Intranasal insulin-drug combination showing promise in Alzheimer’s disease

The combination of intranasal insulin (INI) and the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin had positive effects on cognition, immune and inflammatory biomarkers in one phase in patients with mild cognitive impairment (MCI) or early Alzheimer’s disease disease (AD). 2 attempt.

“We saw encouraging preliminary effects on cognition and insulin white matter integrity and on CSF [cerebrospinal fluid] Total tau for empagliflozin, which could be very important if confirmed,” said Suzanne Craft, PhD, of Wake Forest University School of Medicine, Winston-Salem, North Carolina.

The results were presented at the 17th Clinical Trials on Alzheimer’s Disease (CTAD) conference.

Repurposing insulin/SGLT2i for AD?

Metabolic and vascular diseases are risk factors for AD, and it has been suggested that drugs used to treat metabolic and vascular diseases—such as INI and empagliflozin—could be repurposed for AD treatment.

The phase 2 study included 47 patients with MCI or early AD or amyloid positive controls with memory impairment. Patients were randomly assigned to one of four groups: placebo, INI (40 IU four times daily regular insulin), empagliflozin (10 mg daily), or INI plus empagliflozin (INI + Empa).

Participants were treated for 4 weeks. Fasting lumbar puncture and blood sampling, MRI, and cognitive testing were performed at baseline and after treatment.

Adherence to treatment >90% in all groups. There were no differences between groups in treatment-emergent adverse events (the primary endpoint).

There were no changes or differences in glucose levels or blood pressure. The most common adverse events were vaginal yeast infections (two in the placebo group, one in the Empa group), nasal irritation (two in the INI group, one each in the Empa and INI+empa groups) and headache (one each in the Empa group). placebo and INI groups).

Exploratory cognition, imaging, and AD biomarker results were mostly positive.

The INI-treated group had significantly improved Preclinical Alzheimer’s Cognitive Composite Scores compared to the non-INI-treated group (P = .02), Craft reported.

White matter fractional anisotropy increased in the INI-treated group (P = .01), indicating better myelin health, and CSF total tau decreased in the Empa-treated group (P = .03).

In addition, “the levels of more than 50 innate and adaptive immune/inflammatory markers were attenuated in plasma and CSF after treatment with INI and Empa, including well-known markers such as TREM2, SPP1 and MMP9, as well as novel markers such as PD-L1 and CX3CL1 “, the researchers reported in their conference summary.

“These results support further investigation of combination therapy with intranasal insulin and empagliflozin in AD,” they added.

Craft told participants that longer and larger studies are planned to “validate and expand” these findings. Both users and non-users of anti-amyloid therapies will take part in these studies.

She also noted that other “metabolic enhancers” are currently in clinical trials, including GLP1 receptor agonists and non-pharmacological interventions, that show promise for combination therapy in AD.

Encouraging data

“Increasing research suggests that metabolic pathways (e.g., cellular metabolism) play a role in Alzheimer’s disease and that targeting them, including through personalized approaches, could be a path to treatment,” said Heather Snyder, senior vice president for medical and scientific relations at the Alzheimer’s Disease Alzheimer’s Association, tells Medscape Medical News.

The data from this study are “encouraging and suggest that this novel combination approach may be a viable treatment for metabolic drivers of brain cell health in individuals with Alzheimer’s disease.” We look forward to seeing this approach translate into larger studies with more representative populations said Snyder, who was not involved in the study.

Snyder also noted that “there are barriers and gaps in the investments that help bring exciting new approaches like this into clinical trials.” The Alzheimer’s Association’s Part the Cloud program provided seed funding to make the Work by Dr. Craft to move forward into this early phase of the study.”

The study had no commercial funding. Craft and Snyder reported no relevant disclosures.