Intranasal Insulin Drug Combo Promising for Alzheimer’s

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

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

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

Repurposing Insulin/SGLT2i for AD? 

Metabolic and vascular disorders are risk factors for AD, and it has been suggested that medications to treat metabolic and vascular disorders — like 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 complaints. Patients were randomly allocated to one of four groups: Placebo, INI (40 IU qid regular insulin), empagliflozin (10 mg-gd), or INI plus empagliflozin (INI+empa).

Participants received treatment for 4 weeks. Fasting lumbar puncture and blood draw, MRI and cognitive testing were conducted at baseline and after treatment.

Compliance with treatment >90% in all groups. There were no differences between groups in treatment-related adverse events (the primary outcome).

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

Exploratory cognition, imaging and AD biomarker outcomes were largely positive.

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

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

In addition, “levels of more than 50 plasma and CSF innate and adaptive immune/inflammatory markers were moderated following treatment with INI and empa, including 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 abstract.

“These results support the continued investigation of intranasal insulin and empagliflozin combination therapy for AD,” they added.

Craft told attendees that longer and larger trials are planned to “validate and extend” these results. These trials will include both users and nonusers of anti-amyloid therapies.

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

Encouraging Data 

“Growing research suggests metabolic pathways (such as cellular metabolism) play a role in Alzheimer’s disease, and that targeting it — including through personalized approaches — may be a treatment pathway,” Heather Snyder, senior vice-president of medical and scientific relations at the Alzheimer’s Association, told Medscape Medical News.

The data from this study are “encouraging, suggesting 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 move this 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 investment that help move exciting new approaches like this into clinical trials. The Alzheimer’s Association Part the Cloud program provided the seed funding to help propel Dr Craft’s work into this early phase trial.”

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