Metabolic Modulation in Alzheimer’s Disease: Early Clinical Signals from a Dapagliflozin Pilot Trial

Disrupted energy metabolism is a hallmark of Alzheimer’s disease (AD), fueling interest in therapeutics that recalibrate systemic and cerebral bioenergetics. A new exploratory trial, published in Alzheimer’s & Dementia in May 2025, evaluated whether dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, could influence metabolic or cognitive markers in individuals with early AD.

The 12-week, double-blind trial enrolled 48 participants with probable AD or mild cognitive impairment (MMSE scores between 15 and 26), randomized in a 2:1 ratio to receive either dapagliflozin 10 mg daily or placebo. The primary outcome was cerebral N-acetylaspartate (NAA), assessed via magnetic resonance spectroscopy (MRS) as a marker of mitochondrial integrity. Secondary outcomes included FDG-PET imaging, cognitive performance, plasma AD biomarkers, and systemic metabolic indicators.

The study did not meet its primary endpoint (P = 0.57). No significant change was detected in the NAA-to-creatine ratio. However, dapagliflozin led to several measurable metabolic effects. Participants in the treatment group showed significant reductions in hemoglobin A1c (P = 0.015), fat mass (P = 0.048), and lean mass (P = 0.013). They also exhibited a statistically significant increase in brain glutathione levels (P = 0.044), a marker of antioxidant capacity. In addition, there was a non-significant trend toward increased absolute NAA (P = 0.061), which may suggest some degree of mitochondrial engagement.

Cognitive results were limited. Of seven measures assessed, only the Stroop Interference test, a measure of executive function, showed significant improvement in the dapagliflozin group (P = 0.046). Broader assessments such as the ADAS-Cog and MMSE did not show meaningful differences between groups. FDG-PET findings remained stable, and no significant changes were observed in plasma biomarkers, including p-tau181, p-tau217, or the Aβ42/40 ratio.

The study population was strongly enriched for AD pathology. Ninety-six percent of participants had baseline p-tau217 levels above thresholds consistent with amyloid positivity. APOE ε4 carriage was 68 percent in the dapagliflozin group and 80 percent in the placebo group. These characteristics support the diagnostic validity of the sample, despite the absence of pre-enrollment biomarker confirmation.

Dapagliflozin was well tolerated. No serious treatment-related adverse events occurred, and adherence exceeded 99 percent. The most common drug-related symptoms were mild and limited to urinary complaints. There were no instances of hypoglycemia, ketoacidosis, or renal decline—important considerations in an older, cognitively impaired population.

Although the trial was short and the sample size modest, the findings offer several directions for future research. The absence of ketone elevation despite fat loss suggests that glucose disposal alone may not be enough to alter brain metabolism in non-diabetic individuals. Combining SGLT2 inhibitors with interventions such as ketogenic diets or structured exercise could enhance central metabolic effects. Additionally, more sensitive imaging methods, including PET ligands that target mitochondrial function, may improve the ability to detect brain-specific changes.

While cognitive outcomes remain inconclusive, the study provides early evidence that SGLT2 inhibition can produce both systemic and neurochemical effects in a population with biomarker features strongly consistent with AD pathology. These findings help build the rationale for more definitive trials focused on metabolic modulation in early Alzheimer’s disease.

Reference

Burns JM, Morris JK, Vidoni ED, et al. Effects of the SGLT2 inhibitor dapagliflozin in early Alzheimer's disease: A randomized controlled trial. Alzheimers Dement. 2025;21(6):e70416.