GLP-1 Receptor Agonists and Alzheimer's Disease: A Multi-National Target Trial Emulation

NCT07677865 | Completed DMC

• 1 other identifier: WestChinaH-HX-2026-004-GLP1-AD
• Study Type: observational
• Target: 213,891
• Locations: 1 country
• Sites: 1

Brief 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). 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.

Conditions

Alzheimer Disease; Diabetes Mellitus Type 2; Obesity & Overweight

Keywords

glucagon-like peptide-1 receptor agonist; Alzheimer disease

Outcome Measures

Primary Outcomes (1)

• 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).

  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.

  Up to 10 years

• Rate of Progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease

  Up to 10 years

• Rate of All-Cause Mortality.

  Up to 10 years.

Other Outcomes (1)

• Incidence of Four Negative Control Outcomes.

  Up to 10 years.

Study Arms (2)

GLP-1 Receptor Agonist (GLP-1RA) Initiators

Drug: GLP-1 Receptor Agonists

DPP-4 Inhibitor (DPP-4i) Initiators

Drug: DPP-4 Inhibitors

Interventions

GLP-1 Receptor Agonists DRUG

like semaglutide、tirzepatide、liraglutide，etc.

GLP-1 Receptor Agonist (GLP-1RA) Initiators

DPP-4 Inhibitors DRUG

Sitagliptin,Saxagliptin,Vildagliptin,Linagliptin,Alogliptin etc.

DPP-4 Inhibitor (DPP-4i) Initiators

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• West China Hospital: lead
• Hong Kong University: collaborator
• Boston Children's Hospital: collaborator
• Karolinska University Hospital: collaborator

Study Sites (1)

West China Hospital of Sichuan University

Chengdu, Sichuan, China

Location

MeSH Terms

Conditions

Alzheimer Disease; Diabetes Mellitus, Type 2; Obesity; Overweight

Interventions

Glucagon-Like Peptide-1 Receptor Agonists; Dipeptidyl-Peptidase IV Inhibitors

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hypoglycemic Agents; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 24, 2026
• First Posted: July 1, 2026
• Study Start: January 1, 2007
• Primary Completion: December 31, 2024
• Study Completion: June 24, 2026
• Last Updated: July 1, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP

Locations

CN (1)