Causal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia. Nat Commun 2022 Dec 10;13(1):7652
Date
12/11/2022Pubmed ID
36496454Pubmed Central ID
PMC9741618DOI
10.1038/s41467-022-35157-wScopus ID
2-s2.0-85143664509 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
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.
Author List
Charpignon ML, Vakulenko-Lagun B, Zheng B, Magdamo C, Su B, Evans K, Rodriguez S, Sokolov A, Boswell S, Sheu YH, Somai M, Middleton L, Hyman BT, Betensky RA, Finkelstein SN, Welsch RE, Tzoulaki I, Blacker D, Das S, Albers MWAuthor
Melek Somai MD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
DementiaDiabetes Mellitus, Type 2
Drug Repositioning
Humans
Hypoglycemic Agents
Medical Records
Metformin
Sulfonylurea Compounds
