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

Marie-Laure Charpignon ORCID logo; Bella Vakulenko-Lagun; Bang Zheng ORCID logo; Colin Magdamo; Bowen Su; Kyle Evans; Steve Rodriguez; Artem Sokolov ORCID logo; Sarah Boswell ORCID logo; Yi-Han Sheu; +10 more... Melek Somai; Lefkos Middleton; Bradley T Hyman ORCID logo; Rebecca A Betensky; Stan N Finkelstein; Roy E Welsch; Ioanna Tzoulaki ORCID logo; Deborah Blacker; Sudeshna Das ORCID logo; Mark W Albers ORCID logo; (2022) Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia. Nature Communications, 13 (1). 7652-. ISSN 2041-1723 DOI: 10.1038/s41467-022-35157-w
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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.


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