Abstract
Background/objectives
Diabetic subjects are at increased risk of subtle cognitive impairment since the disease early stages and of dementia later in life. In animal models, glucagon-like peptide-1 receptor agonizts (GLP1-RAs) have been shown to exert neuroprotective effects, expecially in the memory domain. We assessed whether treatment with a GLP1-RA might affect cognitive functions in type 2 diabetic subjects independently on the weight loss it might induce.
Subjects/methods
Forty metformin-treated obese subjects with prediabetes or newly diagnosed type 2 diabetes mellitus, received liraglutide (1.8 mg/d) (n = 20) or lifestyle counseling (dietary intervention and exercise training) (n = 20) until achieving a modest and comparable weight loss (−7% of initial body weight).
Interventions/methods
A detailed neuropsychological assessment before and after weight loss was completed in 16 patients per arm, who were administered a total of seven psychological tests, thus assessing three composite domain z-scores for attention, memory, and executive control.
Results
After comparable weight loss and superimposable glycemic control and insulin sensitivity, a significant increase in short term memory (mean Digit Span Z score from −0.06 to 0.80, p = 0.024) and memory composite z-score (mean memory z-score from −0.67 to 0.032, p = 0.0065) was observed in the liraglutide exposed subjects (between group p = 0.041 and p = 0.033, respectively).
Conclusions
Liraglutide might slow down memory function decline in diabetic patients in early, and possibly preclinical stages of the disease.
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References
Zheng F, Yan L, Yang Z, Zhong B, Xie W. HbA1c, diabetes and cognitive decline: the English Longitudinal Study of Ageing. Diabetologia. 2018;61:839–48.
Callisaya ML, Beare R, Moran C, Phan T, Wang W, Srikanth VK. Type 2 diabetes mellitus, brain atrophy and cognitive decline in older people: a longitudinal study. Diabetologia. 2019;62:448–58.
Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ. 2005;330:1360.
Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. Eur J Pharmacol. 2008;585:97–108.
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;369:540–8.
Sanz CM, Ruidavets JB, Bongard V, Marquié JC, Hanaire H, Ferrières J, et al. Relationship between markers of insulin resistance, markers of adiposity, HbA1c, and cognitive functions in a middle-aged population-based sample: the MONA LISA study. Diabetes Care. 2013;36:1512–21.
Ekblad LL, Rinne JO, Puukka P, Laine H, Ahtiluoto S, Sulkava R, et al. Insulin resistance predicts cognitive decline: an 11-year follow-up of a nationally representative adult population sample. Diabetes Care. 2017;40:751–8.
Bove RM, Brick DJ, Healy BC, Mancuso SM, Gerweck AV, Bredella MA, et al. Metabolic and endocrine correlates of cognitive function in healthy young women. Obesity. 2013;21:1343–9.
Spauwen PJ, Murphy RA, Jónsson PV, Sigurdsson S, Garcia ME, Eiriksdottir G, et al. Associations of fat and muscle tissue with cognitive status in older adults: the AGES-Reykjavik Study. Age Ageing. 2017;46:250–7.
Koekkoek PS, Kappelle LJ, van den Berg E, Rutten GE, Biessels GJ. Cognitive function in patients with diabetes mellitus: guidance for daily care. Lancet Neurol. 2015;14:329–40.
Launer LJ, Miller ME, Williamson JD, Lazar RM, Gerstein HC, Murray AM, et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy. Lancet Neurol. 2011;10:969–77.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.
Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M, et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N Engl J Med. 2015;373:11–22.
Santilli F, Simeone PG, Guagnano MT, Leo M, Maccarone MT, Di Castelnuovo A, et al. Effects of liraglutide on weight loss, fat distribution, and beta-cell function in obese subjects with prediabetes or early type 2 diabetes. Diabetes Care. 2017;40:1556–64.
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;9:1173–9.
Qi L, Ke L, Liu X, Liao L, Ke S, Liu X, et al. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3beta pathway in an amyloid beta protein induced alzheimer disease mouse model. Eur J Pharmacol. 2016;783:23–32.
Chen S, Sun J, Zhao G, Guo A, Chen Y, Fu R, et al. Liraglutide improves water maze learning and memory performance while reduces hyperphosphorylation of tau and neurofilaments in APP/PS1/tau triple transgenic mice. Neurochem Res. 2017;42:2326–35.
Classification and Diagnosis of Diabetes. Standards of medical care in diabetes-2018. Diabetes Care. 2018;41(Suppl 1):s13–27.
Ross R, Leger L, Morris D, de Guise J, Guardo R. Quantification of adipose tissue by MRI: relationship with anthropometric variables. J Appl Physiol. (1985). 1992;72:787–95.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462–70.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–9.
Cretti A, Lehtovirta M, Bonora E, Brunato B, Zenti MG, Tosi F, et al. Assessment of beta-cell function during the oral glucose tolerance test by a minimal model of insulin secretion. Eur J Clin Investig. 2001;31:405–16.
MD Lezak. Neuropsychological assessment (3rd ed.). Oxford University Press, New York, 1995.
Tu MC, Lo CP, Huang CF, Huang WH, Deng JF, Hsu YH. Visual attention performances and related cerebral microstructural integrity among subjects with subjective cognitive decline and mild cognitive impairment. Front Aging Neurosci. 2018;10:268.
Beavers KM, Leng I, Rapp SR, Miller ME, Houston DK, Marsh AP, et al. Effects of longitudinal glucose exposure on cognitive and physical function: results from the action for health in diabetes movement and memory study. J Am Geriatr Soc. 2017;65:137–45.
Kemp AH, Lopez SR, Passos VMA, Bittencourt MS, Dantas EM, Mill JG, et al. Insulin resistance and carotid intima-media thickness mediate the association between resting-state heart rate variability and executive function: a path modelling study. Biol Psychol. 2016;117:216–24.
Palta P, Schneider AL, Biessels GJ, Touradji P, Hill-Briggs F. Magnitude of cognitive dysfunction in adults with type 2 diabetes: a meta-analysis of six cognitive domains and the most frequently reported neuropsychological tests within domains. J Int Neuropsychol Soc. 2014;20:278–91.
Jones G, Macken B. Questioning short-term memory and its measurement: why digit span measures long-term associative learning. Cognition. 2015;144:1–13.
Caffarra P, Vezzadini G, Dieci F, Zonato F, Venneri A. Rey–Osterrieth complex figure: normative values in an Italian population sample. Neurol Sci. 2002;22:443–7.
Della Sala S, Laiacona M, Spinnler H, Ubezio C. A cancellation test: its reliability in assessing attentional deficits in Alzheimer’s disease. Psychol Med. 1992;22:885–901.
Mondini S, Mapelli P, Vestri A, Arcara G. Brief Neuropsychological Examination 2011.
Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol. 2014;2:246–55.
Yaffe K, Falvey C, Hamilton N, Schwartz AV, Simonsick EM, Satterfield S, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol. 2012;69:1170–5.
van Agtmaal MJM, Houben Ajhm, de Wit V, Henry RMA, Schaper NC, Dagnelie PC, et al. Prediabetes Is associated with structural brain abnormalities: the Maastricht study. Diabetes Care. 2018;41:2535–43.
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.
Perna S, Mainardi M, Astrone P, Gozzer C, Biava A, Bacchio R, et al. 12-month effects of incretins versus SGLT2-Inhibitors on cognitive performance and metabolic profile. A randomized clinical trial in the elderly with Type-2 diabetes mellitus. Clin Pharmacol. 2018;10:141–51.
Calsolaro V, Edison P. Novel GLP-1 (Glucagon-Like Peptide-1) analogues and insulin in the treatment for Alzheimer’s disease and other neurodegenerative diseases. CNS Drugs. 2015;29:1023–39.
Hunter K, Holscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci. 2012;13:33.
Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the central/peripheral nervous system: crosstalk in diabetes. Trends Endocrinol Metab. 2017;28:88–103. https://doi.org/10.1016/j.tem.2016.10.001
Hamilton A, Patterson S, Porter D, Gault VA, Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res. 2011;89:481–9.
Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Investig. 2013;123:2730–6.
Femminella GD, Frangou E, Love SB, Busza G, Holmes C, Ritchie C, et al. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019;20:191.
Mansur RB, Ahmed J, Cha DS, Woldeyohannes HO, Subramaniapillai M, Lovshin J, et al. Liraglutide promotes improvements in objective measures of cognitive dysfunction in individuals with mood disorders: a pilot, open-label study. J Affect Disord. 2017;207:114–20.
Lehtisalo J, Lindstrom J, Ngandu T, Kivipelto M, Ahtiluoto S, Ilanne-Parikka P, et al. Association of long-term dietary fat intake, exercise, and weight with later cognitive function in the Finnish Diabetes Prevention Study. J Nutr Health Aging. 2016;20:146–54.
Siervo M, Arnold R, Wells JC, Tagliabue A, Colantuoni A, Albanese E, et al. Intentional weight loss in overweight and obese individuals and cognitive function: a systematic review and meta-analysis. Obes Rev. 2011;12:968–83.
Espeland MA, Luchsinger JA, Baker LD, Neiberg R, Kahn SE, Arnold SE, et al. Effect of a long-term intensive lifestyle intervention on prevalence of cognitive impairment. Neurology. 2017;88:2026–35.
Lampit A, Ebster C, Valenzuela M. Multi-domain computerized cognitive training program improves performance of bookkeeping tasks: a matched-sampling active-controlled trial. Front Psychol. 2014;5:794.
Acknowledgements
We thank Prof Riccardo Bonadonna and Dr Maria Linda Boselli for their contribution in the analysis of the data; for education in the lifestyle arm; Dr Ermanno Angelucci for patients’ recruitment; Drs Marika Leo, Alessia Quirino, and Gabriella Bosco for patients education; Dr Matteo Polimene and Maria Pia Baldassare for help in the neuropsychological data management.
Funding
This study was supported by a grant from the Italian Ministry of University and Research (PRIN no. 2010JS3PMZ to FS).
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FV, PGS, and FS contributed to the study design and protocol, the analysis plan, the supervision of the analysis, study implementation, data acquisition and interpretation, statistical analyses, writing of the manuscript, and critical revision and final approval of the manuscript. PGS and AB contributed to study implementation, data acquisition and interpretation, and writing of the manuscript. MTG, FC, RL, and RT contributed to study implementation, data acquisition and interpretation, and final approval of the manuscript. ADC contributed to statistical analysis and data interpretation. AC contributed to the supervision of the analysis, data interpretation, writing of the manuscript, and critical revision and final approval of the manuscript. FS, FV, and AC are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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AC received lecture fees and fees for serving on advisory boards from Novo Nordisk, Eli Lilly, AstraZeneca, Sanofi Aventis, Merck Sharp & Dohme, and Takeda; and grant support to his institution from Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.
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Vadini, F., Simeone, P.G., Boccatonda, A. et al. Liraglutide improves memory in obese patients with prediabetes or early type 2 diabetes: a randomized, controlled study. Int J Obes 44, 1254–1263 (2020). https://doi.org/10.1038/s41366-020-0535-5
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DOI: https://doi.org/10.1038/s41366-020-0535-5
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