Empagliflozin and Intranasal Insulin May Slow Alzheimer's Decline

Empagliflozin and intranasal insulin have been found to safely enhance brain function in individuals with mild cognitive impairment and early Alzheimer’s disease. These medications, commonly used to treat diabetes and other conditions, demonstrated significant improvements in memory, brain health, and cerebral blood flow (1^✔ ✔Trusted Source
A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD

Go to source). The trial, published in Alzheimer’s & Dementia, the journal of the Alzheimer’s Association, represents the first time empagliflozin has been evaluated in non-diabetic individuals diagnosed with Alzheimer’s.

This approach aims to address the limitations of current anti-amyloid treatments, which offer only modest benefits and are inaccessible to many due to adverse effects or medical contraindications. Moreover, these newer drugs do not target the metabolic and vascular disruptions that contribute to Alzheimer’s progression or help repair brain function already compromised by the disease.

Metabolic Approach for Alzheimer’s

Suzanne Craft, Ph.D., principal investigator and professor of medicine at the Wake Forest Alzheimer’s Disease Research Center, emphasized that modifying metabolic function could be key in altering Alzheimer’s trajectory.

According to Craft, empagliflozin, typically used for heart and diabetes treatment, helped decrease indicators of brain injury and restore blood circulation to vital areas of the brain. Concurrently, the intranasal insulin delivery method improved cognitive function, brain blood vessel health, and immune responses. Together, these results position metabolism as a promising focus area in Alzheimer’s treatment.

The clinical trial enrolled 47 older adults with an average age of 70, all experiencing early signs of Alzheimer’s or mild cognitive impairment. Participants were randomly divided into four groups: one received only intranasal insulin, another only empagliflozin, a third received both, and the final group was given a placebo.

High Tolerability of Empagliflozin and Intranasal Insulin

Both medications were deemed safe and well-tolerated, with mild side effects reported equally across all groups. The nasal insulin device was rated highly for ease of use (4.6 out of 5), and over 97 percent of participants maintained consistent treatment adherence during the study.

The medications produced distinct but complementary effects. Intranasal insulin improved results on sensitive cognitive assessments that detect early memory loss and thinking difficulties. Brain scans revealed increased integrity in white matter connections and altered blood flow in memory-centric brain regions.

Additionally, this treatment decreased levels of plasma GFAP, a protein linked to dysfunction in astrocytes, cells essential for communication between blood vessels and brain tissue.

Reducing Alzheimer’s Pathology with Empagliflozin

Empagliflozin led to notable reductions in cerebrospinal fluid tau, a toxic protein associated with Alzheimer’s pathology. It also decreased neurogranin and other vascular markers associated with disease progression, while promoting beneficial blood flow changes in key areas of the brain. Furthermore, empagliflozin raised levels of HDL cholesterol, suggesting that its metabolic advantages extend to non-diabetic individuals as well.

Both medications influenced several proteins related to immune and inflammatory activity in the brain and bloodstream. The observed changes indicate that the drugs help activate protective immune mechanisms while minimizing harmful inflammation. Notably, intranasal insulin had a pronounced effect on proteins within the nasal-olfactory plexus, a newly identified neural pathway involved in the body’s immune system and brain waste-clearance mechanisms.

Targeting Brain Metabolism and Vascular Health

Although the two treatments function through different mechanisms, they address interconnected problems. Empagliflozin, originally intended for glucose control in diabetes, enhances insulin sensitivity and vascular health across the body and brain. It also decreases oxidative stress and inflammation while boosting cellular energy production.

Intranasal insulin employs a specially designed delivery system that sends insulin directly to the brain through the nasal passage, bypassing the bloodstream. Once inside the brain, insulin interacts with receptors that maintain synaptic health, support blood vessels, preserve white matter, and regulate immune activities. Prior studies demonstrated that lower doses of intranasal insulin slowed white matter degeneration and sustained brain glucose use over a 12-month period.

Standard Cardiovascular Dose of Empagliflozin Used in Trial

This trial administered higher insulin doses, 160 international units per day, using a cartridge pump system from Aptar Pharma, previously validated through brain imaging techniques. This technology ensures accurate, targeted delivery to regions responsible for memory and cognitive performance. Meanwhile, empagliflozin was administered at its standard 10 milligram daily dose used for cardiovascular health in adults without diabetes.

Individuals with Alzheimer’s frequently exhibit brain insulin resistance and vascular issues that hinder proper blood flow and nutrient distribution. These disruptions accelerate amyloid plaque and tau tangle formation while also impairing the brain’s ability to remove these toxic proteins. Both medications tested in this study directly address these upstream contributors to disease progression.

Craft emphasized plans to conduct larger and longer-term trials involving individuals in early or preclinical stages of Alzheimer’s. Given their positive effects on tau pathology, cognition, vascular integrity, and immune regulation, these treatments hold strong potential as standalone or complementary therapies for Alzheimer’s.

Accelerating Access Through Repurposed Medications

Because empagliflozin and intranasal insulin are already approved by the United States Food and Drug Administration for other conditions and have well-known safety records, they offer a faster path to reaching Alzheimer’s patients compared to entirely new drug developments. Their complementary mechanisms may make them valuable candidates for use in combination therapy, providing a multifaceted approach to managing this complex neurological disorder.

To sum up, this clinical trial highlights the potential of repurposing existing medications like empagliflozin and intranasal insulin to improve brain function, memory, and immune responses in individuals with early Alzheimer’s disease. With proven safety profiles and complementary mechanisms, these therapies offer promising alternatives or additions to current treatments and could pave the way for more effective Alzheimer’s interventions in the near future.

Reference:

1. A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD - (https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70704)

Source-Medindia