Neurology Clinical Trial Database
EVOKE
Efficacy and safety of oral semaglutide 14 mg (flexible dose) in early-stage symptomatic Alzheimer's disease (evoke and evoke+): two phase 3, randomised, placebo-controlled trials
Study Overview
Objective
To assess whether oral semaglutide up to 14 mg once daily slows cognitive and functional decline in adults with amyloid-confirmed early Alzheimer's disease (mild cognitive impairment or mild dementia).
Study Summary
- Oral semaglutide 14 mg did NOT slow decline on CDR-SB at week 104: estimated difference vs placebo −0·08 (95% CI −0·35 to 0·20; p=0·57) in evoke and 0·10 (−0·17 to 0·38; p=0·46) in evoke+.
- ADCS-ADL-MCI at week 104 showed no benefit (evoke −0·25 [95% CI −1·22 to 0·72]; evoke+ −0·03 [−0·97 to 0·91]); pooled time to CDR-G ≥1·0 also unchanged (HR 0·98 evoke, 0·96 evoke+).
- CSF substudy: semaglutide reduced canonical AD biomarkers (p-tau181, p-tau217, np-tau) and neuroinflammation/neurodegeneration markers (YKL-40, total tau, neurogranin) by up to ≈10%; plasma hsCRP fell and bodyweight dropped 5·8% (−4·3 kg) vs +0·6% with placebo.
- Safety: TEAEs 91·2% vs 84·8% (placebo); AEs leading to discontinuation ~17% vs ~8%; treatment-related fatalities 1 (semaglutide, haemorrhagic stroke) vs 4 (placebo). Both trials were discontinued for lack of efficacy.
Intervention
Oral semaglutide titrated to 14 mg once daily (flexible dosing) added to standard of care, versus matching placebo, for up to 156 weeks.
Patients per Arm
evoke: semaglutide 928, placebo 927; evoke+: semaglutide 976, placebo 977 (pooled N=3808).
Bottom Line
In two large phase 3 trials totalling 3808 amyloid-positive early Alzheimer's disease participants, oral semaglutide up to 14 mg once daily did NOT slow CDR-SB progression versus placebo at week 104, despite significant reductions in CSF p-tau and neurodegeneration biomarkers and in hsCRP; both trials were discontinued for negative clinical outcome.
Major Points
- Twin multicentre phase 3 RCTs (evoke, evoke+) at 566 sites across 40 countries; 3808 amyloid-confirmed early AD participants (72% MCI, 27% mild dementia) randomised 1:1 to oral semaglutide up to 14 mg daily or placebo for up to 156 weeks.
- Primary endpoint (change in CDR-SB from baseline to week 104) was not met in either trial: estimated difference -0.08 (95% CI -0.35 to 0.20; p=0.57) in evoke and 0.10 (-0.17 to 0.38; p=0.46) in evoke+.
- Confirmatory and supportive secondary endpoints (ADCS-ADL-MCI, ADAS-Cog-13, MoCA, MMSE, ADCOMS, NPI, EQ-5D-5L, composite Z-score, time to CDR global >=1.0) were all null; testing hierarchy stopped after failed primary.
- CSF substudy (n=199) showed significant semaglutide-driven reductions of up to ~10% in p-tau181, p-tau217, non-phosphorylated tau181/205, total tau, YKL-40 and neurogranin; plasma GFAP rose slightly; hsCRP decreased. Biomarker signal did not translate into clinical benefit.
- Safety was consistent with GLP-1 class effects: TEAEs 91.2% vs 84.8%; AEs leading to discontinuation ~17% vs ~8%; SAEs 20.4% vs 23.8%; treatment-related fatalities 1 (semaglutide) vs 4 (placebo). Bodyweight fell 5.8% (-4.3 kg) with semaglutide vs +0.6% (0.2 kg) with placebo. Falls and fractures were numerically fewer on semaglutide.
- Authors interpret the null result as possibly reflecting limited CNS bioavailability of semaglutide, later-stage symptomatic AD population (vs primary prevention in T2D real-world cohorts), and 24-month exposure; earlier-stage or asymptomatic populations may still merit investigation.
Design
Study Type: Two parallel multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials (evoke and evoke+)
Randomization: 1
Blinding: Double-blind (participants, care providers, investigators and outcome assessors masked)
Enrollment Period: May 18, 2021 to Sept 8, 2023
Follow-up Duration: Up to 156 weeks (primary analysis at week 104; 52-week extension)
Centers: 566
Countries: 40 countries (global)
Sample Size: 3808
Analysis: Hybrid hypothetical-treatment policy-composite (HTC) estimand; MMRM for CDR-SB with treatment, visit, APOE-ε4 status, sex, region, baseline AD medication as factors and baseline age as covariate; efficacy in full analysis set (all randomised), safety in all who received ≥1 dose
Inclusion Criteria
- Adults aged 55–85 years with mild cognitive impairment (MCI) or mild dementia due to Alzheimer's disease per NIA-AA 2018 criteria
- Clinical Dementia Rating (CDR) global score of 0.5 with CDR ≥0.5 in at least one instrumental ADL category, OR CDR global score of 1.0
- Repeated Battery for the Assessment of Neuropsychological Status (RBANS) delayed memory index score ≤85
- Mini-Mental State Examination (MMSE) score ≥22
- Amyloid positivity confirmed by amyloid PET (visual read) or CSF Aβ1-42 or CSF Aβ1-42/Aβ1-40 ratio
- If on approved AD symptomatic therapy at screening (donepezil, rivastigmine, galantamine, memantine or aducanumab), stable dose ≥3 months before screening
- evoke+ only: participants with significant small vessel pathology (>1 lacunar infarct and/or Age-Related White Matter Changes [ARWMC] score >2, white matter >20 mm) allowed
Exclusion Criteria
- Non-Alzheimer's cause of cognitive impairment / non-AD dementia
- In the evoke trial: significant small vessel pathology (as defined for evoke+ inclusion)
- Advanced dementia (CDR global > 1.0) or scores outside protocol thresholds (RBANS delayed memory index >85 or MMSE <22)
- Contraindications to GLP-1 receptor agonist therapy (per protocol; e.g. personal/family history of medullary thyroid carcinoma or MEN2, history of pancreatitis)
- Unstable concomitant Alzheimer's disease treatment or planned changes during trial (aside from medically necessary)
- Standard trial exclusions per published protocol (see Cummings et al 2025, appendix 1)
Arms
| Field | Oral semaglutide 14 mg | Control |
|---|---|---|
| Intervention | Oral semaglutide titrated (3 mg → 7 mg → 14 mg) to 14 mg once daily with flexible dosing on top of standard-of-care AD treatment | Matching oral placebo once daily on top of standard-of-care AD treatment |
| Duration | Up to 156 weeks (primary analysis at week 104) | Up to 156 weeks (primary analysis at week 104) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in Clinical Dementia Rating–Sum of Boxes (CDR-SB) from baseline to week 104 (per trial) | Primary | evoke +2.3 (SE 0.1); evoke+ +2.1 (SE 0.1) | evoke +2.3 (SE 0.1); evoke+ +2.2 (SE 0.1) | 0.57 (evoke); 0.46 (evoke+) | |
| Change in ADCS-ADL-MCI baseline→wk 104 | Secondary | Not tested (hierarchy stopped) | |||
| Time to progression to CDR global ≥1.0 in participants with baseline CDR-G 0.5 (per trial) | Secondary | evoke 0.98 (95% CI 0.85–1.14); evoke+ 0.96 (0.83–1.12) | NS | ||
| Change in composite Z-score (CDR-SB + ADCS-ADL-MCI + ADAS-Cog-13) at wk 104 | Secondary | NS | |||
| ADAS-Cog-13, MoCA, ADCOMS, MMSE, NPI (secondary supportive) | Secondary | No differences between treatment groups (appendix 1) | |||
| hsCRP at week 104 (ratio to baseline) | Secondary | Significant | |||
| EQ-5D-5L index score change baseline→wk 104 | Secondary | No difference between groups | |||
| Body weight change baseline→wk 104 (pooled) | Secondary | +0.6% (+0.2 kg) | −5.8% (−4.3 kg) | ||
| Plasma NfL (ETR wk 104) | Secondary | evoke 1.03 (95% CI 1.00–1.07) NS; evoke+ 1.05 (1.01–1.08) unadjusted p=0.0137 | |||
| Plasma GFAP (ETR wk 104) | Secondary | evoke 1.05 (95% CI 1.02–1.08) unadjusted p=0.0012; evoke+ 1.07 (1.04–1.10) unadjusted p<0.0001 | |||
| CSF substudy (n=199) at wk 78 – p-tau181, p-tau217, np-tau181, np-tau205, total tau, YKL-40, neurogranin | Secondary | Semaglutide reduced canonical AD and neurodegeneration/neuroinflammation CSF markers by up to ~10% vs placebo | |||
| MACE (non-adjudicated) cumulative incidence at wk 104 | Secondary | 0.03 (95% CI 0.02–0.04) | 0.03 (95% CI 0.03–0.04) | ||
| Stroke cumulative incidence at wk 104 | Secondary | 0.01 (95% CI 0.01–0.02) | 0.01 (95% CI 0.01–0.01) | ||
| Any TEAE (pooled) | Adverse | Semaglutide 91.2% (1729/1896) vs Placebo 84.8% (1613/1902) | |||
| Any TEAE evoke | Adverse | Semaglutide 90.6% vs Placebo 85.5% | |||
| Any TEAE evoke+ | Adverse | Semaglutide 91.8% vs Placebo 84.1% | |||
| Serious AE evoke | Adverse | Semaglutide 19.0% vs Placebo 25.0% | |||
| Serious AE evoke+ | Adverse | Semaglutide 21.6% vs Placebo 22.7% | |||
| AE leading to permanent discontinuation evoke | Adverse | 17.2% vs 8.1% | |||
| AE leading to permanent discontinuation evoke+ | Adverse | 16.7% vs 8.6% | |||
| Fatal events evoke | Adverse | Semaglutide 3.0% vs Placebo 2.5% | |||
| Fatal events evoke+ | Adverse | Semaglutide 2.4% vs Placebo 2.9% | |||
| Treatment-related fatalities | Adverse | 1 (semaglutide; haemorrhagic stroke in participant with hypertension, atherosclerotic coronary disease, HF, carotid stenosis) vs 4 (placebo; congestive HF, metabolic acidosis, intestinal ischaemia, undetermined) | |||
| Weight decreased evoke | Adverse | 36.3% vs 6.5% | |||
| Weight decreased evoke+ | Adverse | 36.7% vs 8.3% | |||
| Decreased appetite evoke | Adverse | 31.7% vs 5.7% | |||
| Decreased appetite evoke+ | Adverse | 34.4% vs 6.3% | |||
| Nausea evoke | Adverse | 25.2% vs 6.9% | |||
| Nausea evoke+ | Adverse | 23.4% vs 6.8% | |||
| Diarrhoea evoke | Adverse | 14.7% vs 11.2% | |||
| Diarrhoea evoke+ | Adverse | 14.3% vs 8.3% | |||
| Vomiting evoke | Adverse | 12.3% vs 4.1% | |||
| Vomiting evoke+ | Adverse | 12.3% vs 3.2% | |||
| COVID-19 evoke | Adverse | 10.5% vs 11.1% | |||
| COVID-19 evoke+ | Adverse | 11.2% vs 11.4% | |||
| Falls evoke | Adverse | 6.0% vs 9.2% | |||
| Falls evoke+ | Adverse | 7.4% vs 9.0% | |||
| Bone/joint injuries or fractures evoke | Adverse | 5.0% vs 8.8% | |||
| Bone injuries evoke+ | Adverse | 6.3% vs 7.5% | |||
Subgroup Analysis
Post-hoc subgroup analyses for age, sex, and type 2 diabetes status supported the null primary result; no clinically meaningful heterogeneity of effect on CDR-SB at week 104 (appendix 1 pp 42–43).
Criticisms
- Both trials were discontinued for negative clinical outcome; primary endpoint definitively null despite 95% powered design.
- Potential functional unblinding from characteristic GLP-1 adverse events (weight loss 36% vs ~7%; nausea, appetite loss) although similar-sounding symptoms occurred in placebo.
- Studied a late (already symptomatic) AD population; the biological hypothesis (delaying incident AD) is best tested in primary prevention or preclinical AD populations, not MCI/mild dementia.
- Oral formulation has limited CNS bioavailability (CSF geometric mean 0.08 nmol/L; ratio ~1:220 to plasma) and modest CSF biomarker effects (~5–10% vs up to 25% with anti-amyloid mAbs) — CNS exposure may have been insufficient.
- Small vessel pathology inclusion criterion in evoke+ was met by only 2.8% of participants, so the additional cerebrovascular-mixed-pathology question was underpowered.
- Follow-up limited to 104 weeks (primary) / up to 156 weeks (extension); longer exposure durations in real-world cohorts might explain divergence from observational signals.
- Trials sponsored, run and analysed by Novo Nordisk (funder); several authors are Novo Nordisk employees/shareholders.
Funding
Novo Nordisk (sponsor, data collection and analysis; independent Data Monitoring Committee).
Based on: EVOKE (Lancet, 2026)
Authors: Cummings JL, Atri A, Sano M, ..., Feldman HH; evoke and evoke+ Steering Committees and Investigators
Citation: Lancet 2026;407(10544):2167-2179
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