SNIFF-Combo: Intranasal Insulin + Empagliflozin for Alzheimer's Disease (NCT05081219)

SNIFF-Combo: Intranasal Insulin + Empagliflozin for Alzheimer's Disease (NCT05081219)

Overview

SNIFF-Combo: Intranasal Insulin + Empagliflozin for Alzheimer's Disease (NCT05081219)

Overview

SNIFF-Combo (Study of Nasal Insulin to Fight Forgetfulness - Combination Intranasal Insulin and Empagliflozin Trial) is a Phase 2 clinical trial evaluating the combination of [intranasal insulin](/treatments/intranasal-insulin-alzheimers) and [empagliflozin](/treatments/empagliflozin-neuroprotection) — an SGLT2 inhibitor — for the treatment of Alzheimer's disease (AD) and mild cognitive impairment. The trial is based on the hypothesis that brain insulin resistance is a key driver of AD pathology, and that a dual approach targeting both central insulin signaling and systemic glucose metabolism may yield greater benefits than either therapy alone["@craft2020"][@tavares2022].

This combination approach addresses two interconnected metabolic defects in AD: impaired brain insulin signaling and cerebral glucose hypometabolism, both of which are documented even in early-stage disease["@kuller2020"].

Trial Details

| Attribute | Value |
|-----------|-------|
| NCT Number | [NCT05081219](https://clinicaltrials.gov/study/NCT05081219) |
| Title | Study of Nasal Insulin to Fight Forgetfulness - Combination Intranasal Insulin and Empagliflozin Trial |
| Phase | Phase 2 |
| Status | Completed (September 17, 2024) |
| Sponsor | Wake Forest University Health Sciences, Winston-Salem, NC |
| Intervention | Humulin R U-100 Insulin (40 IU intranasal, 4x daily) + Empagliflozin 10 mg oral daily |
| Participants | 47 enrolled |
| Age | 55-85 years |
| Start Date | September 14, 2021 |
| Completion Date | September 17, 2024 |
| ClinicalTrials.gov | [View Trial](https://clinicaltrials.gov/study/NCT05081219) |

Rationale

Brain Insulin Resistance in AD

Alzheimer's disease is increasingly recognized as a metabolic disorder, with brain insulin resistance playing a central role in disease progression. Key observations include:

• Reduced insulin receptor expression and impaired insulin signaling in postmortem AD brain tissue[@craft2020]
• Decreased cerebral glucose uptake on FDG-PET in early AD, correlating with cognitive decline[@tavares2022]
• The "Type 3 Diabetes" hypothesis: Alzheimer's as a brain-specific insulin-resistant state[@craft2020]
• Intranasal insulin has shown promise in improving memory and cognition in AD trials, likely by directly activating insulin receptors in the brain without systemic exposure[@kuller2020]

SGLT2 Inhibitors and Neuroprotection

[SGLT2 inhibitors](/treatments/sglt2-inhibitors-neurodegeneration) like empagliflozin are oral anti-diabetic drugs that block glucose reabsorption in the kidneys. Emerging evidence suggests they confer neuroprotective effects through mechanisms beyond glucose control[@williams2020][@zhou2024]:

• Reduced cerebral glucose toxicity and oxidative stress[@min2021]
• Improved cerebral blood flow and neurovascular coupling
• Decreased neuroinflammation via ketone body production (neuroprotective fuel source)
• Reduced neuronal apoptosis through inhibition of ER stress pathways
• Population studies showing reduced dementia risk in SGLT2 inhibitor users[@zhou2024]

Synergistic Hypothesis

The SNIFF-Combo trial tests whether combining direct central insulin sensitization (via intranasal delivery) with systemic metabolic improvement (via SGLT2 inhibition) produces additive or synergistic benefits:

This dual-targeting approach contrasts with single-agent trials that have largely failed in AD, recognizing that metabolic dysfunction in AD is multi-systemic.

Study Design

Arms

The trial employed a factorial design with four arms:

| Arm | Intranasal Insulin | Oral Empagliflozin |
|-----|--------------------|--------------------|
| 1 | Active | Placebo |
| 2 | Placebo | Active |
| 3 | Active | Active |
| 4 | Placebo | Placebo |

Participants self-administered both intranasal insulin (40 IU four times daily via a specialized nasal delivery device) and oral capsules (empagliflozin 10 mg or matching placebo) for the duration of the intervention period.

Outcomes

Primary Outcome:

• Number of participants with treatment-related serious adverse events (CTCAE v5.0)

• Change in PACC5 (Preclinical Alzheimer Cognitive Composite 5) z-score from baseline
• Change in ADAS-Cog 14 (Alzheimer's Disease Assessment Scale - Cognitive) score
• Changes in CSF biomarkers: Aβ40, Aβ42, total tau, phospho-tau 181
• Cerebral blood flow changes via MRI

Eligibility

Inclusion Criteria:

• Age 55-85 years
• Normal cognition, mild cognitive impairment (MCI), or Alzheimer's disease
• Signed informed consent

• Type 1 or Type 2 diabetes mellitus
• Recent use of insulin or antidiabetic medications
• Other dementias (e.g., Lewy body dementia, frontotemporal dementia)
• Recent stroke or history of seizures
• Active psychiatric conditions
• Significant medical conditions precluding participation

Results

The trial completed with zero treatment-related serious adverse events across all arms, establishing the safety of the combination approach. Results show the combination was well-tolerated even in older adults with and without cognitive impairment.

Cognitive outcomes (PACC5, ADAS-Cog 14) and CSF biomarker data were collected through the study endpoint, with results expected to be published in peer-reviewed journals.

Significance

SNIFF-Combo represents a significant departure from the amyloid-centric therapeutic paradigm that has dominated AD drug development. By targeting brain energy metabolism and insulin signaling — mechanisms that are disrupted early in the disease process and persist throughout — this trial evaluates a fundamentally different therapeutic hypothesis.

The combination of [intranasal insulin](/treatments/intranasal-insulin-alzheimers) (which bypasses the blood-brain barrier limitation that has frustrated insulin-related therapies) with [SGLT2 inhibitors](/treatments/sglt2-inhibitors-neurodegeneration) (which have shown epidemiologic signal for dementia risk reduction) offers a metabolic dual-targeting strategy that addresses multiple upstream drivers of neurodegeneration simultaneously[@craft2020][@zhou2024][@tavares2022].

Related Pages

• [Intranasal Insulin for Alzheimer's Disease](/treatments/intranasal-insulin-alzheimers)
• [SGLT2 Inhibitors and Neurodegeneration](/treatments/sglt2-inhibitors-neurodegeneration)
• [Brain Insulin Resistance in AD](/mechanisms/brain-insulin-resistance-ad)
• [Alzheimer's Disease Treatment Overview](/treatments/alzheimers-disease-overview)