Real-world observations of GLP-1 receptor agonists and SGLT-2 inhibitors as potential treatments for Alzheimer's disease

Pengyue Zhang; Chengsheng Mao; Anna Sun; Yuedi Yang; Yuan Hou; Zhimin Fu; Tousi Babak; James B Leverenz; Andrew A Pieper; Yuan Luo; Jeffrey Cummings; Feixiong Cheng

doi:10.1002/alz.70639

Real-world observations of GLP-1 receptor agonists and SGLT-2 inhibitors as potential treatments for Alzheimer's disease

Alzheimers Dement. 2025 Sep;21(9):e70639. doi: 10.1002/alz.70639.

Authors

Pengyue Zhang¹, Chengsheng Mao², Anna Sun¹, Yuedi Yang¹, Yuan Hou^{3

4}, Zhimin Fu^{5

6}, Tousi Babak⁷, James B Leverenz⁷, Andrew A Pieper^{8

9

10

11

12

13}, Yuan Luo², Jeffrey Cummings¹⁴, Feixiong Cheng^{3

4

15

16}

Affiliations

¹ Department of Biostatistics and Health Data Science, Indiana University, Indianapolis, Indiana, USA.
² Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
³ Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁴ Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
⁵ College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio, USA.
⁶ Department of Medicine, Cleveland Clinic Akron General, Cleveland Clinic, Akron, Ohio, USA.
⁷ Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Akron, Ohio, USA.
⁸ Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio, USA.
⁹ Brain Health Medicines Center, Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
¹⁰ Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.
¹¹ Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
¹² Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
¹³ Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
¹⁴ Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada, Las Vegas, Las Vegas, Nevada, USA.
¹⁵ Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
¹⁶ Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.

Abstract

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors have potential beneficial effects in Alzheimer's disease (AD).

Methods: We conducted pharmacoepidemiologic studies using two large-scale real-world databases. We fitted covariate-adjusted Cox models to compare the risks of AD among initiators of GLP-1 receptor agonists, SGLT-2 inhibitors, and DPP-4 inhibitors.

Results: We identified GLP-1 receptor agonist initiation compared to DPP-4 inhibitors initiation was associated with a reduced risk of AD (hazard ratio [HR] ≤ 0.69 and P value < 0.001) and SGLT-2 inhibitor initiation compared to DPP-4 inhibitor initiation was associated with a reduced risk of AD (HR ≤ 0.67 and P value < 0.001).

Discussion: GLP-1 receptor agonist initiation and SGLT-2 inhibitor initiation are associated with a reduced risk of AD. Randomized clinical trials are warranted to validate the causal beneficial effects of GLP-1 receptor agonists and SGLT-2 inhibitors in AD.

Highlights: Glucagon-like peptide-1 (GLP-1) receptor agonists are significantly associated with a reduced risk of Alzheimer's disease (AD) compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are significantly associated with a reduced risk of AD compared to dipeptidyl peptidase-4 (DPP-4) inhibitors. Two GLP-1 receptor agonists (liraglutide and semaglutide) and three SGLT-2 inhibitors (dapagliflozin, canagliflozin, and empagliflozin) are associated with a reduced risk of AD in drug-specific sensitivity analyses.

Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl peptidase‐4; glucagon‐like peptide‐1; real‐world data; sodium‐glucose cotransporter‐2.

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease* / drug therapy
Alzheimer Disease* / epidemiology
Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
Female
Glucagon-Like Peptide-1 Receptor Agonists*
Humans
Hypoglycemic Agents* / therapeutic use
Male
Pharmacoepidemiology
Sodium-Glucose Transporter 2 Inhibitors* / therapeutic use

Substances

Sodium-Glucose Transporter 2 Inhibitors
Glucagon-Like Peptide-1 Receptor Agonists
Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents

Abstract

MeSH terms

Substances

Grants and funding