Almost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia.
Objective
We aim to investigate if semaglutide is associated with a decreased risk of dementia.
Methods
We conducted emulation target trials based on a nationwide population-based database of patient electronic health records (EHRs) in the US among 1,710,995 eligible patients with type 2 diabetes (T2D) comparing semaglutide with other antidiabetic medications. First-time diagnosis of Alzheimer's disease-related dementia (ADRD) including vascular dementia, frontotemporal dementia, Lewy body dementia and other dementias were examined using Cox proportional hazards and Kaplan–Meier survival analyses during a 3-year follow-up. Models were adjusted by propensity-score matching.
Results
We show that semaglutide was associated with a significantly reduced risk of overall ADRD incidence with a hazard ratio ranging from 0.54 (0.49–0.59) compared with insulin, 0.67 (0.61–0.74) compared with metformin, to 0.80 (0.72–0.89) compared with older generation glucagon-like peptide-1 agonists (GLP-1RAs). The association varied for specific dementia types, with significantly reduced risk of vascular dementia and no evidence of associations with frontotemporal and Lewy body dementias.
Conclusions
These findings provide evidence supporting protective effects of semaglutide on dementias in patients with T2D. Future works are needed to establish the causal relationships through randomized clinical trials and to characterize the underlying mechanisms.
RajanKBWeuveJBarnesLL, et al.Population estimate of people with clinical Alzheimer’s disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement2021; 17: 1966–1975.
2.
MurphySKochanekKXuJ, et al.Mortality in the United States, 2016. NCHS Data Brief2017; 293: 1–8.
3.
NandiACountsNChenS, et al.Global and regional projections of the economic burden of Alzheimer’s disease and related dementias from 2019 to 2050: a value of statistical life approach. EClinicalMedicine2022; 51: 101580.
4.
LivingstonGHuntleyJLiuKY, et al.Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet2024; 404: 572–628.
5.
EngelhartMJGeerlingsMIMeijerJ, et al.Inflammatory proteins in plasma and the risk of dementia: the Rotterdam Study. Arch Neurol2004; 61: 668–672.
6.
KoyamaAO’BrienJWeuveJ, et al.The role of peripheral inflammatory markers in dementia and Alzheimer’s disease: a meta-analysis. J Gerontol A Biol Sci Med Sci2013; 68: 433–440.
7.
SchmidtRSchmidtHCurbJD, et al.Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol2002; 52: 168–174.
8.
MarsoSPBainSCConsoliA, et al.Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med2016; 375: 1834–1844.
9.
DaviesMPieberTRHartoft-NielsenM-L, et al.Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA2017; 318: 1460–1470.
10.
DaviesMFærchLJeppesenOK, et al.Semaglutide 2·4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet2021; 397: 971–984.
11.
LincoffAMBrown-FrandsenKColhounHM, et al.Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med2023; 389: 2221–2232.
12.
BendottiGMontefuscoLLunatiME, et al.The anti-inflammatory and immunological properties of GLP-1 receptor agonists. Pharmacol Res2022; 182: 106320.
13.
DruckerDJ. The benefits of GLP-1 drugs beyond obesity. Science2024; 385: 258–260.
14.
WangZ-JLiX-RChaiS-F, et al.Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer’s disease via the GLP-1R/SIRT1/GLUT4 pathway. Neuropharmacology2023; 240: 109716.
15.
WangZ-JHanW-NChaiS-F, et al.Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice. Neuroscience2024; 563: 222–234.
16.
ZhangYTangCHeY, et al.Semaglutide ameliorates Alzheimer’s disease and restores oxytocin in APP/PS1 mice and human brain organoid models. Biomed Pharmacother2024; 180: 117540.
17.
EdisonPFemminellaGDRitchieCW, et al.Evaluation of liraglutide in the treatment of Alzheimer’s disease. Alzheimers Dement2021; 17: e057848.
18.
EdisonPFemminellaGDRitchieC, et al.MRI Changes following treatment of glp-1 analogue, liraglutide in Alzheimer’s disease. Alzheimers Dement2023; 19: e080538.
19.
EdisonP. Evaluation of Novel GLP-1 analogue in the treatment of Alzheimer’s disease. Alzheimers Dement2024; 20: e089799.
20.
CummingsJLAtriAFeldmanHH, et al.Evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating efficacy, safety, and tolerability of semaglutide in early-stage symptomatic Alzheimer’s disease. Alzheimers Res Ther2025; 17: 14.
21.
Clinicaltrials.gov. A research study investigating Semaglutide in people with early Alzheimer’s disease (EVOKE), https://clinicaltrials.gov/study/NCT04777396 (2024, accessed December 1, 2024).
22.
Clinicaltrials.gov. A research study investigating semaglutide in people with early Alzheimer’s disease (EVOKE plus), https://clinicaltrials.gov/study/NCT04777409 (2024, accessed December 1, 2024).
WangWWangQQiX, et al.Associations of semaglutide with first-time diagnosis of Alzheimer’s disease in patients with type 2 diabetes: target trial emulation using nationwide real-world data in the US. Alzheimers Dement2024; 20: 8661–8672.
25.
HernánMARobinsJM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol2016; 183: 758–764.
26.
HernánMAWangWLeafDE. Target trial emulation: a framework for causal inference from observational data. JAMA2022; 328: 2446–2447.
TriNetX. The world’s largest, living ecosystem of real-world data and evidence. TriNetX, https://trinetx.com/real-world-data/ (2021, accessed January 16, 2024).
29.
WangWVolkowNDBergerNA, et al.Association of semaglutide with tobacco use disorder in patients with type 2 diabetes. Target trial emulation using real-world data. Ann Intern Med2024; 177: 1016–1027.
30.
WangWVolkowNDMsQQW, et al.Semaglutide and opioid overdose risk in patients with type 2 diabetes and opioid use disorder. JAMA Netw Open2024; 7: e2435247.
31.
WangWVolkowNDBergerNA, et al.Associations of semaglutide with incidence and recurrence of alcohol use disorder in real-world population. Nat Commun2024; 15: 4548.
32.
WangWVolkowNDBergerNA, et al.Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study. Mol Psychiatry2024; 29: 2587–2598.
33.
WangWVolkowNDBergerNA, et al.Association of semaglutide with risk of suicidal ideation in a real-world cohort. Nat Med2024; 30: 168–176.
34.
NganduTLehtisaloJSolomonA, et al.A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet2015; 385: 2255–2263.
35.
YaffeKVittinghoffEDublinS, et al.Effect of personalized risk-reduction strategies on cognition and dementia risk profile among older adults: the SMARRT randomized clinical trial. JAMA Intern Med2024; 184: 54–62.
36.
van CharanteEPMRichardEEurelingsLS, et al.Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet2016; 388: 797–805.
37.
ChoSHKangHJParkYK, et al.South Korean study to PrEvent cognitive impaiRment and protect BRAIN health through Multidomain interventions via facE-to-facE and video communication plaTforms in mild cognitive impairment (SUPERBRAIN-MEET): protocol for a Multicenter Randomized Controlled Trial. Dement Neurocognitive Disord2024; 23: 30–43.
38.
SakuraiTSugimotoTAkatsuH. Japan-multimodal intervention trial for the prevention of dementia: a randomized controlled trial. Alzheimers Dement2024; 20: 3918–3930.
39.
KivipeltoMMangialascheFNganduT, et al.World Wide Fingers will advance dementia prevention. Lancet Neurol2018; 17: 27.
40.
BarberaMLehtisaloJPereraD, et al.A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol. Alzheimers Res Ther2024; 16: 23.
41.
The Lancet Neurology. Pointing the way to primary prevention of dementia. Lancet Neurol2017; 16: 677.
42.
RubinoDMGreenwayFLKhalidU, et al.Effect of weekly subcutaneous semaglutide vs daily liraglutide on body weight in adults with overweight or obesity without diabetes: the STEP 8 randomized clinical trial. JAMA2022; 327: 138–150.
43.
FríasJPDaviesMJRosenstockJ, et al.Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med2021; 385: 503–515.
44.
PerkovicVTuttleKRRossingP, et al.Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med2024; 391: 109–121.
45.
NewsomePNBuchholtzKCusiK, et al.A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med2021; 384: 1113–1124.
46.
ZhouMXuRKaelberDC, et al.Tumor necrosis factor (TNF) blocking agents are associated with lower risk for Alzheimer’s disease in patients with rheumatoid arthritis and psoriasis. PLoS One2020; 15: e0229819.
47.
ZhengCFillmoreNRRamos-CejudoJ, et al.Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: a propensity score matched retrospective cohort study in US Veterans. Alzheimers Dement2022; 18: 1248–1259.
48.
XieYChoiTAl-AlyZ. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat Med2025; 31: 951–962.
49.
National Academies of Sciences Engineering, Medicine. Preventing cognitive decline and dementia: A way forward. Washington, DC: The National Academies Press, 2017.
50.
AndreadisPKaragiannisTMalandrisK, et al.Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab2018; 20: 2255–2263.
51.
SmithEE. Clinical presentations and epidemiology of vascular dementia. Clin Sci (Lond)2017; 131: 1059–1068.
52.
OnyikeCUDiehl-SchmidJ. The epidemiology of frontotemporal dementia. Int Rev Psychiatry2013; 25: 130–137.
53.
HuWSongRChengR, et al.Use of GLP-1 receptor agonists and occurrence of thyroid disorders: a meta-analysis of randomized Controlled Trials. Front Endocrinol (Lausanne)2022; 13: 927859.
54.
BritoJPHerrinJSwarnaKS, et al.GLP-1RA use and thyroid cancer risk. JAMA Otolaryngol Head Neck Surg2025; 151: 243–252.
55.
GuerreiroRRossOAKun-RodriguesC, et al.Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol2018; 17: 64–74.
56.
CranePKGibbonsLEDams-O’ConnorK, et al.Association of traumatic brain injury with late-life neurodegenerative conditions and neuropathologic findings. JAMA Neurol2016; 73: 1062–1069.
57.
BrightFWerryELDobson-StoneC, et al.Neuroinflammation in frontotemporal dementia. Nat Rev Neurol2019; 15: 540–555.
58.
SurendranathanASuLMakE, et al.Early microglial activation and peripheral inflammation in dementia with Lewy bodies. Brain2018; 141: 3415–3427.
59.
ThiesWBleilerL. Alzheimer’s disease facts and figures. Alzheimers Dement2013; 9: 208–245.
60.
RodriguezPJCartwrightBMGratzlS, et al.Semaglutide vs tirzepatide for weight loss in adults with overweight or obesity. JAMA Intern Med2024; 184: 1056–1064.
61.
FukudaM. The role of GIP receptor in the CNS for the pathogenesis of obesity. Diabetes2021; 70: 1929–1937.
62.
ZhangZQHölscherC. GIP Has neuroprotective effects in Alzheimer and Parkinson’s disease models. Peptides2020; 125: 170184.
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