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, Mark W. Albers

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number7652
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • General
  • Physics and Astronomy(all)

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