Dual defense: Opportunities and challenges of GLP-1 receptor agonists in reducing dementia risk in type 2 diabetes!

Abstract

We read with great interest a recently published article titled “Glycated hemoglobin and body mass index as mediators of GLP-1RAs and Alzheimer's disease and related dementias in patients with type 2 diabetes” by Tang et al.¹ which used GLP 1RAs in type 2 diabetes mellitus (T2DM) patients over the age of 50 to analyze the effect on Alzheimer's disease and related dementias (ADRD) risk and body mass index (BMI)¹ This study suggests that the use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) lessened the risk of ADRD by 26% when compared to other second-line glucose-lowering medications, such as sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors (DPP4i), α-glucosidase inhibitors, or meglitinides. This reduction occurs majorly independent of the effects exerted on hemoglobin A1c (HbA1c) levels and BMI.¹

GLP-1RAs, also known as “incretin mimetics,” include medications such as exenatide, dulaglutide, semaglutide, and tirzepatide, which are utilized in the management of T2DM and for weight loss. These agents function by enhancing insulin secretion, suppressing glucagon through their interaction with GLP-1 receptors distributed throughout the body. Notably, the central nervous system (CNS) contains abundant GLP-1 receptors in regions associated with memory and learning.² It is hypothesized that GLP-1RAs may engage these receptors to improve the survival outcome of neurons and potentially delay the progression of Alzheimer's disease.³ This new finding is particularly important for patients with T2DM, since according to a study, these patients exhibit a 56% heightened risk of developing Alzheimer's disease, a 73% risk of experiencing any form of dementia, and a 127% heightened risk of vascular dementia.⁴ Additionally, dementia currently affects 55 million individuals worldwide, which is predicted to increase to almost 150 million by the year 2050.⁵

A recent meta-analysis published in 2025 indicates a statistically significant correlation between GLP-1RAs and a decrease in dementia incidence,¹ a finding that does not extend to sodium-glucose cotransporter-2 inhibitors (SGLT2is).⁶ Furthermore, research conducted by Nørgaard et al.⁷ emphasizes the potential of GLP-1RAs to reduce the incidence of dementia in patients with T2DM and those with Alzheimer's disease, while also underscoring the necessity for further investigation in this domain.⁷

In Pakistan, approximately ∼150,000–200,000 people suffer from dementia, highlighting the impact of dementia and the importance of GLP-1Ras.⁸ Despite the benefits, the use is limited mostly due to high costs and a lack of resource allocation by the government into healthcare resources. These agents are hardly available due to a lack of local production, implementation of import taxes, and high demand. This makes these agents inaccessible to the majority of the population, leading to poor health outcomes. In order to combat these obstacles, the Pakistani government must recognize and revise its healthcare policies to focus on combating prevalent diseases, such as ADRD, by making these agents accessible and affordable to the general population. Other than accessibility issues, certain concerns have been raised regarding the adverse effects of this drug. According to Drucker, ⁹ psychiatric symptoms, such as agitation and eating disorders, have been correlated with GLP 1RAs use. Chen et al.¹⁰ report similar findings, stating that long-term activation of GLP 1 receptors can result in sleeping disorders and other psychiatric events. This indicates that, although GLP-1RAs are beneficial, these drugs can cause emotional dysregulation in vulnerable populations and highlights the need for further investigations to be conducted to understand the effects of GLP-1 RAs on preventing cognitive decline and dementia.⁷

In conclusion, to fully evaluate the effectiveness and safety profile in detail, we encourage more studies with follow-up and diverse patients because factors like the impact of HbA1c levels on ADRD risk and subsequently, the relationship with GLP-1RAs, are not fully understood yet. In order to address the pressing global issue of the high incidence of dementia, we presume that further research could establish this as a novel therapeutic approach for treating ADRD risk and related disorders, especially in T2DM patients.

Writing and referencing: Saman Adnan. Writing and reviewing: Muniza Qureshi. Reviewing: Sania Arif and Kinza Fatima.

The authors declare no competing interests. Author disclosures are available in the supporting information.

Institutional Review Board (IRB) approval was not required because no data were collected for this article.