A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD

Abstract

Introduction: Agents targeting metabolic/vascular disorders are promising candidates to treat Alzheimer's disease (AD) and enhance safety and efficacy of other therapies.

Methods: In a 2×2 factorial double-blinded randomized trial, participants with mild cognitive impairment (MCI), early AD, or who were amyloid positive received intranasal insulin (INI; 40 IU q.i.d.), the sodium-glucose cotransporter-2 inhibitor empagliflozin (10 mg q.d. oral tablet), both, or placebo for 4 weeks. The primary outcome was treatment-related adverse events (TRAEs). Secondary outcomes included the modified Preclinical Alzheimer's Cognitive Composite-5 (mPACC5), fluid biomarkers, cerebral blood flow (CBF), and fractional anisotropy (FA).

Results: TRAEs were mild and similar for all groups. INI increased mPACC5, modulated FA and CBF, and reduced plasma glial fibrillary acidic protein. Empagliflozin lowered cerebrospinal fluid tau and modulated CBF. Both agents moderated immune/inflammatory/neurovascular markers.

Discussion: INI and empagliflozin treatment was safe with promising effects on cognition, fluid, and imaging biomarkers. A longer and larger trial is needed to confirm these results.

Clinical trial registration: NCT05081219 HIGHLIGHTS: Agents targeting metabolic or vascular disorders are promising candidates to prevent or treat Alzheimer's disease (AD). Intranasal insulin and empagliflozin were safe alone or in combination for mild cognitive impairment/AD. Insulin improved cognition and markers of inflammation and immune function. Empagliflozin reduced markers of vascular injury and neurodegeneration. A longer, larger trial is needed to validate these results.

Keywords: Alzheimer's disease; empagliflozin; immune function; insulin; metabolism.

FIGURE 1

Consolidated Standards of Reporting Trials (CONSORT) diagram. EMPA, empagliflozin; INI, intranasal insulin; LP, lumbar puncture; TRAE, treatment‐related adverse event.

FIGURE 2

A, mPACC5 change scores for the non‐INI‐treated versus INI‐treated and non–EMPA‐treated versus EMPA‐treated groups. B, Change in plasma GFAP (pg/mL) for the placebo, INI‐only, EMPA‐only, and INI+EMPA groups. C, Change in CSF total tau (pg/mL) for the placebo, INI‐only, EMPA‐only, and INI+EMPA groups. * Nominal p < 0.05. CSF, cerebrospinal fluid; EMPA, empagliflozin; GFAP, glial fibrillary acidic protein; INI, intranasal insulin; mPACC5, modified Preclinical Alzheimer's Cognitive Composite 5.

FIGURE 3

Change in CSF (A) CNS and (B) inflammation biomarkers; change in plasma (C) CNS and (D) inflammation biomarkers for INI‐only, EMPA‐only and INI+EMPA groups versus placebo. The x axis of each volcano plot shows the magnitude and direction of the intervention effect, represented by the LFC (with the sign of the LFC reflecting the direction of the effect). The y axis shows the statistical significance of the group difference in change, represented by the minus log₁₀‐transformed p value (i.e. –log₁₀[p]), with smaller p values appearing higher on the plot. A threshold of nominal p < 0.05 and log2 fold change of > 0.05 and ← 0.05 (trend) was used for the exploratory analysis to identify significant analytes as potential biomarkers in each treatment arm. CNS, central nervous system; CSF, cerebrospinal fluid; EMPA, empagliflozin; INI, intranasal insulin; LFC, log fold change; PBO, placebo.