Effects of the SGLT2 inhibitor dapagliflozin in early Alzheimer's disease: A randomized controlled trial

  • Alzheimers Dement. 2025 Jun;21(6):e70416. doi: 10.1002/alz.70416.
Jeffrey M Burns  1 ,  Jill K Morris  1 ,  Eric D Vidoni  1 ,  Heather M Wilkins  1 ,  In-Young Choi  1 ,  Phil Lee  1 ,  Suzanne L Hunt  1 ,  Jonathan D Mahnken  1 ,  William M Brooks  1 ,  Rebecca J Lepping  1 ,  Aditi Gupta  1 ,  Russell Esterline  2 ,  Jan Oscarsson  3 ,  Russell H Swerdlow  1
Affiliations
  • 1. University of Kansas Medical Center, Kansas City, Kansas, USA.
  • 2. Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca Pharmaceuticals, Gaithersburg, Maryland, USA.
  • 3. Late-Stage Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Mölndal, Sweden.
PMID: 40566796 DOI: 10.1002/alz.70416
Abstract

Introduction: Due to its metabolic effects, dapagliflozin, a sodium-glucose transporter 2 (SGLT2) inhibitor, holds potential as an Alzheimer's Disease (AD) therapeutic.

Methods: We conducted a double-blind, randomized, placebo-controlled, parallel-group, 12-week single-site study to investigate the effect of dapagliflozin in participants with probable AD (Mini-Mental State Examination [MMSE] score 15-26). We planned to enroll 48 participants with 2:1 randomization to 10 mg dapagliflozin once daily (n = 32) versus matching placebo (n = 16). The primary objective was the effect of dapagliflozin on cerebral N-acetylaspartate (NAA). We also assessed safety, glycemic control, body composition, brain metabolism, and cognition.

Results: There was no change in the primary outcome. There were no significant adverse event differences. Hemoglobin A1c, fat mass, and fat-free lean mass decreased; brain glutathione increased; and Stroop Interference test (but not other cognitive test) performance improved.

Discussion: Treated participants manifested metabolic effects observed in clinical studies of other cohorts. In AD, dapagliflozin use may affect the brain.

Highlights: Dapagliflozin did not alter magnetic resonance spectroscopy N-acetylaspartate (primary outcome) in this exploratory Alzheimer's Disease (AD) trial. Dapagliflozin-induced glucose disposal is sufficient to alter systemic metabolism. AD patients taking dapagliflozin exhibited metabolic effects seen in diabetics.

Keywords
Alzheimer's; MRS; SGLT2; dapagliflozin; glucose; metabolism.