Associations of semaglutide with Alzheimer's disease-related dementias in patients with type 2 diabetes: A real-world target trial emulation study

Abstract

BackgroundAlmost half of the dementia cases are preventable. Semaglutide treats several medical conditions that are risk factors for dementia.ObjectiveWe aim to investigate if semaglutide is associated with a decreased risk of dementia.MethodsWe conducted emulation target trials based on a nationwide population-based database of patient electronic health records (EHRs) in the US among 1,710,995 eligible patients with type 2 diabetes (T2D) comparing semaglutide with other antidiabetic medications. First-time diagnosis of Alzheimer's disease-related dementia (ADRD) including vascular dementia, frontotemporal dementia, Lewy body dementia and other dementias were examined using Cox proportional hazards and Kaplan-Meier survival analyses during a 3-year follow-up. Models were adjusted by propensity-score matching.ResultsWe show that semaglutide was associated with a significantly reduced risk of overall ADRD incidence with a hazard ratio ranging from 0.54 (0.49-0.59) compared with insulin, 0.67 (0.61-0.74) compared with metformin, to 0.80 (0.72-0.89) compared with older generation glucagon-like peptide-1 agonists (GLP-1RAs). The association varied for specific dementia types, with significantly reduced risk of vascular dementia and no evidence of associations with frontotemporal and Lewy body dementias.ConclusionsThese findings provide evidence supporting protective effects of semaglutide on dementias in patients with T2D. Future works are needed to establish the causal relationships through randomized clinical trials and to characterize the underlying mechanisms.

Keywords: Alzheimer's disease related dementias; Alzheimer’s disease; Lewy body dementia; dementia; frontotemporal dementia; semaglutide; target trial emulation; type 2 diabetes; vascular dementia.

Figure 1.

Study flow diagram. DPP-4i: dipeptidyl-peptidase-4 inhibitor; GLP-1RA: glucagon-like peptide-1 receptor agonist; SGLT2i: sodium-glucose cotransporter-2 inhibitor; SU: sulfonylurea; T2D: type 2 diabetes mellitus; TZD: thiazolidinedione. *The combined total of patients (n = 1,646,728) in the comparison arm is not a sum of the patients from each of the 7 comparison antidiabetic medication groups because a patient could be prescribed more than one antidiabetic medication during the study period, though there was no overlap between semaglutide and each of the comparison medication groups. ^†Other GLP-1RAs included albiglutide (1.2%), dulaglutide (85.1%), exenatide (18.0%), liraglutide (57.0%), and lixisenatide (2.4%).

Figure 2.

Comparison of overall ADRD incidences between matched semaglutide versus other antidiabetic medication groups in patients with T2D who had no prior AD/ADRD during a 3-year follow-up. The exposure and comparison groups were propensity-score matched for variables listed in Table 1, and the status of variables was based on the presence of related clinical codes anytime up to 1 day before the index event (first prescription of semaglutide vs comparison medication classes during 12/2017–12/2021). Individuals in the matched groups were followed starting 30 days after the index event until the occurrence of the outcome, death, loss to follow-up, or 3 years after the index event, whichever occurred first. Hazard rates were calculated using a Cox proportional hazards model with censoring applied. Overall risk=the number of patients with outcomes during the follow-up time window/number of patients in the cohort at the beginning of the time window.

Figure 3.

Cumulative ADRD incidences for comparing matched semaglutide with insulin, metformin and other GLP-1RAs groups, respectively, in patients with T2D who had no prior AD/ADRD for a 3-year follow-up.

Figure 4.

Comparison of incidence of vascular dementia, FTD, LBD and other dementias during the 3-year follow-up between matched semaglutide versus other antidiabetic medication groups in patients with T2D who had no prior diagnosis of AD/ADRD.

Figure 5.

Comparison of dementia-related medication prescriptions during the 3-year follow-up between matched semaglutide and other antidiabetic medication groups in patients with T2D who had no prior diagnosis of AD/ADRD.

Figure 6.

Comparison of outpatient visits during the 3-year follow-up between propensity-score matched semaglutide and other antidiabetic medication groups in patients with T2D who had no prior diagnosis of AD/ADRD.