Safety and efficacy of intranasal insulin in patients with Alzheimer’s disease: a systematic review and meta-analysis
Background and aim: We performed this meta-analysis to evaluate the safety and efficacy of intranasal insulin in Alzheimer's disease (AD) patients.
Methods: A literature search was conducted for PubMed, Scopus, and Web of Science from inception till August 2022. Documents were screened for qualified articles, and all concerned outcomes were pooled as risk ratios (RR) or mean difference (MD) in the meta-analysis models using Review Manager (RevMan version 5.4).
Results: Our results from 12 studies favored intranasal insulin over placebo in terms of Alzheimer Disease’s Assessment Scale–cognitive subscale (ADAS-cog) 20IU, (MD = -0.13, 95% CI [-0.22, -0.05], P = 0.003). The overall effect did not favor either of the two groups for ADAS-cog 40IU, memory composite 20IU and 40IU, and adverse events. (MD = -0.08, 95% CI [-0.16, 0.01], P = 0.08), (MD = 0.65, 95% CI [-0.08, 1.39], P = 0.08), (MD = 0.25, 95% CI [-0.09, 0.6], P = 0.15), (MD = 1.28, 95% CI [0.75, 2.21], P = 0.36), respectively.
Conclusion: Ultimately, this meta-analysis showed that intranasal insulin in small doses (20IU) significantly affects patients with AD. Further studies are recommended on reliable insulin delivery devices to increase insulin in the central nervous system.
Relevance for patients: Intranasal insulin has shown promising results in treating patients with AD. The lower doses (20 IU) can play a positive role in improving the disease. As research continues, it is likely that this treatment will become more widely accepted and utilized in clinical practice.
[1] Michailidis M, Tata DA, Moraitou D, Kavvadas D, Karachrysafi S, Papamitsou T, et al. Antidiabetic Drugs in the Treatment of Alzheimer’s Disease. Int J Mol Sci 2022;23:4641.
[2] Kazkayasi I, Telli G, Nemutlu E, Uma S. Intranasal Metformin Treatment Ameliorates Cognitive Functions Via Insulin Signaling Pathway in ICV-STZ-induced Mice Model of Alzheimer’s Disease. Life Sci 2022;299:120538.
[3] Akel H, Csóka I, Ambrus R, Bocsik A, Gróf I, Mészáros M, et al. In Vitro Comparative Study of Solid Lipid and PLGA Nanoparticles Designed to Facilitate Noseto-brain Delivery of Insulin. Int J Mol Sci 2021;22:13258.
[4] Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the Brain: Sources, Localization and Functions. Mol Neurobiol 2013;47:145-71.
[5] Maher MA, Kandeel WA, Hammam OA, Attia YM, Mahmoud S, Salah M. Histopathological Evaluation of Insulin-DMSO Formula Designed for Direct Nose-to-brain Delivery. Histol Histopathol 2021;37:431-9.
[6] Bazrgar M, Khodabakhsh P, Dargahi L, Mohagheghi F, Ahmadiani A. MicroRNA Modulation is a Potential Molecular Mechanism for Neuroprotective Effects of Intranasal Insulin Administration in Amyloid βeta Oligomer Induced Alzheimer’s Like Rat Model. Exp Gerontol 2022;164:111812.
[7] Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews. BMJ 2021;372:n71.
[8] Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A Revised Tool for Assessing Risk of Bias in Randomised Trials. BMJ 2019;366:l4898.
[9] Claxton A, Baker LD, Wilkinson CW, Trittschuh EH, Chapman D, Watson GS, et al. Sex and ApoE Genotype Differences in Treatment Response to Two Doses of Intranasal Insulin in Adults with Mild Cognitive Impairment or Alzheimer’s Disease. J Alzheimers Dis 2013;35:789-97.
[10] Craft S, Raman R, Chow TW, Rafii MS, Sun CK, Rissman RA, et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol 2020;77:1099-109.
[11] Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, et al. Intranasal Insulin Therapy for Alzheimer Disease and Amnestic Mild Cognitive Impairment: A Pilot Clinical Trial. Arch Neurol 2012;69:29-38.
[12] Rosenbloom M, Barclay TR, Kashyap B, Hage L, O’Keefe LR, Svitak A, et al. A Phase II, Single-center, Randomized, Double-blind, Placebo-controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer’s Disease. Drugs Aging 2021;38:407-15.
[13] Mustapic M, Tran J, Craft S, Kapogiannis D. Extracellular Vesicle Biomarkers Track Cognitive Changes Following Intranasal Insulin in Alzheimer’s Disease. J Alzheimers Dis 2019;69:489-98.
[14] Craft S, Claxton A, Baker LD, Hanson AJ, Cholerton B, Trittschuh EH, et al. Effects of Regular and Long-acting Insulin on Cognition and Alzheimer’s Disease Biomarkers: A Pilot Clinical Trial. J Alzheimers Dis 2017;57:1325-34.
[15] Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, et al. Long-Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-stage Alzheimer’s Disease Dementia. J Alzheimers Dis 2015;44:897-906.
[16] Rosenbloom MH, Barclay TR, Pyle M, Owens BL, Cagan AB, Anderson CP, et al. A Single-dose Pilot Trial of Intranasal Rapid-acting Insulin in Apolipoprotein E4 Carriers with Mild-moderate Alzheimer’s Disease. CNS Drugs 2014;28:1185-9.
[17] Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, et al. Intranasal Insulin Improves Cognition and Modulates Beta-amyloid in Early AD. Neurology 2008;70:440-8.
[18] Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal Insulin Administration Dosedependently Modulates Verbal Memory and Plasma Amyloid-beta in Memory-impaired Older Adults. J Alzheimers Dis 2008;13:323-31.
[19] Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML, et al. Effects of Intranasal Insulin on Cognition in Memory-impaired Older Adults: Modulation by APOE Genotype. Neurobiol Aging 2006;27:451-8.
[20] Kellar D, Register T, Lockhart SN, Aisen P, Raman R, Rissman RA, et al. Intranasal Insulin Modulates Cerebrospinal Fluid Markers of Neuroinflammation in Mild Cognitive Impairment and Alzheimer’s Disease: A Randomized Trial. Sci Rep 2022;12:1346.
[21] Prabakaran A, Agrawal M, Dethe MR, Ahmed H, Yadav A, Gupta U, et al. Nose-to-brain Drug Delivery for the Treatment of Alzheimer’s Disease: Current Advancements and Challenges. Expert Opin Drug Deliv 2022;19:87-102.
[22] Anderson NH, Woodburn K. Old-age psychiatry. In: Companion to Psychiatric Studies. Amsterdam: Elsevier; 2010. p. 635-92.
[23] Chen YX, Liang N, Li XL, Yang SH, Wang YP, Shi NN. Diagnosis and Treatment for Mild Cognitive Impairment: A Systematic Review of Clinical Practice Guidelines and Consensus Statements. Front Neurol 2021;12:719849.
[24] Gale SA, Acar D, Daffner KR. Dementia. Am J Med 2018;131:1161-9.
[25] Ito K, Hutmacher MM. Predicting the Time to Clinically Worsening in Mild Cognitive Impairment Patients and its Utility in Clinical Trial Design by Modeling a Longitudinal Clinical Dementia Rating Sum of Boxes from the ADNI Database. J Alzheimers Dis 2014;40:967-79.
[26] Evans S, McRae-McKee K, Wong MM, Hadjichrysanthou C, De Wolf F, Anderson R. The Importance of Endpoint Selection: How Effective does a Drug Need to be for Success in a Clinical Trial of a Possible Alzheimer’s Disease Treatment? Eur J Epidemiol 2018;33:635-44.
[27] Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S, et al. Insulin Analogues Differently Activate Insulin Receptor Isoforms and Post-receptor Signalling. Diabetologia 2010;53:1743-53.
[28] Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, et al. Stimulation of Beta-amyloid Precursor Protein Trafficking by Insulin Reduces Intraneuronal Betaamyloid and Requires Mitogen-activated Protein Kinase Signaling. J Neurosci 2001;21:2561-70.
[29] Lee CC, Kuo YM, Huang CC, Hsu KS. Insulin Rescues Amyloid Beta-induced Impairment of Hippocampal Longterm Potentiation. Neurobiol Aging 2009;30:377-87.
[30] De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, et al. Protection of Synapses Against Alzheimer’s-linked Toxins: Insulin Signaling Prevents the Pathogenic Binding of Abeta Oligomers. Proc Natl Acad Sci U S A 2009;106:1971-6.
[31] Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal Fluid and Plasma Insulin Levels in Alzheimer’s Disease: Relationship to Severity of Dementia and Apolipoprotein E Genotype. Neurology 1998;50:164-8.
[32] Lochhead JJ, Wolak DJ, Pizzo ME, Thorne RG. Rapid Transport within Cerebral Perivascular Spaces Underlies Widespread Tracer Distribution in the Brain After Intranasal Administration. J Cereb Blood Flow Metab 2015;35:371-81.
[33] Cao B, Rosenblat JD, Brietzke E, Park C, Lee Y, Musial N, et al. Comparative Efficacy and Acceptability of Antidiabetic Agents for Alzheimer’s Disease and Mild Cognitive Impairment: A Systematic Review and Network Meta-analysis. Diabetes Obes Metab 2018;20:2467-71.