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Cited by 168Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholinesterase and Neurodegenerative Diseases

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

Open access
Cummings, Jeffrey L., Atri, Alireza, Feldman, Howard H., Hansson, Oskar, Sano, Mary, Knop, Filip K., Johannsen, Peter, León, Teresa +1 more·2025·Alzheimer's Research & Therapy
DOI 10.1186/s13195-024-01666-7PMC PMC11708093

Published version of a preprint

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Abstract

BACKGROUND: Disease-modifying therapies targeting the diverse pathophysiology of Alzheimer's disease (AD), including neuroinflammation, represent potentially important and novel approaches. The glucagon-like peptide-1 receptor agonist semaglutide is approved for the treatment of type 2 diabetes and obesity and has an established safety profile. Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes. Large randomized controlled trials are needed to assess the efficacy and safety of semaglutide in early-stage symptomatic AD. METHODS: evoke and evoke+ are randomized, double-blind, placebo-controlled phase 3 trials investigating the efficacy, safety, and tolerability of once-daily oral semaglutide versus placebo in early-stage symptomatic AD. Eligible participants were men or women aged 55-85 years with mild cognitive impairment or mild dementia due to AD with confirmed amyloid abnormalities (assessed by positron emission tomography or cerebrospinal fluid [CSF] analysis). After a maximum 12-week screening phase, an anticipated 1840 patients in each trial are randomized (1:1) to semaglutide or placebo for 156 weeks (104-week main treatment phase and 52-week extension). Randomized participants follow an 8-week dose escalation regimen (3 mg [weeks 0-4], 7 mg [weeks 4-8], and 14 mg [weeks 8-156]). The primary endpoint is the semaglutide-placebo difference on change from baseline to week 104 in the Clinical Dementia Rating - Sum of Boxes score. Analyses of plasma biomarkers, collected from all participants, and a CSF sub-study (planned n = 210) will explore semaglutide effects on AD biomarkers and neuroinflammation. RESULTS: Enrollment was undertaken between May 18, 2021, and September 8, 2023. Completion of the trials' main phase is expected in September 2025, and the 52-week extension (in which participants and investigators remain blinded to treatment assignment) will continue to October 2026. CONCLUSION: evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation. The trials will provide data on the potential disease-modifying effects of semaglutide and will be important in evaluating its utility in the treatment of early-stage symptomatic AD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04777396 and NCT04777409. Date: 02/03/2021.

AI snapshot

Written from the paper’s full text.

TL;DR

evoke and evoke+ are two identically designed phase 3 randomized, double-blind, placebo-controlled trials of once-daily oral semaglutide up to 14 mg versus placebo in early-stage symptomatic Alzheimer’s disease, with the primary endpoint being change in CDR-SB from baseline to week 104. Enrollment completed September 8, 2023; main phase completion is expected in September 2025, with the 52-week blinded extension continuing to October 2026.

Key findings

  • Planned enrollment is 1840 participants per trial randomized 1:1 to semaglutide or placebo for 156 weeks (104-week main treatment phase plus 52-week extension), with oral semaglutide dose escalation from 3 mg (weeks 0–4) to 7 mg (weeks 4–8) to 14 mg (weeks 8–156).
  • The primary endpoint is change in CDR-SB from baseline to week 104; sample size assumes a mean difference of −0.44 points, SD 2.6 points, one-sided significance level 0.025, and 95% power.
  • Eligible participants are aged 55–85 years with MCI or mild dementia due to AD and confirmed amyloid abnormalities; expected composition is 80% MCI (CDR global 0.5) and 20% mild AD dementia (CDR global 1.0), with up to 30% having type 2 diabetes; evoke+ additionally permits significant small vessel pathology.
  • A CSF sub-study is planned for 210 participants across 15 countries, and plasma biomarkers are collected from all participants; enrollment occurred May 18, 2021–September 8, 2023.

Methods

  • Two randomized, double-blind, placebo-controlled, parallel-group phase 3 trials with identical designs except evoke+ allows participants with significant small vessel pathology; participants from 40 countries and 566 centers may continue or initiate approved AD treatments.
  • Primary analysis is change in CDR-SB from baseline to week 104; confirmatory secondary endpoints are change in ADCS-ADL-MCI and time to progression to CDR global score ≥1.0 among participants with baseline CDR 0.5; no futility or interim analyses are planned, and time-to-dementia progression uses pooled evoke/evoke+ data.
  • Biomarker assessments include plasma NfL, p-tau181, GFAP, and hs-CRP at baseline and weeks 52, 104, and 156; the CSF sub-study samples pre-randomization and at week 78 for AD, neuroinflammation, neurodegeneration, blood–brain barrier, oxidative stress, and vascular markers.

Limitations

  • Stated: implementing the protocol in 40 countries and 50 languages poses logistical challenges and assumes outcome measure variability and effect sizes remain within the sample size assumptions; the design may lead to higher screening failure rates in non-White populations, so trial populations may not be representative.
  • Stated: continuation or initiation of approved AD medications, including amyloid-lowering monoclonal antibodies, was not a randomization stratification factor and may confound results if use differs across treatment arms; a sensitivity analysis may be required.
  • Evident: this is a design paper; no efficacy, safety, or tolerability results are reported, and baseline characteristics are to be described in a separate publication.

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Integrity signals

Registry

Crossref · 10.1186/s13195-024-01666-7

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 103 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Participants with overweight or obesity comprise 34.7% and 15.5%, respectively, of the evoke/evoke+ population.

    “Weight loss could be beneficial to some participants with overweight or obesity, who comprise 34.7% and 15.5%, respectively, of the evoke/evoke+ population [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Scheltens P, Atri A, Feldman H, Hansson O, Knop F, Sano M, et al. Baseline characteristics from evoke and evoke+: two phase 3 randomized placebo-controlled trials of oral semaglutide in patients with early Alzheimer’s disease. J Prev Alzheimers Dis. 2023;10(Suppl 1):S92–3. Poster LP018; Presented at CTAD 2023.

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  • Premisecitation

    Neuroinflammation occurs at early disease stages of Alzheimer's disease.

    “and occurs at early disease stages [2, 5–7]”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [2] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405. source

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    • cites [5] Bellaver B, Povala G, Ferreira PCL, Ferrari-Souza JP, Leffa DT, Lussier FZ, et al. Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer’s disease. Nat Med. 2023;29(7):1775–81. source

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    • cites [6] Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat Genet. 2022;54(4):412–36. source

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    • cites [7] Bieger A, Rocha A, Bellaver B, Machado L, Da Ros L, Borelli WV, et al. Neuroinflammation biomarkers in the AT(N) framework across the Alzheimer’s disease continuum. J Prev Alzheimers Dis. 2023;10(3):401–17.

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  • Premisecitation

    GLP-1 receptor agonists activate GLP-1 receptors that are found throughout the body, including the brain.

    “GLP-1RAs activate GLP-1 receptors that are found throughout the body, including the brain [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, et al. GLP-1 receptor agonists: beyond their pancreatic effects. Front Endocrinol (Lausanne). 2021;12:721135. source

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  • Premisecitation

    The potential effects of semaglutide in Alzheimer's disease may be mediated indirectly rather than via direct brain action, since semaglutide may have limited ability to cross the blood-brain barrier.

    “these effects may be mediated indirectly rather than via direct brain action, since semaglutide may have limited ability to cross the BBB [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer’s and Parkinson’s disease therapeutics. Biochem Pharmacol. 2020;180:114187. source

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  • Interpretationreasoning

    Semaglutide may have a disease-modifying, neuroprotective effect in Alzheimer's disease through multimodal mechanisms including neuroinflammatory, vascular, and other Alzheimer's disease-related processes.

    “Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 22
  • May combine two claims. 25

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GLP-1 receptor agonists are approved for the treatment of type 2 diabetes and obesity, and their safety and tolerability profiles are well established in these populations; the most common adverse events are gastrointestinal-related.

    “Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes (T2D) and obesity, and their safety and tolerability profiles are well established in these populations; the most common adverse events are gastrointestinal [GI]-related [14, 15].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Htike ZZ, Zaccardi F, Papamargaritis D, Webb DR, Khunti K, Davies MJ. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes Metab. 2017;19(4):524–36. source

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    • cites [15] Gao X, Hua X, Wang X, Xu W, Zhang Y, Shi C, et al. Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022;13:935823. source

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    Premisecitation

    GLP-1 receptor agonists are involved in multiple biological pathways that could be beneficial in Alzheimer's disease including improvement of blood-brain barrier integrity and vascular health, promotion of homeostasis in microglia and astrocytes, positive effects on adaptive immune cells, improvement of synaptic viability, and neuroprotection.

    “They are involved in multiple biological pathways that could be beneficial in AD including improvement of BBB integrity and vascular health, promotion of homeostasis in microglia and astrocytes, positive effects on adaptative immune cells (including natural killer cells and activated regulatory T cells), improvement of synaptic viability, and neuroprotection [17–26].”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [17] Brundin L, Bergkvist L, Brundin P. Fire prevention in the Parkinson’s disease brain. Nat Med. 2018;24(7):900–2. source

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    • cites [18] De Barra C, Khalil M, Mat A, O’Donnell C, Shaamile F, Brennan K, et al. Glucagon-like peptide-1 therapy in people with obesity restores natural killer cell metabolism and effector function. Obesity (Silver Spring). 2023;31(7):1787–97. source

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    • cites [19] 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. source

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    • cites [20] Li Z, Chen X, Vong JSL, Zhao L, Huang J, Yan LYC, et al. Systemic GLP-1R agonist treatment reverses mouse glial and neurovascular cell transcriptomic aging signatures in a genome-wide manner. Commun Biol. 2021;4(1):656. source

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    • cites [21] Park JS, Kam TI, Lee S, Park H, Oh Y, Kwon SH, et al. Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease. Acta Neuropathol Commun. 2021;9(1):78. source

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    • cites [22] Rode AKO, Buus TB, Mraz V, Al-Jaberi FAH, Lopez DV, Ford SL, et al. Induced human regulatory T cells express the glucagon-like peptide-1 receptor. Cells. 2022;11(16):2587. source

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    • cites [23] Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med. 2018;24(7):931–8. source

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    • cites [24] Zhang Q, Liu C, Shi R, Zhou S, Shan H, Deng L, et al. Blocking C3d+/GFAP+ A1 astrocyte conversion with semaglutide attenuates blood-brain barrier disruption in mice after ischemic stroke. Aging Dis. 2022;13(3):943–59. source

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    • cites [25] Zhao L, Li Z, Vong JSL, Chen X, Lai HM, Yan LYC, et al. Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain. Nat Commun. 2020;11(1):4413. source

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    • cites [26] Ludwig MQ, Belmont-Rausch DM, Bentsen MA, Secher A, Hansen SAN, Egerod KL, et al. A lipopolysaccharide mouse model mirrors neuroinflammatory transcriptional signatures of human Alzheimer’s disease, and the glucagon-like peptide-1 receptor agonist semaglutide attenuates neuroinflammation in this model. Alzheimers Dement. 2022;18(S10):e063862. source

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    Premisecitation

    Anti-amyloid antibodies slow cognitive decline in Alzheimer's disease and their use is associated with side effects including amyloid-related imaging abnormalities.

    “Anti-amyloid antibodies are intravenously administered therapies that slow cognitive decline in AD; their use is associated with side effects including amyloid-related imaging abnormalities [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Yadollahikhales G, Rojas JC. Anti-amyloid immunotherapies for Alzheimer’s disease: a 2023 clinical update. Neurotherapeutics. 2023;20(4):914–31. source

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    Premisecitation

    Alzheimer's disease is characterized by the presence of amyloid β protein plaques, phosphorylated tau-containing neurofibrillary tangles, and neurodegeneration.

    “Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) protein plaques, phosphorylated tau (p-tau)–containing neurofibrillary tangles, and neurodegeneration [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397(10284):1577–90. source

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    Premisecitation

    Microvascular dysfunction may contribute to disease progression in Alzheimer's disease.

    “Additionally, microvascular dysfunction may contribute to disease progression [9, 10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Govindpani K, McNamara LG, Smith NR, Vinnakota C, Waldvogel HJ, Faull RL, et al. Vascular dysfunction in Alzheimer’s disease: a prelude to the pathological process or a consequence of it? J Clin Med. 2019;8(5):651. source

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    • cites [10] Steinman J, Sun HS, Feng ZP. Microvascular alterations in Alzheimer’s disease. Front Cell Neurosci. 2020;14:618986. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Neuroinflammation is a key contributor to the pathobiology of Alzheimer's disease.

    “Neuroinflammation has been identified as a key contributor to the pathobiology of AD [2–4]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14(4):388–405. source

      Not checked in the free run.

    • cites [3] Cummings JL, Tong G, Ballard C. Treatment combinations for Alzheimer’s disease: current and future pharmacotherapy options. J Alzheimers Dis. 2019;67(3):779–94. source

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    • cites [4] Dhapola R, Hota SS, Sarma P, Bhattacharyya A, Medhi B, Reddy DH. Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer’s disease. Inflammopharmacology. 2021;29(6):1669–81. source

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    Premisecitation

    Anti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab have been approved by the US Food and Drug Administration for Alzheimer's disease.

    “with the approval by the US Food and Drug Administration (FDA) of the anti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab [11, 12].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimers Dement (N Y). 2023;9(2):e12385. source

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    • cites [12] Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023;330(6):512–27. source

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    Premisecitation

    Blood-brain barrier dysfunction is observed early in the disease course of Alzheimer's disease and comprises one aspect of the pathogenesis of chronic neuroinflammation.

    “Within the neurovascular unit, blood–brain barrier (BBB) dysfunction is observed early in the disease course of AD and comprises one aspect of the pathogenesis of chronic neuroinflammation [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer’s disease. Neurobiol Dis. 2017;107:41–56. source

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  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Participants and investigators will remain blinded to treatment assignment throughout the trial period (main and extension phases).

    “Participants and investigators will remain blinded to treatment assignment throughout the trial period (main and extension phases).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Treatment compliance was assessed and reinforced through drug accountability information (counting returned tablets) and through documented discussions with participants and study partners.

    “Treatment compliance was assessed and reinforced through drug accountability information (counting returned tablets) and through documented discussions with participants and study partners.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    evoke and evoke+ are randomized (1:1), double-blind, placebo-controlled, parallel-group trials investigating the efficacy and safety of oral semaglutide versus placebo in participants with early-stage symptomatic Alzheimer's disease.

    “evoke (NCT04777396) and evoke+ (NCT04777409) are randomized (1:1), double-blind, placebo-controlled, parallel-group trials investigating the efficacy and safety of oral semaglutide versus placebo in participants with early-stage symptomatic AD (Fig. 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    All PET scans, including historical images, were assessed centrally in accordance with FDA guidelines for the Imaging Endpoint Process Standards.

    “All PET scans, including historical images, were assessed centrally in accordance with FDA guidelines for the Imaging Endpoint Process Standards [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] FDA. Guidance for Industry: Clinical Trial Imaging Endpoint Process Standards. 2018.

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  • May combine two claims.

    Premisecitation

    In the ELAD study, patients receiving liraglutide retained more temporal lobe volume and total cortical volume than those receiving placebo and had greater preservation of cognitive function after 12 months of treatment.

    “In the ELAD study, patients receiving liraglutide retained more temporal lobe volume and total cortical volume than those receiving placebo and had greater preservation of cognitive function (assessed by the Alzheimer’s Disease Assessment Scale Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery) after 12 months of treatment [30].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Edison P, Femminella GD, Ritchie CW, Holmes C, Walker Z, Ridha BH, et al. Evaluation of liraglutide in the treatment of Alzheimer’s disease. Alzheimers Dement. 2021;17(S9):e057848. source

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  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic Alzheimer's disease, including exploration of effects on Alzheimer's disease biomarkers and neuroinflammation.

    “evoke and evoke+ are the first large-scale trials to investigate the disease-modifying potential of semaglutide in participants with early-stage symptomatic AD, including exploration of effects on AD biomarkers and neuroinflammation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Semaglutide is a potent, long-acting GLP-1 receptor agonist approved for the treatment of type 2 diabetes (once daily oral and once weekly subcutaneous) and obesity (once weekly subcutaneous).

    “Semaglutide is a potent, long-acting GLP-1RA approved for the treatment of T2D (once daily [OD] oral and once weekly [OW] subcutaneous [s.c.]) and obesity (OW s.c.) [38–40].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.

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    • cites [39] FDA. OZEMPIC prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed 3 January 2025.

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    • cites [40] FDA. WEGOVY prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf. Accessed 3 January 2025.

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  • May combine two claims.

    Premisecitation

    GLP-1 receptor agonists may be beneficial for preservation of brain glucose metabolism and cognitive function in Alzheimer's disease, as supported by the results of two randomized, placebo-controlled trials in patients with mild-to-moderate Alzheimer's disease dementia treated with the GLP-1 receptor agonist liraglutide for 6 months and 12 months, respectively.

    “GLP-1RAs may be beneficial for preservation of brain glucose metabolism and cognitive function in AD as supported by the results of two randomized, placebo-controlled trials in patients with mild-to-moderate AD dementia treated with the GLP-1RA liraglutide for 6 months and 12 months, respectively [29–31].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Gejl M, Gjedde A, Egefjord L, Møller 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. source

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    • cites [30] Edison P, Femminella GD, Ritchie CW, Holmes C, Walker Z, Ridha BH, et al. Evaluation of liraglutide in the treatment of Alzheimer’s disease. Alzheimers Dement. 2021;17(S9):e057848. source

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    • cites [31] Edison P, Femminella GD, Ritchie C, Nowell J, Holmes C, Walker Z, et al. MRI changes following treatment of GLP-1 analogue, liraglutide in Alzheimer’s disease. Alzheimers Dement. 2023;19(S21):e080538. source

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  • May combine two claims.

    Premisecitation

    Real-world evidence studies from the USA and Denmark showed a significant 11-42% lower risk of all-cause dementia and up to 64% lower risk of Alzheimer's disease after GLP-1 receptor agonist exposure for the treatment of type 2 diabetes.

    “Real-world evidence studies from the USA and Denmark showed a significant 11–42% lower risk of all-cause dementia and up to 64% lower risk of AD after GLP-1RA exposure for the treatment of T2D [32, 34–37].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [32] Nørgaard CH, Friedrich S, Hansen CT, Gerds T, Ballard C, Møller DV, et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N Y). 2022;8(1):e12268. source

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    • cites [34] Akimoto H, Negishi A, Oshima S, Wakiyama H, Okita M, Horii N, et al. Antidiabetic drugs for the risk of Alzheimer disease in patients with type 2 DM using FAERS. Am J Alzheimers Dis Other Demen. 2020;35:1533317519899546. source

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    • cites [35] Wium-Andersen IK, Osler M, Jørgensen 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. source

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    • cites [36] Wang T, Buse JB, Pate V, Stürmer T. 1802-PUB: Liraglutide as a potential drug repurposing candidate for Alzheimer’s disease and related dementia—real-world evidence. Diabetes. 2023;72(Suppl 1):1802–PUB. source

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    • cites [37] Wang W, Wang Q, Qi X, Gurney M, Perry G, Volkow ND, 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. Alzheimer’s & Dementia. 2024;20(12):8661–72. source

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    Premisecitation

    In clinical trials, semaglutide reduced peripheral inflammation and decreased the risk of major adverse cardiovascular events compared with placebo.

    “In clinical trials, semaglutide reduced peripheral inflammation [41] and decreased the risk of major adverse cardiovascular (CV) events (MACE) compared with placebo [38–40, 42–45].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [41] Verma S, Bhatta M, Davies M, Deanfield JE, Garvey WT, Jensen C, et al. Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials. EClinicalMedicine. 2023;55:101737. source

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    • cites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.

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    • cites [39] FDA. OZEMPIC prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed 3 January 2025.

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    • cites [40] FDA. WEGOVY prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf. Accessed 3 January 2025.

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    • cites [42] Husain M, Bain SC, Jeppesen OK, Lingvay I, Sorrig R, Treppendahl MB, et al. Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk. Diabetes Obes Metab. 2020;22(3):442–51. source

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    • cites [43] Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–44. source

      Not checked in the free run.

    • cites [44] Husain M, Birkenfeld AL, Donsmark M, Dungan K, Eliaschewitz FG, Franco DR, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019;381(9):841–51. source

      Not checked in the free run.

    • cites [45] Strain WD, Frenkel O, James MA, Leiter LA, Rasmussen S, Rothwell PM, et al. Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomized SUSTAIN 6 and PIONEER 6. Stroke. 2022;53(9):2749–57. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Liraglutide has been shown to reduce neurodegeneration and the speed of decline in cognitive function in people with Alzheimer's disease.

    “liraglutide has been shown to reduce neurodegeneration and the speed of decline in cognitive function in people with AD [29, 30].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Gejl M, Gjedde A, Egefjord L, Møller 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. source

      Not checked in the free run.

    • cites [30] Edison P, Femminella GD, Ritchie CW, Holmes C, Walker Z, Ridha BH, et al. Evaluation of liraglutide in the treatment of Alzheimer’s disease. Alzheimers Dement. 2021;17(S9):e057848. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The safety profile of semaglutide has been extensively studied outside of Alzheimer's disease and is well characterized in type 2 diabetes and obesity.

    “The safety profile of semaglutide has been extensively studied outside of AD and is well characterized in T2D and obesity [15, 57–59].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Gao X, Hua X, Wang X, Xu W, Zhang Y, Shi C, et al. Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022;13:935823. source

      Not checked in the free run.

    • cites [57] Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: the PIONEER programme. Diabetes Obes Metab. 2020;22(8):1263–77. source

      Not checked in the free run.

    • cites [58] Lincoff AM, Brown-Frandsen K, Colhoun HM, Deanfield J, Emerson SS, Esbjerg S, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221–32. source

      Not checked in the free run.

    • cites [59] Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, Rasmussen S, Davies M, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med. 2023;389(12):1069–84. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These observations suggest that semaglutide may have at least limited direct access to the brain as well as exerting peripheral effects.

    “These observations suggest that semaglutide may have at least limited direct access to the brain as well as exerting peripheral effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Clinical data using semaglutide and liraglutide at equivalent exposure levels show beneficial effects on neuroinflammation, dementia risk, and cognitive decline.

    “Clinical data using semaglutide and liraglutide at equivalent exposure levels show beneficial effects on neuroinflammation, dementia risk, and cognitive decline [29, 30, 32].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Gejl M, Gjedde A, Egefjord L, Møller 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. source

      Not checked in the free run.

    • cites [30] Edison P, Femminella GD, Ritchie CW, Holmes C, Walker Z, Ridha BH, et al. Evaluation of liraglutide in the treatment of Alzheimer’s disease. Alzheimers Dement. 2021;17(S9):e057848. source

      Not checked in the free run.

    • cites [32] Nørgaard CH, Friedrich S, Hansen CT, Gerds T, Ballard C, Møller DV, et al. Treatment with glucagon-like peptide-1 receptor agonists and incidence of dementia: data from pooled double-blind randomized controlled trials and nationwide disease and prescription registers. Alzheimers Dement (N Y). 2022;8(1):e12268. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Implementing the protocol in 40 countries and 50 languages has logistical challenges.

    “First, implementing the protocol in 40 countries and 50 languages has logistical challenges and assumes that the outcome measure variability and effect sizes are similar enough to stay within the assumptions of the sample size modeling.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The outcome measure variability and effect sizes are similar enough across the 40 countries and 50 languages to stay within the assumptions of the sample size modeling.

  • May combine two claims.

    Study design and conductreasoning

    The option to continue or initiate new Alzheimer's disease medication during the trial was not a randomization stratification factor and may therefore act as a confounding factor if their use across treatment arms is unequal.

    “Furthermore, the option to continue or initiate new AD medication during the trial, including the amyloid lowering monoclonal antibodies, was not a randomization stratification factor and may therefore act as a confounding factor if their use across treatment arms is unequal.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The evoke/evoke+ trials enrolled participants with late-stage mild cognitive impairment, who may be more likely to progress to mild Alzheimer's disease dementia during the trial.

    “To fully assess the effects of semaglutide in slowing disease progression, the evoke/evoke+ trials enrolled participants with late-stage MCI (defined as a CDR global score of 0.5 along with a CDR domain score of ≥ 0.5 in at least one of the three activities of daily living categories), who may be more likely to progress to mild AD dementia during the trial.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In each trial, participants are stratified by CSF sub-study participation (yes/no) to ensure 1:1 randomization in the sub-study population.

    “In each trial, participants are stratified by CSF sub-study participation (yes/no) to ensure 1:1 randomization in the sub-study population (Fig. 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Small vessel pathology is a common comorbidity in patients with Alzheimer's disease and has been implicated in the pathogenesis of Alzheimer's disease.

    “Small vessel pathology is a common comorbidity in patients with AD and has been implicated in the pathogenesis of AD [68].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Kim HW, Hong J, Jeon JC. Cerebral small vessel disease and Alzheimer’s disease: a review. Front Neurol. 2020;11:927. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Structural brain imaging for screening can be done either via MRI or CT scan, and the latter allows for patients for whom MRI is contraindicated to be included in the trials, which may further contribute to the representativeness of the trial populations.

    “Additionally, structural brain imaging for screening can be done either via MRI or CT scan. The latter allows for patients for whom MRI is contraindicated (e.g. many participants with pacemakers) to be included in the trials, which may further contribute to the representativeness of the trial populations.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Enrollment was completed on September 8, 2023.

    “Enrollment was completed on September 8, 2023, and the baseline characteristics of the participants will be described in a separate publication.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The 14 mg oral semaglutide dose was selected based on its well-established safety profile and approval for the treatment of type 2 diabetes, with exposure levels overlapping with those for the 1.0 mg subcutaneous formulation.

    “The 14 mg oral semaglutide dose selection was based on its well-established safety profile and approval for the treatment of T2D [38], with exposure levels overlapping with those for the 1.0 mg s.c. formulation [64].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.

      Not checked in the free run.

    • cites [64] Meier JJ. Efficacy of semaglutide in a subcutaneous and an oral formulation. Front Endocrinol (Lausanne). 2021;12:645617. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Semaglutide may protect vascular structure and improve endothelial permeability, and treatment may provide additional benefits to the subpopulation of participants with small vessel pathology in evoke+.

    “Given that semaglutide may protect vascular structure and improve endothelial permeability, treatment may provide additional benefits to this subpopulation of participants in evoke+.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    The strategy of allowing continuation or initiation of other Alzheimer's disease treatments is potentially important in the retention of participants who initiate other treatments during the long evoke/evoke+ trials and likely reflects how semaglutide would be used in real-world therapeutic regimens.

    “This strategy is potentially important in the retention of participants who initiate other treatments during the long evoke/evoke+ trials and likely reflects how semaglutide would be used in real-world therapeutic regimens.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    The inclusion of participants from 40 countries and 566 centers should facilitate the enrollment of an ethnically diverse population, improving the representativeness of the trial population.

    “The inclusion of participants from 40 countries and 566 centers should facilitate the enrollment of an ethnically diverse population, improving the representativeness of the trial population.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    evoke and evoke+ are the first large-scale, global trials to investigate the disease-modifying potential of semaglutide on slowing of disease progression in participants with early-stage biomarker-confirmed Alzheimer's disease, including exploration of the effect of semaglutide on plasma and CSF biomarkers of multiple pathophysiologic processes including neuroinflammation.

    “evoke and evoke+ are the first large-scale, global trials to investigate the disease-modifying potential of semaglutide on slowing of disease progression in participants with early-stage biomarker-confirmed AD, including exploration of the effect of semaglutide on plasma and CSF biomarkers of multiple pathophysiologic processes including neuroinflammation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Biomarker results supportive of disease modification include effects on key pathophysiologic features of Alzheimer's disease, including an impact on tau biology and neurodegenerative processes.

    “Likewise, biomarker results supportive of disease modification include effects on key pathophysiologic features of AD, including an impact on tau biology and neurodegenerative processes [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Cummings J. The role of biomarkers in Alzheimer’s disease drug development. Adv Exp Med Biol. 2019;1118:29–61. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    One of the main challenges of clinical trials in Alzheimer's disease, particularly in the US, is the recruitment of a representative sample of participants that includes minority groups, allowing the generalizability of the trial results to the wider population.

    “One of the main challenges of clinical trials in AD, particularly in the US, is the recruitment of a representative sample of participants that includes minority groups, allowing the generalizability of the trial results to the wider population [67].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Raman R, Aisen PS, Carillo MC, Detke M, Grill JD, Okonkwo OC, et al. Tackling a major deficiency of diversity in Alzheimer’s disease therapeutic trials: an CTAD Task Force report. J Prev Alzheimers Dis. 2022;9(3):388–92.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Biomarkers play an increasingly important role in Alzheimer's disease drug development and clinical trials.

    “Biomarkers play an increasingly important role in AD drug development and clinical trials [72, 73].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [72] Boxer AL, Sperling R. Accelerating Alzheimer’s therapeutic development: the past and future of clinical trials. Cell. 2023;186(22):4757–72. source

      Not checked in the free run.

    • cites [73] Cummings J. The role of biomarkers in Alzheimer’s disease drug development. Adv Exp Med Biol. 2019;1118:29–61. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    The trial design may lead to higher screening failure rates in non-White populations and thus trial populations may not be representative.

    “Additionally, the trial design may lead to higher screening failure rates in non-White populations and thus trial populations may not be representative.”
    Quote in the paperNot a substantial claim
38 of 38

  • The paper relies on this without support.

    Participants with concurrent significant small vessel pathology are often excluded in Alzheimer’s disease trials.

    “evoke+ allows the inclusion of participants with significant small vessel pathology (defined as more than one lacunar infarct and/or age-related white matter changes > 2 [white matter > 20 mm] [55]) to ensure evaluation of participants with concurrent significant small vessel pathology, who are often excluded in AD trials.”

  • The authors state this as an assumption.

    The outcome measure variability and effect sizes are similar enough across the 40 countries and 50 languages to stay within the assumptions of the sample size modeling.

    “First, implementing the protocol in 40 countries and 50 languages has logistical challenges and assumes that the outcome measure variability and effect sizes are similar enough to stay within the assumptions of the sample size modeling.”
2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Scheltens P, Atri A, Feldman H, Hansson O, Knop F, Sano M, et al. Baseline characteristics from evoke and evoke+: two phase 3 randomized placebo-controlled trials of oral semaglutide in patients with early Alzheimer’s disease. J Prev Alzheimers Dis. 2023;10(Suppl 1):S92–3. Poster LP018; Presented at CTAD 2023.

Cited by

Sorted by citations

Related

Authors
Cummings, J. L., Atri, A., Feldman, H. H., Hansson, O., Sano, M., Knop, F. K., Johannsen, P., León, T., & Scheltens, P.
Affiliations
  • University of Nevada, Las Vegas (US)
  • Brigham and Women's Hospital (US)
  • University of California San Diego (US)
  • Lund University (SE)
  • Icahn School of Medicine at Mount Sinai (US)
  • University of Copenhagen (DK)
  • Novo Nordisk (Denmark) (DK)
  • Amsterdam University Medical Centers (NL)
Corresponding author
Cummings, Jeffrey L.
ORCID
Venue
Alzheimer's Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2025-01-08
Volume
17
Issue
1
Pages
14-14
ISSN
1758-9193 (ISSN-L)
DOI
10.1186/s13195-024-01666-7
PMC
PMC11708093
OpenAlex
W4406156729
Semantic Scholar
83cf7fabb38bd8e2044f0a5796858ec8b399724a
Cited by
168
References
68
Citations by year
2026: 99 · 2025: 68 · 2024: 1
FWCI
106.43
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s Research & Therapy (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lund University Publications (Lund University) (submittedVersion, cc-by-nc-nd)
Funders
Novo Nordisk A/S
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
Keywords
semaglutide, Alzheimer's disease, GLP-1 receptor agonists, disease-modifying therapy, mild cognitive impairment, mild dementia, neuroinflammation, Clinical Dementia Rating, plasma biomarkers, cerebrospinal fluid biomarkers, dose escalation, trial design
MeSH terms
Semaglutide, Aged, Aged, 80 and over, Alzheimer Disease, Double-Blind Method, Glucagon-Like Peptides, Female, Humans, Male, Middle Aged, Treatment Outcome

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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