Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease

Jasmine Morales; Nico Gabriel; Loki Natarajan; Andrea Z LaCroix; Aladdin H Shadyab; Ronghui Xu; James Silverman; Howard H Feldman; Inmaculada Hernandez; Powder for Pennies Collaboration

doi:10.1002/alz.13872

Pharmacoepidemiology evaluation of bumetanide as a potential candidate for drug repurposing for Alzheimer's disease

Alzheimers Dement. 2024 Aug;20(8):5236-5246. doi: 10.1002/alz.13872. Epub 2024 Jun 21.

Authors

Collaborators

Powder for Pennies Collaboration:
Vahan Aslanyan⁸, Anne Bang⁹, Elizabeth Bevins⁷, Gene L Bowman¹⁰, Ben Boyarko^{6

11}, Xu Chen⁷, Claire D Clelland¹², Hiroko H Dodge¹⁰, January Durant⁶, Steve D Edland^{6

7}, A Carol Evans⁶, Doug R Galasko^{6

7}, William H Gerwick¹¹, Barry D Greenberg¹³, Michelle Herman⁶, Tatiana Herold⁶, Vivian Hook¹¹, Diane M Jacobs^{6

7}, Jeffrey Kaye¹⁴, Doo Yeon Kim¹⁰, Edward H Koo⁷, Ken S Kosik¹⁵, Gabriel Léger^{6

7}, Jody-Lynn Lupo⁶, Karen Messer^{1

6}, Jeremiah D Momper¹¹, Haakon B Nygaard¹⁶, Judy Pa^{6

7}, Luisa Quinti¹⁰, Carolyn Revta⁶, Jessica E Rexach¹⁷, Stacey J Sukoff Rizzo¹⁸, Kevin D Rynearson^{6

7}, Lon Schneider⁸, Barbara Slusher¹³, Rudolph E Tanzi¹⁰, Paul R Territo¹⁹, Jennifer S Yokoyama¹²

Affiliations

¹ Herbert Wertheim School of Public Health & Human Longevity Science, University of California, San Diego, La Jolla, California, USA.
² Division of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
³ Division of Geriatrics, Gerontology, and Palliative Care, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
⁴ Department of Mathematics, University of California, San Diego, La Jolla, California, USA.
⁵ Halicioglu Data Science Institute, University of California, San Diego, La Jolla, California, USA.
⁶ Alzheimer's Disease Cooperative Study, University of California, San Diego, School of Medicine, La Jolla, California, USA.
⁷ Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
⁸ Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁹ Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA.
¹⁰ Department of Neurology, Mass General Research Institute, Charlestown, Massachusetts, USA.
¹¹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, California, USA.
¹² Department of Neurology, UCSF Weill Institute for Neurosciences, School of Medicine, San Francisco, California, USA.
¹³ School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
¹⁴ School of Medicine, Oregon Health and Science University, Portland, Oregon, USA.
¹⁵ Department of Molecular, Cellular, and Development Biology, University of California, Goleta, California, USA.
¹⁶ Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.
¹⁷ Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
¹⁸ Aging Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁹ School of Medicine, Indiana University, Indianapolis, Indiana, USA.

Abstract

Introduction: Bumetanide, a loop diuretic, was identified as a candidate drug for repurposing for Alzheimer's disease (AD) based on its effects on transcriptomic apolipoprotein E signatures. Cross-sectional analyses of electronic health records suggest that bumetanide is associated with decreased prevalence of AD; however, temporality between bumetanide exposure and AD development has not been established.

Methods: We evaluated Medicare claims data using Cox proportional hazards regression to evaluate the association between time-dependent use of bumetanide and time to first AD diagnosis while controlling for patient characteristics. Multiple sensitivity analyses were conducted to test the robustness of the findings.

Results: We sampled 833,561 Medicare beneficiaries, 60.8% female, with mean (standard deviation) age of 70.4 (12). Bumetanide use was not significantly associated with AD risk (hazard ratio 1.05; 95% confidence interval, 0.99-1.10).

Discussion: Using a nationwide dataset and a retrospective cohort study design, we were not able to identify a time-dependent effect of bumetanide lowering AD risk.

Highlights: Bumetanide was identified as a candidate for repurposing for Alzheimer's disease (AD). We evaluated the association between bumetanide use and risk of AD. We used Medicare data and accounted for duration of bumetanide use. Bumetanide use was not significantly associated with risk of AD.

Keywords: Alzheimer's disease; drug repurposing; loop diuretics; pharmacoepidemiology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / drug therapy
Alzheimer Disease* / epidemiology
Bumetanide* / therapeutic use
Cross-Sectional Studies
Drug Repositioning*
Female
Humans
Male
Medicare*
Pharmacoepidemiology*
Proportional Hazards Models
Sodium Potassium Chloride Symporter Inhibitors / therapeutic use
United States / epidemiology

Substances

Bumetanide
Sodium Potassium Chloride Symporter Inhibitors

Abstract

Publication types

MeSH terms

Substances

Grants and funding