Potential Synergistic Association of Donepezil and Metformin With COVID-19 Mortality in Dementia Patients
Bingnan Li, Andreas Handel, Ye Shen, Yuan Ke, Joy A Phillips, Veronika I Zarnitsyna, , Adam B Wilcox, Adam M Lee, Alexis Graves, Alfred (Jerrod) Anzalone, Amin Manna, Amit Saha, Amy Olex, Andrea Zhou, Andrew E Williams, Andrew M Southerland, Andrew T Girvin, Anita Walden, Anjali Sharathkumar, Benjamin Amor, Benjamin Bates, Brian Hendricks, Brijesh Patel, G Caleb Alexander, Carolyn T Bramante, Cavin Ward-Caviness, Charisse Madlock-Brown, Christine Suver, Christopher G Chute, Christopher Dillon, Chunlei Wu, Clare Schmitt, Cliff Takemoto, Dan Housman, Davera Gabriel, David A Eichmann, Diego Mazzotti, Donald E Brown, Eilis Boudreau, Elaine L Hill, Emily Carlson Marti, Emily R Pfaff, Evan French, Farrukh M Koraishy, Federico Mariona, Fred Prior, George Sokos, Greg Martin, Harold P Lehmann, Heidi Spratt, Hemalkumar B Mehta, J W Awori Hayanga, Jami Pincavitch, Jaylyn Clark, Jeremy Richard Harper, Jessica Yasmine Islam, Jin Ge, Joel Gagnier, Johanna J Loomba, John B Buse, Jomol Mathew, Joni L Rutter, Julie A McMurry, Justin Guinney, Justin Starren, Karen Crowley, Katie Rebecca Bradwell, Kellie M Walters, Ken Wilkins, Kenneth R Gersing, Kenrick Cato, Kimberly Murray, Kristin Kostka, Lavance Northington, Lee Pyles, Lesley Cottrell, Lili M Portilla, Mariam Deacy, Mark M Bissell, Marshall Clark, Mary Emmett, Matvey B Palchuk, Melissa A Haendel, Meredith Adams, Meredith Temple-O'Connor, Michael G Kurilla, Michele Morris, Nasia Safdar, Nicole Garbarini, Noha Sharafeldin, Ofer Sadan, Patricia A Francis, Penny Wung Burgoon, Philip R O Payne, Randeep Jawa, Rebecca Erwin-Cohen, Rena C Patel, Richard A Moffitt, Richard L Zhu, Rishikesan Kamaleswaran, Robert Hurley, Robert T Miller, Saiju Pyarajan, Sam G Michael, Samuel Bozzette, Sandeep K Mallipattu, Satyanarayana Vedula, Scott Chapman, Shawn T O'Neil, Soko Setoguchi, Stephanie S Hong, Steven G Johnson, Tellen D Bennett, Tiffany J Callahan, Umit Topaloglu, Valery Gordon, Vignesh Subbian, Warren A Kibbe, Wenndy Hernandez, Will Beasley, Will Cooper, William Hillegass, Xiaohan Tanner ZhangAbstract
Background
Older adults with dementia face markedly elevated mortality from COVID-19. Both donepezil and metformin have anti-inflammatory effects and are associated with improved outcomes in respiratory viral infections, but whether their combined use is associated with lower COVID-19 mortality remains unknown.
Methods
We conducted a retrospective cohort study using the National Clinical Cohort Collaborative (N3C) data enclave, including adults aged ≥65 years with primary SARS-CoV-2 infection. We evaluated the association between donepezil monotherapy (5 mg or 10 mg) and COVID-19 mortality using 1-to-1 propensity score-matched analyses. Analyses were stratified by diabetes and metformin use.
Results
Among patients with dementia, 30-day mortality was lower in patients receiving donepezil 5 mg compared with matched untreated controls (10.3% vs 13.2%; p = 0.00046) and similarly for 10 mg (10.3% vs 13.4%; p = 0.0014). Among patients with dementia and diabetes, donepezil–metformin use was associated with the lowest mortality, approaching levels in matched individuals without dementia or diabetes. Metformin or donepezil alone was associated with modest reductions. Among donepezil users, those with diabetes treated with metformin had lower mortality than those without diabetes (30-day: 7.6% vs 10.2%, p = 0.016; significant only after FDR correction). No significant mortality differences by diabetes or metformin use were observed among dementia patients not receiving donepezil.
Conclusions
Donepezil use was associated with reduced COVID-19 mortality in older adults with dementia, with findings consistent with a potential synergistic association with metformin. These findings warrant further study of cholinergic modulation, alone or with metabolic therapies, to reduce severe COVID-19 outcomes.