Alzheimer DiseaseGLP1-AD-TTENCT07677865
GLP-1 Receptor Agonists and Alzheimer's Disease: A Multi-National Target Trial Emulation
An observational study of Alzheimer Disease and Diabetes Mellitus Type 2, run by West China Hospital at 1 site in China.
Trial summary
Background: Seven large real-world cohort studies (N > 4 million) have consistently reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a 19-54% lower incidence of Alzheimer's disease (AD). Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Alzheimer Disease, Diabetes Mellitus Type 2, Obesity & Overweight
- What is being tested?
- GLP-1 Receptor Agonists and DPP-4 Inhibitors
- How many people
- 0 participants
- Where
- 1 siteChina
- Study dates
- 1 Jan 2007to 24 Jun 2026
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Adults aged ≥ 40 years with type 2 diabetes (ICD-10 E11) or obesity (E66) from five EHR-linked cohorts across four continents: Optum Clinformatics (USA), Mass General Brigham Biobank (USA), CPRD Aurum (UK), Swedish National Diabetes Register (Sweden), and Hong Kong Hospital Authority CDARS (Hong Kong SAR)
Who may be able to join
- • Age ≥ 40 years
- Diagnosis of type 2 diabetes (ICD-10 E11) or obesity (E66)
- ≥ 2 years of continuous enrolment in the cohort
- Baseline HbA1c < 10.5%
- No prior diagnosis of any neurodegenerative disease
- No prior use of any GLP-1RA or DPP-4i
Who cannot join
- • Prior diagnosis of Alzheimer's disease or other neurodegenerative diseases
- Prior use of GLP-1 receptor agonists or DPP-4 inhibitors
- Age < 40 years
- Baseline HbA1c ≥ 10.5%
- Less than 2 years of continuous enrolment
Trial locations and contacts
1 site in 1 country.
About this study
Official title: GLP-1 Receptor Agonists Prevent Alzheimer's Disease Onset, Not Progression: Resolving the Real-World-Randomised Trial Paradox Across Five Continents
Background: Seven large real-world cohort studies (N > 4 million) have consistently reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a 19-54% lower incidence of Alzheimer's disease (AD). However, in November 2025, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide in 3,808 patients with biomarker-confirmed early-stage AD failed to slow clinical progression. This paradox between real-world evidence (RWE) and randomised evidence has not been systematically examined. Moreover, prior RWE studies were conducted predominantly in North American and European populations, leaving a critical generalisability gap for East Asian populations, who face the world's largest AD burden.
Objective: To resolve the RWE-RCT paradox by testing whether the GLP-1RA effect on AD differs between cognitively unimpaired adults (primary prevention paradigm) and patients with established cognitive impairment (treatment paradigm), and to assess whether the protective effect is consistent across European, African, and East Asian ancestries.
Read more
Study Design: This is a multi-centre, retrospective, observational cohort study using a target trial emulation framework. The investigator analysed patient-level electronic health records (EHR) from five cohorts across four continents: Optum® Clinformatics® (USA), Mass General Brigham Biobank (USA), CPRD Aurum (UK), the Swedish National Diabetes Register (Sweden), and the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (HKHA CDARS), which covers approximately the entire Hong Kong population.
Study Population: A total of 2,138,917 adults aged ≥ 40 years with type 2 diabetes or obesity, with ≥ 2 years of continuous enrolment and no prior neurodegenerative disease diagnosis. GLP-1RA initiators (n = 612,418) were compared with DPP-4 inhibitor initiators (n = 1,526,499) using propensity-score overlap weighting, Fine-Gray competing-risk adjustment, negative-control outcomes, and instrumental-variable analysis to address confounding and surveillance bias.
- Being tested
- GLP-1 Receptor Agonists, DPP-4 Inhibitors
- Keywords
- glucagon-like peptide-1 receptor agonist, Alzheimer disease
- Medical subject headings
- Alzheimer Disease, Diabetes Mellitus, Type 2, Obesity, Overweight
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GLP-1 Receptor AgonistsDrug
like semaglutide、tirzepatide、liraglutide，etc.
DPP-4 InhibitorsDrug
Sitagliptin,Saxagliptin,Vildagliptin,Linagliptin,Alogliptin etc.
| Study group | Role | What they receive |
|---|---|---|
| GLP-1 Receptor Agonist (GLP-1RA) Initiators | Not described Receives: Drug: GLP-1 Receptor Agonists | |
| DPP-4 Inhibitor (DPP-4i) Initiators | Not described Receives: Drug: DPP-4 Inhibitors |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of Alzheimer's Disease
Measurement Tool: International Classification of Diseases, Tenth Revision (ICD-10) diagnostic code G30 (Alzheimer's disease), extracted from linked electronic health records (EHR) and hospitalization databases across all participating cohorts. Diagnostic validity was confirmed via chart review against biomarker-confirmed AD (amyloid PET, CSF Aβ42, or plasma p-tau217), with a positive predictive value (PPV) ranging from 68.9% to 71.3% in validation samples.
Unit of Measure: Time to first incident diagnosis, expressed as Hazard Ratio (HR) with 95% confidence intervals, comparing GLP-1 receptor agonist initiators versus DPP-4 inhibitor initiators. Incidence rates are also reported as number of events per 1,000 person-years.
Scale Information: Not applicable (this is a time-to-event diagnostic outcome, not a rating scale).
Measured: Up to 10 years (from index date of medication initiation to date of first AD diagnosis, death, or end of follow-up, whichever occurs first).
Secondary outcomes (3)
Incidence of All-Cause Dementia.
Measurement Tool: ICD-10 codes for any dementia diagnosis, including Alzheimer's disease (G30), vascular dementia (F01), and unspecified dementia (F03), extracted from EHR and hospitalization records.
Unit of Measure: Time to first diagnosis, expressed as Hazard Ratio (HR) with 95% CI.
Scale Information: Not applicable (diagnostic outcome).
Measured: Up to 10 years
Rate of Progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease
Measurement Name: Rate of Progression from MCI to AD.
Measurement Tool: ICD-10 code G31.84 (Mild cognitive impairment) at baseline, followed by subsequent ICD-10 code G30 (Alzheimer's disease) during follow-up, extracted from EHR.
Unit of Measure: Time to progression, expressed as Hazard Ratio (HR) with 95% CI, specifically analyzed within the EVOKE-eligible patient subgroup (those with baseline cognitive impairment).
Scale Information: Not applicable (diagnostic progression outcome).
Measured: Up to 10 years
Rate of All-Cause Mortality.
Measurement Tool: Death records linked from national or regional death registries (e.g., Hong Kong Death Registry, Swedish National Death Registry, UK Office for National Statistics).
Unit of Measure: Time to death, expressed as Hazard Ratio (HR) with 95% CI, analyzed using Fine-Gray subdistribution hazard models to account for competing risks.
Scale Information: Not applicable (mortality outcome).
Measured: Up to 10 years.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jul 2026
- Study start1 Jan 2007
- Primary completion31 Dec 2024
- Study completion24 Jun 2026
Why it stopped: poor accrual and funding issues
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- More trials run by West China HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- West China Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Hong Kong University, Boston Children's Hospital, Karolinska University Hospital
- Responsible party
- Principal investigator, Zhigang Lan, West China Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07677865
- Sponsor's protocol ID
- WestChinaH-HX-2026-004-GLP1-AD
- Acronym
- GLP1-AD-TTE
- Status last verified
- Oct 2026
- First submitted
- 24 Jun 2026
- Last updated
- 16 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 16 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- GLP-1 Receptor Agonists Prevent Alzheimer's Disease Onset, Not Progression: Resolving the Real-World-Randomised Trial Paradox Across Five Continents
- ClinicalTrials.gov ID
- NCT07677865
- Acronym / sponsor ID
- GLP1-AD-TTE / WestChinaH-HX-2026-004-GLP1-AD
- Keywords
- glucagon-like peptide-1 receptor agonist, Alzheimer disease
- Study type
- Observational
- Recruitment status
- WithdrawnReason stopped: poor accrual and funding issues
- Enrolment
- 0 participants (actual)
- Lead sponsor
- West China HospitalUniversity, hospital or other
- Collaborators
- Hong Kong University, Boston Children's Hospital, Karolinska University Hospital
- Study start
- 1 Jan 2007 (actual)
- Primary completion
- 31 Dec 2024 (actual)
- Study completion
- 24 Jun 2026 (actual)
- First posted
- 1 Jul 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: Seven large real-world cohort studies (N > 4 million) have consistently reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) are associated with a 19-54% lower incidence of Alzheimer's disease (AD). However, in November 2025, the phase 3 EVOKE and EVOKE+ trials of oral semaglutide in 3,808 patients with biomarker-confirmed early-stage AD failed to slow clinical progression. This paradox between real-world evidence (RWE) and randomised evidence has not been systematically examined. Moreover, prior RWE studies were conducted predominantly in North American and European populations, leaving a critical generalisability gap for East Asian populations, who face the world's largest AD burden.
Objective: To resolve the RWE-RCT paradox by testing whether the GLP-1RA effect on AD differs between cognitively unimpaired adults (primary prevention paradigm) and patients with established cognitive impairment (treatment paradigm), and to assess whether the protective effect is consistent across European, African, and East Asian ancestries.
Study Design: This is a multi-centre, retrospective, observational cohort study using a target trial emulation framework. The investigator analysed patient-level electronic health records (EHR) from five cohorts across four continents: Optum® Clinformatics® (USA), Mass General Brigham Biobank (USA), CPRD Aurum (UK), the Swedish National Diabetes Register (Sweden), and the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System (HKHA CDARS), which covers approximately the entire Hong Kong population.
Study Population: A total of 2,138,917 adults aged ≥ 40 years with type 2 diabetes or obesity, with ≥ 2 years of continuous enrolment and no prior neurodegenerative disease diagnosis. GLP-1RA initiators (n = 612,418) were compared with DPP-4 inhibitor initiators (n = 1,526,499) using propensity-score overlap weighting, Fine-Gray competing-risk adjustment, negative-control outcomes, and instrumental-variable analysis to address confounding and surveillance bias.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GLP-1 Receptor Agonist (GLP-1RA) Initiators | – | Drug: GLP-1 Receptor Agonists |
| DPP-4 Inhibitor (DPP-4i) Initiators | – | Drug: DPP-4 Inhibitors |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Adults aged ≥ 40 years with type 2 diabetes (ICD-10 E11) or obesity (E66) from five EHR-linked cohorts across four continents: Optum Clinformatics (USA), Mass General Brigham Biobank (USA), CPRD Aurum (UK), Swedish National Diabetes Register (Sweden), and Hong Kong Hospital Authority CDARS (Hong Kong SAR)
Key inclusion criteria (6 listed)
- • Age ≥ 40 years
Key exclusion criteria (5 listed)
- • Prior diagnosis of Alzheimer's disease or other neurodegenerative diseases
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GLP-1 Receptor Agonistslike semaglutide、tirzepatide、liraglutide，etc. | Drug | GLP-1 Receptor Agonist (GLP-1RA) Initiators |
| DPP-4 InhibitorsSitagliptin,Saxagliptin,Vildagliptin,Linagliptin,Alogliptin etc. | Drug | DPP-4 Inhibitor (DPP-4i) Initiators |
Primary outcome
Incidence of Alzheimer's Disease
Time frame: Up to 10 years (from index date of medication initiation to date of first AD diagnosis, death, or end of follow-up, whichever occurs first).
Measurement Tool: International Classification of Diseases, Tenth Revision (ICD-10) diagnostic code G30 (Alzheimer's disease), extracted from linked electronic health records (EHR) and hospitalization databases across all participating cohorts. Diagnostic validity was confirmed via chart review against biomarker-confirmed AD (amyloid PET, CSF Aβ42, or plasma p-tau217), with a positive predictive value (PPV) ranging from 68.9% to 71.3% in validation samples. Unit of Measure: Time to first incident diagnosis, expressed as Hazard Ratio (HR) with 95% confidence intervals, comparing GLP-1 receptor agonist initiators versus DPP-4 inhibitor initiators. Incidence rates are also reported as number of events per 1,000 person-years. Scale Information: Not applicable (this is a time-to-event diagnostic outcome, not a rating scale).
3 secondary outcomes
Incidence of All-Cause Dementia.
Time frame: Up to 10 years
Rate of Progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease
Time frame: Up to 10 years
Rate of All-Cause Mortality.
Time frame: Up to 10 years.
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Oct 2026.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Alzheimer Disease and Diabetes Mellitus Type 2, run by West China Hospital at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 16 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Incidence of Alzheimer's Disease (time frame: Up to 10 years (from index date of medication initiation to date of first AD diagnosis, death, or end of follow-up, whichever occurs first).). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Oct 2026; AzTrials last refreshed its copy on 6 Nov 2026.