Effect of dulaglutide on cognitive impairment in type 2 diabetes: an exploratory analysis of the REWIND trial
Open accessAbstract
Background Diabetes is an independent risk factor for cognitive impairment. We aimed to investigate the association between the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide and cognitive impairment as an exploratory analysis within the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) trial.Methods REWIND is a randomised, double-blind placebo-controlled trial at 371 sites in 24 countries. We included men and women (aged ≥50 years) with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors, glycated haemoglobin of up to 9·5% (80 mmol/mol) on a maximum of two oral glucose-lowering drugs with or without basal insulin, and a body-mass index of at least 23 kg/m 2. Participants were randomly assigned (1:1) subcutaneous injections once a week of either dulaglutide (1·5 mg) or an equal volume of matching placebo. Randomisation was done using a computer-generated code with stratification by site. Participants and all study personnel were masked to treatment allocation until the database was locked. Participants were followed up at least every 6 months for the composite primary outcome of stroke, myocardial infarction, or death from cardiovascular or unknown causes. Cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). We present here the exploratory primary cognitive outcome, which was the first occurrence of a follow-up score on MoCA or DSST that was 1·5 SDs or more below the baseline mean score in the participant's country. All analyses were done using an intention-to-treat approach. The REWIND trial is registered with ClinicalTrials.gov, NCT01394952.Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were randomly assigned to either dulaglutide (n=4949) or placebo (n=4952). During median follow-up of 5·4 (IQR 5·1-5·9) years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 were assigned dulaglutide and 4372 were assigned placebo. The cognitive outcome occurred in 4·05 per 100 patient-years in participants assigned dulaglutide and 4·35 per 100 patient-years in people assigned placebo (hazard ratio [HR] 0·93, 95% CI 0·85-1·02; p=0·11). After post-hoc adjustment for individual standardised baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0·86, 95% CI 0·79-0·95; p=0·0018).Interpretation Long-term treatment with dulaglutide might reduce cognitive impairment in people with type 2 diabetes. Further studies of this drug focused on brain health and cognitive function are clearly indicated.Funding Eli Lilly and Company.
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Clinical studies reported a reduction in cognitive impairment and lower dementia incidence among type 2 diabetes patients treated with GLP-1R agonists.
“the neuroprotective effects of GLP-1R agonists were substantiated by clinical studies that reported a reduction in cognitive impairment and lower dementia incidence among type 2 diabetes patients.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [608]
An exploratory analysis of the REWIND trial demonstrated that long-term treatment with the GLP-1 receptor agonist dulaglutide reduced cognitive decline in patients with type 2 diabetes.
“An exploratory analysis of the REWIND trial demonstrated that long-term treatment with the GLP-1RA dulaglutide reduced cognitive decline in patients with T2D [33].”
Cites
The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment
Nasreddine, Z. S., Phillips, N. A., Bédirian, V., Charbonneau, S., Whitehead, V., Collin, I., Cummings, J. L., & Chertkow, H. (2005) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2005.53221.x · Cited by 25,553 · see citing works
Analysing controlled trials with baseline and follow up measurements
Vickers, A. J., & Altman, D. G. (2001) · BMJ · doi:10.1136/bmj.323.7321.1123 · Cited by 2,116 · see citing works
Kristensen, S. L., Rørth, R., Jhund, P. S., Docherty, K. F., Sattar, N., Preiss, D., Køber, L., Petrie, M. C., & McMurray, J. J. V. (2019) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30249-9 · Cited by 1,663 · see citing works
Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies
Cukierman, T., Gerstein, H. C., & Williamson, J. D. (2005) · Diabetologia · doi:10.1007/s00125-005-0023-4 · Cited by 1,049 · see citing works
Self-citationGlucagon-like peptide-1 receptor is involved in learning and neuroprotection
During, M. J., Cao, L., Zuzga, D. S., Francis, J. S., Fitzsimons, H. L., Jiao, X., Bland, R. J., Klugmann, M., Banks, W. A., Drucker, D. J., et al. (2003) · Nature Medicine · doi:10.1038/nm919 · Cited by 851 · see citing works
Diabetes mellitus and risk of dementia: A meta‐analysis of prospective observational studies
Gudala, K., Bansal, D., Schifano, F., & Bhansali, A. (2013) · Journal of Diabetes Investigation · doi:10.1111/jdi.12087 · Cited by 727 · see citing works
Exenatide and the treatment of patients with Parkinson's disease
Aviles-Olmos, I., Dickson, J., Kefalopoulou, Z., Djamshidian, A., Ell, P., Soderlund, T., Whitton, P., Wyse, R., Isaacs, T., Lees, A., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68295 · Cited by 529 · see citing works
Novel genetic loci associated with hippocampal volume
Hibar, D. P., Adams, H. H. H., Jahanshad, N., Chauhan, G., Stein, J. L., Hofer, E., Renteria, M. E., Bis, J. C., Arias-Vasquez, A., Ikram, M. K., et al. (2017) · Nature Communications · doi:10.1038/ncomms13624 · Cited by 299 · see citing works
The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial
Gerstein, H. C., Hart, R., Colhoun, H. M., Diaz, R., Lakshmanan, M., Botros, F. T., Probstfield, J., Riddle, M. C., Rydén, L., Atisso, C. M., et al. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(19)30423-1 · Cited by 137 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Sattar, N., Lee, M. M. Y., Kristensen, S. L., Branch, K. R. H., Del Prato, S., Khurmi, N. S., Lam, C. S. P., Lopes, R. D., McMurray, J. J. V., Pratley, R. E., et al. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00203-5 · Cited by 1,599 · see citing works
Self-citationMicrobiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
Efficacy and Safety of GLP-1 Medicines for Type 2 Diabetes and Obesity
Drucker, D. J. (2024) · Diabetes Care · doi:10.2337/dci24-0003 · Cited by 383 · see citing works
Pearson-Stuttard, J., Bennett, J., Cheng, Y. J., Vamos, E. P., Cross, A. J., Ezzati, M., & Gregg, E. W. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30431-9 · Cited by 335 · see citing works
GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential
Ma, X., Liu, Z., Ilyas, I., Little, P. J., Kamato, D., Sahebka, A., Chen, Z., Luo, S., Zheng, X., Weng, J., et al. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.59965 · Cited by 299 · see citing works
Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1
Hammoud, R., & Drucker, D. J. (2023) · Nature Reviews Endocrinology · doi:10.1038/s41574-022-00783-3 · Cited by 244 · see citing works
The expanding incretin universe: from basic biology to clinical translation
Drucker, D. J., & Holst, J. J. (2023) · Diabetologia · doi:10.1007/s00125-023-05906-7 · Cited by 243 · see citing works
Nørgaard, C. H., Friedrich, S., Hansen, C. T., Gerds, T., Ballard, C., Møller, D. V., Knudsen, L. B., Kvist, K., Zinman, B., Holm, E., et al. (2022) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1002/trc2.12268 · Cited by 206 · see citing works
Drug repositioning and repurposing for Alzheimer disease
Ballard, C., Aarsland, D., Cummings, J., O’Brien, J., Mills, R., Molinuevo, J. L., Fladby, T., Williams, G., Doherty, P., Corbett, A., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0397-4 · Cited by 201 · see citing works
Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., Gupta, D., & Edison, P. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101979 · Cited by 179 · see citing works
Cummings, J. L., Atri, A., Feldman, H. H., Hansson, O., Sano, M., Knop, F. K., Johannsen, P., León, T., & Scheltens, P. (2025) · Alzheimer's Research & Therapy · doi:10.1186/s13195-024-01666-7 · Cited by 168 · see citing works
Wu, C.-Y., Iskander, C., Wang, C., Xiong, L. Y., Shah, B. R., Edwards, J. D., Kapral, M. K., Herrmann, N., Lanctôt, K. L., Masellis, M., et al. (2023) · Diabetes Care · doi:10.2337/dc22-1705 · Cited by 139 · see citing works
Incretin and insulin signaling as novel therapeutic targets for Alzheimer’s and Parkinson’s disease
Nowell, J., Blunt, E., & Edison, P. (2023) · Molecular Psychiatry · doi:10.1038/s41380-022-01792-4 · Cited by 136 · see citing works
Tang, H., Shao, H., Shaaban, C. E., Yang, K., Brown, J., Anton, S., Wu, Y., Bress, A., Donahoo, W. T., DeKosky, S. T., et al. (2023) · Journal of the American Geriatrics Society · doi:10.1111/jgs.18306 · Cited by 106 · see citing works
GLP1 Receptor Agonists—Effects beyond Obesity and Diabetes
Wilbon, S. S., & Kolonin, M. G. (2023) · Cells · doi:10.3390/cells13010065 · Cited by 101 · see citing works
Alzheimer’s disease as type 3 diabetes: understanding the link and implications
Kciuk, M., Kruczkowska, W., Gałęziewska, J., Wanke, K., Kałuzińska-Kołat, Ż., Aleksandrowicz, M., & Kontek, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252211955 · Cited by 98 · see citing works
Role of glucagon-like peptide-1 receptor agonists in Alzheimer’s disease and Parkinson’s disease
Hong, C.-T., Chen, J.-H., & Hu, C.-J. (2024) · Journal of Biomedical Science · doi:10.1186/s12929-024-01090-x · Cited by 78 · see citing works
Tian, S., Jiang, J., Wang, J., Zhang, Z., Miao, Y., Ji, X., & Bi, Y. (2023) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.3673 · Cited by 79 · see citing works
Li, Q., Jia, M., Yan, Z., Li, Q., Sun, F., He, C., Li, Y., Zhou, X., Zhang, H., Liu, X., et al. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.020734 · Cited by 77 · see citing works
Bajaj, H. S., Gerstein, H. C., Rao-Melacini, P., Basile, J., Colhoun, H., Conget, I., Cushman, W. C., Dagenais, G. R., Franek, E., Hanefeld, M., et al. (2021) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(21)00115-7 · Cited by 56 · see citing works
Self-citationOld, V. J., Davies, M. J., Papamargaritis, D., Choudhary, P., & Watson, E. L. (2025) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.13677 · Cited by 55 · see citing works
Forny Germano, L., Koehler, J. A., Baggio, L. L., Cui, F., Wong, C. K., Rittig, N., Cao, X., Matthews, D., & Drucker, D. J. (2024) · Molecular Metabolism · doi:10.1016/j.molmet.2024.102019 · Cited by 50 · see citing works
Li, Z., Chen, X., Vong, J. S. L., Zhao, L., Huang, J., Yan, L. Y. C., Ip, B., Wing, Y. K., Lai, H.-M., Mok, V. C. T., et al. (2021) · Communications Biology · doi:10.1038/s42003-021-02208-9 · Cited by 42 · see citing works
Onset age of diabetes and incident dementia: A prospective cohort study
Wang, Y., Li, C., Liang, J., Gao, D., Pan, Y., Zhang, W., Zhang, Y., Zheng, F., & Xie, W. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.02.138 · Cited by 36 · see citing works
Arredouani, A. (2025) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2025.108824 · Cited by 36 · see citing works
Hong, B., Bea, S., Ko, H. Y., Kim, W. J., Cho, Y. M., & Shin, J.-Y. (2024) · Annals of Internal Medicine · doi:10.7326/m23-3220 · Cited by 33 · see citing works
Luan, S., Cheng, W., Wang, C., Gong, J., & Zhou, J. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1047883 · Cited by 25 · see citing works
Noguchi, T., Katoh, H., Nomura, S., Okada, K., & Watanabe, M. (2024) · Frontiers in Neuroscience · doi:10.3389/fnins.2024.1342944 · Cited by 20 · see citing works
- Authors
- Cukierman-Yaffe, T., Gerstein, H. C., Colhoun, H. M., Diaz, R., García-Pérez, L.-E., Lakshmanan, M., Bethel, A., Xavier, D., Probstfield, J., Riddle, M. C., Rydén, L., Atisso, C. M., Hall, S., Rao-Melacini, P., Basile, J., Cushman, W. C., Franek, E., Keltai, M., Lanas, F., Leiter, L. A., Lopez-Jaramillo, P., Pirags, V., Pogosova, N., Raubenheimer, P. J., Shaw, J. E., Sheu, W. H.-H., & Temelkova-Kurktschiev, T.
- Affiliations
- Population Health Research Institute (CA)
- University of Edinburgh (GB)
- Eli Lilly (United States) (US)
- St.John's Medical College Hospital (IN)
- University of Washington (US)
- Oregon Health & Science University (US)
- Karolinska Institutet (SE)
- Medical University of South Carolina (US)
- Memphis VA Medical Center (US)
- Central Clinical Hospital (PL)
- Universidad de La Frontera (CL)
- St. Michael's Hospital (CA)
- University of Cape Town (ZA)
- Baker Heart and Diabetes Institute (AU)
- Taichung Veterans General Hospital (TW)
- Bulgarian National Bank (BG)
- Corresponding author
- Gerstein, Hertzel C
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2020-07
- Volume
- 19
- Issue
- 7
- Pages
- 582-590
- ISSN
- 1474-4422 (ISSN-L)
- OpenAlex
- W3036438870
- Cited by
- 300
- References
- 9
- Citations by year
- 2026: 45 · 2025: 67 · 2024: 69 · 2023: 38 · 2022: 37 · 2021: 35 · 2020: 8
- FWCI
- 22.25
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-10-01)
- Open access
- green
- repositorio.ufro.cl
- Licence
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Omeka S (Universidad de La Frontera) (submittedVersion, cc-by-nc-nd)
- Funders
- Eli Lilly and Company
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- dulaglutide, cognitive impairment, type 2 diabetes, GLP-1 receptor agonists, REWIND trial, Montreal Cognitive Assessment, Digit Symbol Substitution Test, cognitive decline, cardiovascular outcomes
- MeSH terms
- Adult, Aged, Diabetes Mellitus, Type 2, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Hypoglycemic Agents, Immunoglobulin Fc Fragments, Male, Middle Aged, Recombinant Fusion Proteins, Treatment Outcome, Cognitive Dysfunction
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