Intranasal Insulin and Empagliflozin Demonstrate Therapeutic Potential as Combination Treatment for Alzheimer Disease

Suzanne Craft, PhD

New data from a placebo-controlled phase 2 trial (NCT05081219) showed that a combination treatment approach with intranasal insulin (INI) and empagliflozin (empa), two compounds that improve metabolic and vascular function, had positive effects on cognition and several other immune/inflammatory biomarkers in patients with mild cognitive impairment (MCI) or early Alzheimer disease (AD). Overall, the data supported the continued investigation of this combination method for AD and suggest these agents may also be useful in combination with approved anti-amyloid therapies.¹

Otherwise known as the SNIFF study, patients with MCI or early AD, or amyloid positive controls with memory complaints were assigned to 1 of 4 arms: placebo, INI (40 IU QID regular insulin), empa (10 mg QD), or insulin plus empa (INI+empa). Over a 4-week treatment period, investigators compared insulin-treated (INI and INI+empa) vs non-insulin-treated (placebo and empa only) patients on cerebrospinal fluid (CSF) and plasma biomarkers, diffusion tensor imaging (DTI) global white matter fractional anisotropy, and cognitive function.

Presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29-November 1 in Madrid, Spain, results showed that the insulin-treated group had significantly improved Preclinical Alzheimer’s Cognitive Composite (PACC5) scores relative to the non-insulin group (P <.05). Led by senior author Suzanne Craft, PhD, a professor of gerontology and geriatric medicine at Wake Forest University School of Medicine, plasma biomarkers such as CSF SNAP25, SMOC1, BDNF, and VCAM1 were all significantly increased following insulin treatment (all P <.05).

In the study, those on INI also demonstrated increased plasma amyloid-ß42 levels that was statistically significant (P <.05). Within the combination treatment group, these patients had levels of more than 50 plasma and CSF innate and adaptive immune/inflammatory markers moderated following treatment. These included markers such as TREM2, SPP1, and CX3CL1 (ps ranging from 0.00001 to 0.05).

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Additional data from the phase 2 study showed that several immune and inflammatory markers were linked to baseline phosphorylated-tau 217 levels. In MRI analysis, DTI fractional anisotropy significantly increased in the insulin-treated group (P <.05). As for safety, only occasional, mild adverse events occurred, with no differences between treatment arms.

The use of medications originally developed for metabolic and vascular disorders to treat AD is rooted in research that highlights the role of metabolic and cardiovascular health in cognitive decline. Over the years, various treatments designed for diabetes, hypertension, and lipid management have shown potential in AD prevention or mitigation, largely because of their effects on inflammation, blood flow, insulin sensitivity, and oxidative stress–factors implicated in AD pathology.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, like empagliflozin, are a newer drug class, developed in the 2010s for type 2 diabetes. These therapies are known to improve glucose control and provide cardiovascular benefits. Recent research has explored their potential to benefit cognitive health, likely due to effects on oxidative stress, inflammation, and cerebral blood flow. Preclinical studies have also suggested a possible role in reducing AD pathology, through clinical data are still emerging.

A preclinical study published in 2020 showed that empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of AD and type 2 diabetes. At the central level, the therapy limited cortical thinning and reduced neuronal loss in treated mice. In empagliflozin-treated mice, hemorrhage and microglia burdens were reduced, senile plaque burden decreased, and cognitive deficits in APP/PS1xdb/db mice improved.²

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REFERENCES
1. Erichsen J, Register T, Sutphen C, et al. Immunometabolic and vascular modulators for combination therapy in AD: results of a phase 2 trial of intranasal insulin and the SGLT2 inhibitor empagliflozin. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 29-November 1, 2024; ABSTRACT OC03
2. Hierro-Bujalance C, Infante-Garcia C, Marco A, et al. Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes. Alzheimers Res Ther. 2020;12(1):40. doi:10.1186/s13195-020-00607-4