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Randomized Controlled Trial
. 2025 Jun;21(6):e70416.
doi: 10.1002/alz.70416.

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

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
Randomized Controlled Trial

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

Jeffrey M Burns et al. Alzheimers Dement. 2025 Jun.

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.

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Conflict of interest statement

J.M.B. received honoraria and travel reimbursements from AstraZeneca. R.H.S., I.Y.C., P.L., and W.B. received travel reimbursement from AstraZeneca to attend meetings. R.E. and J.O. are employed by AstraZeneca and are AstraZeneca stockholders. J.K.M., E.D.V., H.W., S.L.H., J.D.M., R.J.C., and A.G. have no disclosures to report related to the work presented here. Author disclosures are available in the Supporting Information.

Figures

FIGURE 1
FIGURE 1
Consolidated Standards of Reporting Trials (CONSORT) diagram for the dapagliflozin clinical trial.
FIGURE 2
FIGURE 2
Magnetic resonance spectroscopy (MRS)–determined N‐acetylaspartate (NAA) levels. (A) Pre minus post value change scores for the placebo and dapagliflozin treatment groups with referencing of NAA to creatine (Cr). (B) Pre minus post value change scores for the placebo and dapagliflozin treatment groups without referencing of NAA to Cr.
FIGURE 3
FIGURE 3
Brain GSH measures using multiple quantum filtering (MQF) magnetic resonance spectroscopy (MRS) technique. (A) MRS slice position for GSH mapping (left), GSH maps of pre‐ (middle), and post‐treatment (right). (B) Mean GSH level comparisons between pre‐ and post‐intervention in the control group (left) and the treatment group (middle). (C) A representative GSH spectrum from a voxel is shown below the GSH map, indicated by a red arrow (right). *Indicates p‐value < 0.05.
See this image and copyright information in PMC

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