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Diabetes Therapies for Dementia

  • Chris Moran
  • Michele L. Callisaya
  • Velandai Srikanth
  • Zoe ArvanitakisEmail author
Dementia (K.S. Marder, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Dementia

Abstract

Purpose of review

Type 2 diabetes (T2D) is a well-established risk factor for the development of dementia. Dementia and T2D share some underlying pathophysiology that has led to interest in the potential to repurpose drugs used in the management of T2D to benefit brain health. This review describes the scientific data available on the use of T2D medications for the risk reduction or management of dementia, in people with and without T2D.

Recent findings

Results from basic laboratory research support the potential for commonly-used medications for T2D, including those with direct glucose-lowering properties, to have a beneficial effect on brain health. However, human studies have been mostly observational in nature and report conflicting results. Preliminary data suggest that intranasal insulin, metformin, and GLP-1 agonists show promise for dementia, but confirmatory evidence for their benefit in dementia is still lacking.

Summary

Current evidence does not support the repurposing of T2D medications for dementia risk reduction or management. Research in the field of T2D and dementia is active, and further data are required before definitive conclusions can be drawn.

Keywords

Type 2 diabetes Dementia Drugs 

Notes

Compliance with Ethical Standards

Conflict of Interest

Chris Moran, Michele L. Callisaya, and Velandai Srikanth each declares no potential conflicts of interest. Zoe Arvanitakis reports grants from National Institutes of Health (R01 NS084965 and RF1 AG059621), during the conduct of the study; other from Amylyx, outside the submitted work.

Human and Animal Rights and Informed Consent

This article is a review of the published scientific literature, and no human or animal subjects were studied by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9(1):63–75 e2.PubMedGoogle Scholar
  2. 2.
    Walker VM, Davies NM, Jones T, Kehoe PG, Martin RM. Can commonly prescribed drugs be repurposed for the prevention or treatment of Alzheimer's and other neurodegenerative diseases? Protocol for an observational cohort study in the UK clinical practice research datalink. BMJ Open. 2016;6(12):e012044.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia aging study. Diabetes. 2002;51(4):1256–62.PubMedGoogle Scholar
  4. 4.
    Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol. 2006;5(1):64–74.PubMedGoogle Scholar
  5. 5.
    Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540–8.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168–81.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Moran C, Beare R, Phan TG, Bruce DG, Callisaya ML, Srikanth V, et al. Type 2 diabetes mellitus and biomarkers of neurodegeneration. Neurology. 2015;85(13):1123–30.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Moran C, Beare R, Wang W, Callisaya M, Srikanth V, Alzheimer's disease neuroimaging I. Type 2 diabetes mellitus, brain atrophy, and cognitive decline. Neurology. 2019.Google Scholar
  9. 9.
    Moran C, Phan TG, Chen J, Blizzard L, Beare R, Venn A, et al. Brain atrophy in type 2 diabetes: regional distribution and influence on cognition. Diabetes Care. 2013;36(12):4036–42.PubMedPubMedCentralGoogle Scholar
  10. 10.
    • Vieira MNN, Lima-Filho RAS, De Felice FG. Connecting Alzheimer's disease to diabetes: underlying mechanisms and potential therapeutic targets. Neuropharmacology. 2018;136(Pt B):160–71 An excellent review article expanding upon the potential mechanistic pathways that may be relevant in the repurposing of drugs used in the management of T2D for the prevention or management of dementia.PubMedGoogle Scholar
  11. 11.
    Areosa Sastre A, Vernooij RW, Gonzalez-Colaco Harmand M, Martinez G. Effect of the treatment of type 2 diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev. 2017;6:CD003804.PubMedGoogle Scholar
  12. 12.
    Cha DS, Vahtra M, Ahmed J, Kudlow PA, Mansur RB, Carvalho AF, et al. Repurposing of anti-diabetic agents for the treatment of cognitive impairment and mood disorders. Curr Mol Med. 2016;16(5):465–73.PubMedGoogle Scholar
  13. 13.
    • Weinstein G, Davis-Plourde KL, Conner S, Himali JJ, Beiser AS, Lee A, et al. Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer's disease: pooled analysis from 5 cohorts. PLoS One. 2019;14(2):e0212293 A recent and large study combining 5 separate cohort studies that sheds important light on the associations between commonly-used glucose-lowering drugs in T2D and dementia risk. PubMedPubMedCentralGoogle Scholar
  14. 14.
    Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L, et al. Effects of the insulin sensitizer metformin in Alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord. 2017;31(2):107–13.PubMedPubMedCentralGoogle Scholar
  15. 15.
    American Diabetes A. Standards of Medical Care in Diabetes 2018. Diabetes care. 2018;40(S1).Google Scholar
  16. 16.
    Rena G, Pearson ER, Sakamoto K. Molecular mechanism of action of metformin: old or new insights? Diabetologia. 2013;56(9):1898–906.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Alzoubi KH, Khabour OF, Al-Azzam SI, Tashtoush MH, Mhaidat NM. Metformin eased cognitive impairment induced by chronic L-methionine administration: potential role of oxidative stress. Curr Neuropharmacol. 2014;12(2):186–92.PubMedPubMedCentralGoogle Scholar
  18. 18.
    El-Mir MY, Detaille D, G RV, Delgado-Esteban M, Guigas B, Attia S, et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. Journal of molecular neuroscience: MN. 2008;34(1):77–87.PubMedGoogle Scholar
  19. 19.
    Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer's-like changes. Neuropharmacology. 2011;60(6):910–20.PubMedGoogle Scholar
  20. 20.
    Zhao RR, Xu XC, Xu F, Zhang WL, Zhang WL, Liu LM, et al. Metformin protects against seizures, learning and memory impairments and oxidative damage induced by pentylenetetrazole-induced kindling in mice. Biochem Biophys Res Commun. 2014;448(4):414–7.PubMedGoogle Scholar
  21. 21.
    Chen Y, Zhou K, Wang R, Liu Y, Kwak YD, Ma T, et al. Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci U S A. 2009;106(10):3907–12.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: a population-based case-control study. J Am Geriatr Soc. 2012;60(5):916–21.PubMedGoogle Scholar
  23. 23.
    Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, Brodaty H, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013;36(10):2981–7.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Hsu CC, Wahlqvist ML, Lee MS, Tsai HN. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J Alzheimers Dis. 2011;24(3):485–93.PubMedGoogle Scholar
  25. 25.
    Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. J Alzheimers Dis. 2014;41(1):61–8.PubMedGoogle Scholar
  26. 26.
    Chin-Hsiao T. Metformin and the risk of dementia in type 2 diabetes patients. Aging Dis. 2019;10(1):37–48.PubMedPubMedCentralGoogle Scholar
  27. 27.
    • Bohlken J, Jacob L, Kostev K. Association between the use of antihyperglycemic drugs and dementia risk: a case-control study. J Alzheimers Dis. 2018;66(2):725–32 A large study examining the use of monotherapy and combination therapy of glucose lowering drugs on dementia risk. PubMedGoogle Scholar
  28. 28.
    Orkaby AR, Cho K, Cormack J, Gagnon DR, Driver JA. Metformin vs sulfonylurea use and risk of dementia in US veterans aged >/=65 years with diabetes. Neurology. 2017;89(18):1877–85.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. Jama. 2002;287(3):360–72.PubMedGoogle Scholar
  30. 30.
    Osborne C, West E, Nolan W, McHale-Owen H, Williams A, Bate C. Glimepiride protects neurons against amyloid-beta-induced synapse damage. Neuropharmacology. 2016;101:225–36.PubMedGoogle Scholar
  31. 31.
    Chen F, Dong RR, Zhong KL, Ghosh A, Tang SS, Long Y, et al. Antidiabetic drugs restore abnormal transport of amyloid-beta across the blood-brain barrier and memory impairment in db/db mice. Neuropharmacology. 2016;101:123–36.PubMedGoogle Scholar
  32. 32.
    Tseng CH. Pioglitazone reduces dementia risk in patients with type 2 diabetes mellitus: a retrospective cohort analysis. J Clin Med 2018;7(10).PubMedCentralGoogle Scholar
  33. 33.
    Lu CH, Yang CY, Li CY, Hsieh CY, Ou HT. Lower risk of dementia with pioglitazone, compared with other second-line treatments, in metformin-based dual therapy: a population-based longitudinal study. Diabetologia. 2018;61(3):562–73.PubMedGoogle Scholar
  34. 34.
    Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging. 2011;32(9):1626–33.PubMedGoogle Scholar
  35. 35.
    Ryan CM, Freed MI, Rood JA, Cobitz AR, Waterhouse BR, Strachan MW. Improving metabolic control leads to better working memory in adults with type 2 diabetes. Diabetes Care. 2006;29(2):345–51.PubMedGoogle Scholar
  36. 36.
    Singh S, Loke YK, Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Jama. 2007;298(10):1189–95.PubMedGoogle Scholar
  37. 37.
    Palleria C, Leporini C, Maida F, Succurro E, De Sarro G, Arturi F, et al. Potential effects of current drug therapies on cognitive impairment in patients with type 2 diabetes. Front Neuroendocrinol. 2016;42:76–92.PubMedGoogle Scholar
  38. 38.
    During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med. 2003;9(9):1173–9.PubMedGoogle Scholar
  39. 39.
    Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: interaction between type 2 diabetes and Alzheimer's disease. Behav Brain Res. 2009;205(1):265–71.PubMedGoogle Scholar
  40. 40.
    McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci. 2011;31(17):6587–94.PubMedGoogle Scholar
  41. 41.
    Talbot K. Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag. 2014;4(1):31–40.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Gejl M, Gjedde A, Egefjord L, Moller A, Hansen SB, Vang K, et al. In Alzheimer's disease, 6-month treatment with GLP-1 analog prevents decline of brain glucose metabolism: randomized, placebo-controlled, double-blind clinical trial. Front Aging Neurosci. 2016;8:108.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol. 2009;5(5):262–9.PubMedGoogle Scholar
  44. 44.
    Rizzo MR, Barbieri M, Boccardi V, Angellotti E, Marfella R, Paolisso G. Dipeptidyl peptidase-4 inhibitors have protective effect on cognitive impairment in aged diabetic patients with mild cognitive impairment. J Gerontol A Biol Sci Med Sci. 2014;69(9):1122–31.PubMedGoogle Scholar
  45. 45.
    Kim YG, Jeon JY, Kim HJ, Kim DJ, Lee KW, Moon SY, Han S Risk of dementia in older patients with type 2 diabetes on dipeptidyl-peptidase IV inhibitors versus sulfonylureas: a real-world population-based cohort study. J Clin Med 2018;8(1).PubMedCentralGoogle Scholar
  46. 46.
    Isik AT, Soysal P, Yay A, Usarel C. The effects of sitagliptin, a DPP-4 inhibitor, on cognitive functions in elderly diabetic patients with or without Alzheimer's disease. Diabetes Res Clin Pract. 2017;123:192–8.PubMedGoogle Scholar
  47. 47.
    Biessels GJ, Janssen J, van den Berg E, Zinman B, Espeland MA, Mattheus M, et al. Rationale and design of the CAROLINA(R) - cognition substudy: a randomised controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus. BMC Neurol. 2018;18(1):7.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Rosenstock J, Perkovic V, Alexander JH, Cooper ME, Marx N, Pencina MJ, et al. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA((R))): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018;17(1):39.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Cukierman-Yaffe T, Bosch J, Diaz R, Dyal L, Hancu N, Hildebrandt P, et al. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol. 2014;2(7):562–72.PubMedGoogle Scholar
  50. 50.
    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(1):29–38.PubMedGoogle Scholar
  51. 51.
    Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta. 2009;1792(5):482–96.PubMedGoogle Scholar
  52. 52.
    Craft S, Asthana S, Newcomer JW, Wilkinson CW, Matos IT, Baker LD, et al. Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry. 1999;56(12):1135–40.PubMedGoogle Scholar
  53. 53.
    McNay EC, Recknagel AK. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol Learn Mem. 2011;96(3):432–42.PubMedPubMedCentralGoogle Scholar
  54. 54.
    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;45(4):1269–70.PubMedGoogle Scholar
  55. 55.
    de la Monte SM. Brain insulin resistance and deficiency as therapeutic targets in Alzheimer's disease. Curr Alzheimer Res. 2012;9(1):35–66.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Chiu SL, Chen CM, Cline HT. Insulin receptor signaling regulates synapse number, dendritic plasticity, and circuit function in vivo. Neuron. 2008;58(5):708–19.PubMedPubMedCentralGoogle Scholar
  57. 57.
    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 beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci. 2001;21(8):2561–70.PubMedGoogle Scholar
  58. 58.
    Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P, Sheline Y, et al. Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging. 1996;17(1):123–30.PubMedGoogle Scholar
  59. 59.
    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(3):451–8.PubMedGoogle Scholar
  60. 60.
    Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis 2008;13(3):323–31.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Stein MS, Scherer SC, Ladd KS, Harrison LC. A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer's disease. J Alzheimers Dis. 2011;26(3):477–84.PubMedGoogle Scholar
  62. 62.
    Derakhshan F, Toth C. Insulin and the brain. Curr Diabetes Rev. 2013;9(2):102–16.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Chris Moran
    • 1
    • 2
    • 3
    • 4
  • Michele L. Callisaya
    • 1
    • 4
  • Velandai Srikanth
    • 1
    • 2
    • 4
  • Zoe Arvanitakis
    • 5
    Email author
  1. 1.Peninsula Clinical School, Central Clinical SchoolMonash UniversityFrankstonAustralia
  2. 2.Departments of Medicine and Geriatric Medicine, Peninsula HealthFrankstonAustralia
  3. 3.Department of Aged Care, Caulfield Hospital, Alfred HealthCaulfieldAustralia
  4. 4.Menzies Institute for Medical ResearchUniversity of TasmaniaHobartAustralia
  5. 5.Department of Neurological Sciences, Rush Memory Clinic, Rush Alzheimer’s Disease CenterRush University Medical CenterChicagoUSA

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