Response to the letter titled reply to “Associations of semaglutide with first‐time diagnosis of Alzheimer's disease in patients with type 2 diabetes: Target trial emulation using nationwide real‐world data in the US”

To the Editor,

1.

We appreciate the opportunity to address the comments by Dr Rydberg regarding our study. ¹ The author raised a very interesting question regarding the early separation of the survival curves, given that Alzheimer's disease often takes many years to develop. Patients in our study population were at high risk for developing AD with an average age of 58 years. In addition, all participants had type 2 diabetes as well as a high burden of comorbidities, including hypertension, obesity, cardiovascular disease, and depression—factors that are well‐established risk factors for AD. In addition, the matched semaglutide and comparison groups are heterogeneous even though they were well‐matched. Patients with different characteristics (e.g., age, gender, obesity) have varying risks for progressing to AD. Early divergence in outcomes between the two groups suggested that semaglutide slowed the progression of AD in patients with very high risk, likely through damped neuroinflammation, enhanced neuroprotection, and other mechanisms. The survival curve for the semaglutide group remained flatter than that of the comparison group throughout the 3‐year follow‐up period, suggesting that semaglutide could have slowed the progression of AD for patients with varying risks, rather than just those with very high risk. However, these are our speculations, the actual underlying mechanisms remain unknown and warrant further investigation. We acknowledge the limitations inherent in electronic health record (EHR)‐based observational studies and the inability to draw causal conclusions. Our findings provide real‐world data supporting the potential benefits of semaglutide for AD prevention, particularly in high‐risk populations, and call for future randomized clinical trials to confirm the causal relationship between semaglutide and AD prevention.

CONFLICT OF INTEREST STATEMENT

The author declares no conflicts of interest. Author disclosures are available in the Supporting Information.

Supporting information

Supporting Information