute, Imperial College London, London, UK. i.tzoulaki@imperial.ac.uk.; Department of Hygiene and Epidemiology, University of Ioannina, Ioannina, Greece. i.tzoulaki@imperial.ac.uk., Blacker D; Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. dblacker@mgh.harvard.edu.; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. dblacker@mgh.harvard.edu., Das S; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. sdas5@mgh.harvard.edu., Albers MW; Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. albers.mark@mgh.harvard.edu.; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA, USA. albers.mark@mgh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Dec 10; Vol. 13 (1), pp. 7652. Date of Electronic Publication: 2022 Dec 10.
DOI: 10.1038/s41467-022-35157-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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