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

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.

Previous observational studies of the diabetes drugs metformin vs. sulfonylureas have yielded mixed results about whether metformin reduces the risk of dementia, relative to the sulfonylureas. Here, the authors apply a novel competing risks approach to emulate dementia-related target trials in electronic health records of diabetic patients and a complementary systems pharmacology evaluation on human neural cells.