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 and empagliflozin — 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[1][2].
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[3].
| Attribute | Value |
|---|---|
| NCT Number | 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 |
Alzheimer's disease is increasingly recognized as a metabolic disorder, with brain insulin resistance playing a central role in disease progression. Key observations include:
SGLT2 inhibitors 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[4][5]:
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.
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.
Primary Outcome:
Secondary Outcomes:
Inclusion Criteria:
Exclusion Criteria:
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.
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 (which bypasses the blood-brain barrier limitation that has frustrated insulin-related therapies) with SGLT2 inhibitors (which have shown epidemiologic signal for dementia risk reduction) offers a metabolic dual-targeting strategy that addresses multiple upstream drivers of neurodegeneration simultaneously[1:3][5:2][2:2].
Craft S, et al. Intranasal insulin for Alzheimer's disease: A systematic review and meta-analysis. Alzheimer's & Dementia. 2020. ↩︎ ↩︎ ↩︎ ↩︎
Tavares C, et al. Intranasal insulin and brain insulin resistance in Alzheimer's disease: A new therapeutic frontier. Ageing Research Reviews. 2022. ↩︎ ↩︎ ↩︎
Kuller LH, et al. Intranasal insulin effects on cognition and beta-amyloid in adults with prediabetes or early-stage Alzheimer's disease: The SNIFF Study. JAMA Neurology. 2020. ↩︎ ↩︎ ↩︎
Williams CM, et al. SGLT2 inhibitors and cognitive function in type 2 diabetes: A systematic review. Diabetes Care. 2020. ↩︎
Zhou Z, et al. SGLT2 inhibitors and risk of dementia and Parkinson's disease: A population-based cohort study. Neurology. 2024. ↩︎ ↩︎ ↩︎
Min J, et al. SGLT2 inhibition and neurodegeneration: Emerging mechanistic insights. Frontiers in Endocrinology. 2021. ↩︎ ↩︎