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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
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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.
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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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In the paper
“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].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“and occurs at early disease stages [2, 5–7]”
§ 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 > Background
What the sources say
- Not checked yetcites [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 yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“GLP-1RAs activate GLP-1 receptors that are found throughout the body, including the brain [16].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“these effects may be mediated indirectly rather than via direct brain action, since semaglutide may have limited ability to cross the BBB [49].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Semaglutide may have a disease-modifying, neuroprotective effect in AD through multimodal mechanisms including neuroinflammatory, vascular, and other AD-related processes.”
§ 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 > Abstract > Background
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIn the paper
“However, studies in animals have shown that semaglutide interacts with the circumventricular regions and specifically accesses GLP-1R–positive brain regions following peripheral administration, including the area postrema in the hindbrain, the arcuate nucleus of the hypothalamus, and the lateral septal nucleus [50].”
§ 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 > Background
What the sources say
- Not checked yetcites [50] Gabery S, Salinas CG, Paulsen SJ, Ahnfelt-Rønne J, Alanentalo T, Baquero AF, et al. Semaglutide lowers body weight in rodents via distributed neural pathways. JCI Insight. 2020;5(6):e133429. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“In a registry-based cohort, a reduced rate of dementia was observed with increasing exposure to GLP‐1RAs versus other non-insulin diabetes treatments [32].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Preclinical results in murine models treated with GLP-1RAs suggest that the potential effects of semaglutide in AD may be exerted via impact on several AD-related pathophysiologic processes including neuroinflammatory pathways, vascular and BBB integrity, reduced synaptic loss, and neuroprotection [19, 21, 23–26, 46–48];”
§ 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 > Background
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [46] Perry T, Lahiri DK, Sambamurti K, Chen D, Mattson MP, Egan JM, et al. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (Abeta) levels and protects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res. 2003;72(5):603–12. source
- Not checked yetcites [47] Grieco M, Giorgi A, Gentile MC, d’Erme M, Morano S, Maras B, et al. Glucagon-like peptide-1: a focus on neurodegenerative diseases. Front Neurosci. 2019;13:1112. source
- Not checked yetcites [48] Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, et al. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal CA1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;46(4):877–88. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“This 8-week dose-escalation period is based on previous clinical trial evidence supporting a low starting dose and gradual titration of semaglutide [38, 51].”
§ 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 > Methods > Trial design
What the sources say
- Not checked yetcites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [51] Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Consistent with other GLP-1RAs, the most frequently expected adverse events in individuals receiving semaglutide are GI-related events, such as nausea, vomiting, and diarrhea [38, 60].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [60] Shu Y, He X, Wu P, Liu Y, Ding Y, Zhang Q. Gastrointestinal adverse events associated with semaglutide: a pharmacovigilance study based on FDA adverse event reporting system. Front Public Health. 2022;10:996179. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- Probably not a substantial claim. 22
- It may state two separate claims as one. 25
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [17] Brundin L, Bergkvist L, Brundin P. Fire prevention in the Parkinson’s disease brain. Nat Med. 2018;24(7):900–2. source
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [13] Yadollahikhales G, Rojas JC. Anti-amyloid immunotherapies for Alzheimer’s disease: a 2023 clinical update. Neurotherapeutics. 2023;20(4):914–31. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Additionally, microvascular dysfunction may contribute to disease progression [9, 10].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
- Not checked yetcites [10] Steinman J, Sun HS, Feng ZP. Microvascular alterations in Alzheimer’s disease. Front Cell Neurosci. 2020;14:618986. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Neuroinflammation has been identified as a key contributor to the pathobiology of AD [2–4]”
§ 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 > Background
What the sources say
- Not checked yetcites [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 yetcites [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
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“with the approval by the US Food and Drug Administration (FDA) of the anti-amyloid monoclonal antibodies aducanumab, lecanemab, and donanemab [11, 12].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
- Not checked yetcites [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
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [8] Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer’s disease. Neurobiol Dis. 2017;107:41–56. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Participants and investigators will remain blinded to treatment assignment throughout the trial period (main and extension phases).”
§ 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 > Methods > Trial design
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment compliance was assessed and reinforced through drug accountability information (counting returned tablets) and through documented discussions with participants and study partners.”
§ 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 > Methods > Trial design
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Methods > Trial design
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“All PET scans, including historical images, were assessed centrally in accordance with FDA guidelines for the Imaging Endpoint Process Standards [54].”
§ 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 > Methods > Participants
What the sources say
- Not checked yetcites [54] FDA. Guidance for Industry: Clinical Trial Imaging Endpoint Process Standards. 2018.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Abstract > Conclusion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [39] FDA. OZEMPIC prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [40] FDA. WEGOVY prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf. Accessed 3 January 2025.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [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 yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
- Not checked yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Background
What the sources say
- Not checked yetcites [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
- Not checked yetcites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [39] FDA. OZEMPIC prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [40] FDA. WEGOVY prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [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
- Not checked yetcites [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 yetcites [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 yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“liraglutide has been shown to reduce neurodegeneration and the speed of decline in cognitive function in people with AD [29, 30].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The safety profile of semaglutide has been extensively studied outside of AD and is well characterized in T2D and obesity [15, 57–59].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These observations suggest that semaglutide may have at least limited direct access to the brain as well as exerting peripheral effects.”
§ 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 > Background
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Clinical data using semaglutide and liraglutide at equivalent exposure levels show beneficial effects on neuroinflammation, dementia risk, and cognitive decline [29, 30, 32].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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 yetcites [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
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Limitations
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Limitations
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ 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 > Methods > CSF sub-study
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Small vessel pathology is a common comorbidity in patients with AD and has been implicated in the pathogenesis of AD [68].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [68] Kim HW, Hong J, Jeon JC. Cerebral small vessel disease and Alzheimer’s disease: a review. Front Neurol. 2020;11:927. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Enrollment was completed on September 8, 2023, and the baseline characteristics of the participants will be described in a separate publication.”
§ 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 > Conclusions
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [38] FDA. RYBELSUS prescribing information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/213051s000lbl.pdf. Accessed 3 January 2025.
- Not checked yetcites [64] Meier JJ. Efficacy of semaglutide in a subcutaneous and an oral formulation. Front Endocrinol (Lausanne). 2021;12:645617. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Given that semaglutide may protect vascular structure and improve endothelial permeability, treatment may provide additional benefits to this subpopulation of participants in evoke+.”
§ 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 > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ 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 > Conclusions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“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].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [73] Cummings J. The role of biomarkers in Alzheimer’s disease drug development. Adv Exp Med Biol. 2019;1118:29–61. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Biomarkers play an increasingly important role in AD drug development and clinical trials [72, 73].”
§ 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 > Discussion
What the sources say
- Not checked yetcites [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 yetcites [73] Cummings J. The role of biomarkers in Alzheimer’s disease drug development. Adv Exp Med Biol. 2019;1118:29–61. source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Additionally, the trial design may lead to higher screening failure rates in non-White populations and thus trial populations may not be representative.”
§ 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 > Limitations
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“Two phase III clinical trials are ongoing, 45 and re‐evaluation with more recent data is warranted.”
From Critical evaluation of real‐world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation (2026) · cites this paper as [45]
Citations
Cites
NIA‐AA Research Framework: Toward a biological definition of Alzheimer's disease
Jack, C. R., Bennett, D. A., Blennow, K., Carrillo, M. C., Dunn, B., Haeberlein, S. B., Holtzman, D. M., Jagust, W., Jessen, F., Karlawish, J., et al. (2018) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2018.02.018 · Cited by 10,537
Self-citationThe Clinical Dementia Rating (CDR): Current version and scoring rules
Morris, J. C. (1993) · Neurology · doi:10.1212/wnl.43.11.2412-a · Cited by 9,882
Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes
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Metadata
- 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
- Published
- 2025-01-08
- Volume
- 17
- Issue
- 1
- Pages
- 14-14
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC11708093
- OpenAlex
- W4406156729
- Semantic Scholar
- 83cf7fabb38bd8e2044f0a5796858ec8b399724a
- Cited by
- 168
- References
- 68
- Citations by year
- 2026: 99 · 2025: 68
- FWCI
- 106.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › 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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