Semaglutide May Reduce Dementia Risk
August 15, 2025 4 minutes read
By Seema Gupta, MD, MSPH
Synopsis: In a large nationwide population-based study, semaglutide significantly reduced Alzheimer’s disease-related dementia risk compared to insulin, metformin, and older glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes.
Source: Wang W, Davis PB, Qi X, et al. Associations of semaglutide with Alzheimer’s disease-related dementias in patients with type 2 diabetes: A real-world target trial emulation study. J Alzheimers Dis. 2025; Jun 24:13872877251351329. doi: 10.1177/13872877251351329. [Online ahead of print].
Type 2 diabetes (T2D) and obesity have become intertwined global health crises, with epidemiological data confirming their explosive growth across both higher-income and developing nations. About 537 million adults were living with diabetes in 2021 — 90% to 95% of which was type 2 — and projections suggest this number could reach approximately 783 million by 2045.1
Parallel to this, global obesity rates have more than doubled over recent decades. In 2022, about 2.5 billion adults were overweight, and 890 million were obese, representing roughly 16% of all adults worldwide.2 The strong epidemiological link between obesity and T2D is well documented: As body mass index (BMI) increases, the lifetime risk of developing diabetes climbs dramatically — from around 7% to 70% in men and 12% to 74% in women. While these conditions collectively burden healthcare systems, they are characterized by insulin resistance, oxidative stress, and chronic inflammation, which also contributes to neurodegeneration.3 The 2024 Lancet Commission on Dementia recognized diabetes and obesity as modifiable risk factors that contribute to the development of dementia and those affected by both conditions are at increased risk for neurodegenerative and cerebrovascular disorders, such as dementia, Parkinson’s disease, and stroke.4
Extensive cohort studies have identified glucagon-like peptide-1 receptor agonists (GLP-1RAs) as particularly promising in reducing the risk of dementia, highlighting their potential neuroprotective properties beyond glycemic control.5 Originally developed to manage T2D, GLP-1RAs have transformed the clinical landscape by not only improving blood glucose levels, promoting significant weight loss, and reducing cardiovascular risk, but also by showing growing potential in protecting cognitive function. This emerging evidence suggests that GLP-1RAs may serve a dual purpose — addressing both metabolic and neurological health — positioning them as a unique therapeutic option against both diabetes and dementia.
In their study, Wang et al examined electronic health records (EHRs) of more than 1.71 million U.S. adults with T2D and with or without obesity and with no prior diagnosis of Alzheimer’s disease (AD) or AD-related dementia. The study evaluated semaglutide (n = 64,267 patients) against seven other antidiabetic medications (n = 1,646,728 patients) in relation to the incidence of first-time diagnoses of AD-related dementia, as well as specific subtypes, including vascular dementia, frontotemporal dementia, and Lewy body dementia, over a three-year follow-up period.
Researchers found that patients treated with semaglutide showed a significantly reduced risk of AD-related dementia compared to those on other antidiabetic therapies. Specifically, semaglutide use was associated with a 46% lower risk compared to insulin (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.49-0.59), a 33% lower risk compared to metformin (HR, 0.67; 95% CI, 0.61-0.74), and a 20% lower risk relative to older-generation GLP-1RAs (HR, 0.80; 95% CI, 0.72-0.89). The strongest protective effect was observed in cases of vascular dementia, while no significant associations were found for frontotemporal dementia or Lewy body dementia.
Commentary
The findings presented in the study by Wang et al underscore the urgent and interconnected public health challenges posed by T2D, obesity, and neurodegenerative diseases. With global rates of diabetes and obesity rising at alarming rates — projected to affect billions and carry trillions in healthcare costs — the downstream neurological consequences are gaining attention as a major facet of this crisis. As modifiable risk factors for dementia, diabetes and obesity add significant weight to this conversation, suggesting that targeting these metabolic conditions could have ripple effects for preventing neurodegeneration.
The emerging role of GLP-1RAs, particularly semaglutide, is especially compelling. Originally introduced as a treatment for glycemic control and weight reduction, GLP-1RAs now are showing potential to transcend metabolic management and offer neuroprotective benefits. Wang et al’s large-scale real-world study provides strong epidemiologic support for this possibility. Their findings suggest that semaglutide could play a dual therapeutic role — simultaneously mitigating the risks of cardiovascular, metabolic, and now possibly cognitive decline.
While further mechanistic and longitudinal studies are needed to establish causality and understand how GLP-1RAs confer neuroprotection, the implications are profound. If substantiated, this class of drugs could represent a paradigm shift in how clinicians’ approach both diabetes management and dementia prevention. Integrating such therapies into broader public health strategies may offer a rare opportunity in clinical care to simultaneously address some of the most burdensome chronic diseases of our time.
Seema Gupta, MD, MSPH, is Clinical Assistant Professor, Department of Family and Community Health, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV.
References
- Magliano DJ, Boyko DJ; International Diabetes Federation. IDF Diabetes Atlas. 10th ed. International Diabetes Federation; 2022. https://diabetesatlas.org/atlas/tenth-edition/
- Huang X, Wu Y, Ni Y, et al. Global, regional, and national burden of type 2 diabetes mellitus caused by high BMI from 1990 to 2021, and forecasts to 2045: Analysis from the global burden of disease study 2021. Front Public Health. 2025;13:1515797.
- Hong C-T, Chen J-H, Hu C-J. Role of glucagon-like peptide-1 receptor agonists in Alzheimer’s disease and Parkinson’s disease. J Biomed Sci. 2024;31(1):102.
- Patel V, Edison P. Cardiometabolic risk factors and neurodegeneration: A review of the mechanisms underlying diabetes, obesity and hypertension in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2024;95(6):581-589.
- Tian S, Jiang J, Wang J, et al. Comparison on cognitive outcomes of antidiabetic agents for type 2 diabetes: A systematic review and network meta-analysis. Diabetes Metab Res Rev. 2023;39(7):e3673.
In a large nationwide population-based study, semaglutide significantly reduced Alzheimer’s disease-related dementia risk compared to insulin, metformin, and older glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes.
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