BACKGROUND: The effect of antidiabetic medication on cognitive function is unclear. We analyzed the association between five antidiabetic drugs and change in Mini-Mental State Examination (MMSE) scores in patients with diabetes and dementia. METHODS: Using the Swedish Dementia Registry and four supplementary Swedish registers/databases, we identified 1873 patients (4732 observations) with diagnosis of type 2 diabetes (diabetes) and Alzheimer's disease or mixed-pathology dementia who were followed up at least once after dementia diagnosis. Use of metformin, insulin, sulfonylurea, thiazolidinediones (TZD), and dipeptidyl-peptidase-4 inhibitors (DPP-4i) was identified at baseline. Prevalent-user, incident-user, and drug-drug cohorts were sampled, and propensity-score matching was used to analyze comparable subjects. Beta coefficients with 95% confidence intervals (CI) from the random intercept and slope linear mixed-effects models determined the association between the use of antidiabetic medications and decline in MMSE score points between the follow-ups. Inverse-probability weighting was used to account for patient dropout. RESULTS: Compared to non-users, prevalent users of metformin (beta 0.89, 95% CI 0.44; 1.33) and DPP-4i (0.72, 0.06; 1.37) experienced a slower cognitive decline with time. Secondly, compared to DPP-4i, the use of insulin (-1.00, -1.95; -0.04) and sulfonylureas (-1.19; -2.33; -0.04) was associated with larger point-wise decrements in MMSE with annual intervals. CONCLUSIONS: In this large cohort of patients with diabetes and dementia, the use of metformin and DPP-4i was associated with a slower decline in MMSE scores. Further examination of the cognitive effects of metformin and incretin-based medications is warranted.

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Neurology 2nd Faculty of Medicine Charles University Motol University Hospital Prague Czech Republic

Division of Clinical Geriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institutet Neo Blickagången 16 14152 Huddinge Sweden

Division of Neurogeriatrics Center for Alzheimer Research Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Growth and Metabolism Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Theme Aging Karolinska University Hospital Huddinge Sweden

Zobrazit více v PubMed

Bunn F, Burn AM, Goodman C, Rait G, Norton S, Robinson L, et al. Comorbidity and dementia: a scoping review of the literature. BMC Med. 2014;12:192. PubMed PMC

Biessels GJ, Despa F. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nat Rev Endocrinol. 2018;14:591–604. PubMed PMC

Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E. Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis. 2018;65(4):1225–1236. PubMed PMC

Wu CY, Ouk M, Wong YY, Anita NZ, Edwards JD, Yang P, et al. Relationships between memory decline and the use of metformin or DPP4 inhibitors in people with type 2 diabetes with normal cognition or Alzheimer’s disease, and the role APOE carrier status. Alzheimers Dement. 2020;16:1663–73. PubMed PMC

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):916–921. PubMed

Liu Q, Li S, Quan H, Li J. Vitamin B12 status in metformin treated patients: systematic review. PLoS One. 2014;9(6):e100379. PubMed PMC

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):168–181. PubMed PMC

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. PubMed PMC

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):562–572. PubMed

Wium-Andersen IK, Osler M, Jorgensen MB, Rungby J, Wium-Andersen MK. Antidiabetic medication and risk of dementia in patients with type 2 diabetes: a nested case-control study. Eur J Endocrinol. 2019;181(5):499–507. PubMed

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):1877–1885. PubMed PMC

Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetologia. 2018;61(12):2461–2498. PubMed

Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009;301(15):1565–1572. PubMed PMC

Punthakee Z, Miller ME, Launer LJ, Williamson JD, Lazar RM, Cukierman-Yaffee T, et al. Poor cognitive function and risk of severe hypoglycemia in type 2 diabetes: post hoc epidemiologic analysis of the ACCORD trial. Diabetes Care. 2012;35(4):787–793. PubMed PMC

American Diabetes A 12 Older adults: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S152–SS62. PubMed

Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M, et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord. 2010;30(2):131–146. PubMed PMC

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. PubMed PMC

Grieco M, Giorgi A, Gentile MC, d'Erme M, Morano S, Maras B, et al. Glucagon-like peptide-1: a focus on neurodegenerative d. Front Neurosci. 2019;13:1112. PubMed PMC

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;123:192–198. PubMed

Biessels GJ, Verhagen C, Janssen J, van den Berg E, Zinman B, Rosenstock J, et al. Effect of linagliptin on cognitive performance in patients with type 2 diabetes and cardiorenal comorbidities: the CARMELINA randomized trial. Diabetes Care. 2019;42(10):1930–1938. PubMed

Religa D, Fereshtehnejad SM, Cermakova P, Edlund AK, Garcia-Ptacek S, Granqvist N, et al. SveDem, the Swedish Dementia Registry - a tool for improving the quality of diagnostics, treatment and care of dementia patients in clinical practice. PLoS One. 2015;10(2):e0116538. PubMed PMC

Eriksdotter M, Kåwe K, Mattsson UB, Nilsson A, Mayer-Standar S, Nägga K, et al. Svenska Demensregister Årsrapport 2018 Accessible online: https://www.ucr.uu.se/svedem/om-svedem/arsrapporter/svedem-arsrapport2018/viewdocument/967. Svenska Demensregistret; 2019.

Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450. PubMed PMC

World Health Organization . The International Classification of Diseases 10th revision (ICD-10) 1993.

Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. PubMed

Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43(11):1130–1139. PubMed

Ludvigsson JF, Svedberg P, Olen O, Bruze G, Neovius M. The longitudinal integrated database for health insurance and labour market studies (LISA) and its use in medical research. Eur J Epidemiol. 2019;34(4):423–437. PubMed PMC

Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, Bergman U, et al. The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf. 2007;16(7):726–735. PubMed

Brooke HL, Talback M, Hornblad J, Johansson LA, Ludvigsson JF, Druid H, et al. The Swedish cause of death register. Eur J Epidemiol. 2017;32(9):765–773. PubMed PMC

Handels R, Jonsson L, Garcia-Ptacek S, Eriksdotter M, Wimo A. Controlling for selective dropout in longitudinal dementia data: application to the SveDem registry. Alzheimers Dement. 2020;16(5):789–796. PubMed PMC

R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2020. URL https://www.R-project.org/.

Scherrer JF, Salas J, Floyd JS, Farr SA, Morley JE, Dublin S. Metformin and sulfonylurea use and risk of incident dementia. Mayo Clin Proc. 2019;94(8):1444–1456. PubMed PMC

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):725–732. PubMed

Hettich MM, Matthes F, Ryan DP, Griesche N, Schroder S, Dorn S, et al. The anti-diabetic drug metformin reduces BACE1 protein level by interfering with the MID1 complex. PLoS One. 2014;9(7):e102420. PubMed PMC

Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology. 2011;60(6):910–920. PubMed

Lu XY, Huang S, Chen QB, Zhang D, Li W, Ao R, et al. Metformin ameliorates abeta pathology by insulin-degrading enzyme in a transgenic mouse model of Alzheimer’s disease. Oxidative Med Cell Longev. 2020;2020:2315106. PubMed PMC

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):3907–3912. PubMed PMC

Son SM, Shin HJ, Byun J, Kook SY, Moon M, Chang YJ, et al. Metformin facilitates amyloid-beta generation by beta- and gamma-secretases via autophagy activation. J Alzheimers Dis. 2016;51(4):1197–1208. PubMed

Secnik J, Xu H, Schwertner E, Hammar N, Alvarsson M, Winblad B, et al. Dementia diagnosis is associated with changes in antidiabetic drug prescription: an open-cohort study of approximately 130,000 Swedish subjects over 14 years. J Alzheimers Dis. 2020;76(4):1581–94. PubMed PMC

Chen KC, Chung CH, Lu CH, Tzeng NS, Lee CH, Su SC, et al. Association between the use of dipeptidyl peptidase 4 inhibitors and the risk of dementia among patients with type 2 diabetes in Taiwan. J Clin Med. 2020;9(3):660. PubMed PMC

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):1122–1131. PubMed

Borzi AM, Condorelli G, Biondi A, Basile F, Vicari ESD, Buscemi C, et al. Effects of vildagliptin, a DPP-4 inhibitor, in elderly diabetic patients with mild cognitive impairment. Arch Gerontol Geriatr. 2019;84:103896. PubMed

Cukierman-Yaffe T, Bosch J, Jung H, Punthakee Z, Gerstein HC. Hypoglycemia and incident cognitive dysfunction: a post hoc analysis from the ORIGIN trial. Diabetes Care. 2019;42(1):142–147. PubMed

Morales J. The pharmacologic basis for clinical differences among GLP-1 receptor agonists and DPP-4 inhibitors. Postgrad Med. 2011;123(6):189–201. PubMed

Kosaraju J, Holsinger RMD, Guo L, Tam KY. Linagliptin, a dipeptidyl peptidase-4 inhibitor, mitigates cognitive deficits and pathology in the 3xTg-AD mouse model of Alzheimer’s disease. Mol Neurobiol. 2017;54(8):6074–6084. PubMed

Athauda D, Foltynie T. Insulin resistance and Parkinson's disease: a new target for disease modification? Prog Neurobiol. 2016;145-146:98–120. PubMed

Andrews JS, Desai U, Kirson NY, Zichlin ML, Ball DE, Matthews BR. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials. Alzheimers Dement (N Y) 2019;5:354–363. PubMed PMC

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. PubMed PMC

National Board of Health and Welfare / Socialstyrelsen: National Guidelines for Diabetes Care. Support for governance and management / Nationella Riktlinjer för Diabetesvård. Stöd för Styrning och Ledning. Accessible online: https://www.socialstyrelsen.se/globalassets/sharepoint-dokument/artikelkatalog/nationella-riktlinjer/2018-10-25.pdf2018:[135 p.].

Takeda and Zinfandel Pharmaceuticals discontinue TOMMORROW trial following planned futility analysis. [press release]. 2018; Available from: https://www.takeda.com/newsroom/newsreleases/2018/takeda-tommorrow-trial/.