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

Abstract

Introduction: Emerging preclinical evidence suggests that semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) for type 2 diabetes mellitus (T2DM) and obesity, protects against neurodegeneration and neuroinflammation. However, real-world evidence for its ability to protect against Alzheimer's disease (AD) is lacking.

Methods: We conducted emulation target trials based on a nationwide database of electronic health records (EHRs) of 116 million US patients. Seven target trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with seven other antidiabetic medications. First-ever diagnosis of AD occurred within a 3-year follow-up period and was examined using Cox proportional hazards and Kaplan-Meier survival analyses.

Results: Semaglutide was associated with significantly reduced risk for first-time AD diagnosis, most strongly compared with insulin (hazard ratio [HR], 0.33 [95% CI: 0.21 to 0.51]) and most weakly compared with other GLP-1RAs (HR, 0.59 [95% CI: 0.37 to 0.95]). Similar results were seen across obesity status, gender, and age groups.

Discussion: These findings support further studies to assess semaglutide's potential in preventing AD.

Highlights: Semaglutide was associated with 40% to 70% reduced risks of first-time AD diagnosis in T2DM patients compared to other antidiabetic medications, including other GLP-1RAs. Semaglutide was associated with significantly lower AD-related medication prescriptions. Similar reductions were seen across obesity status, gender, and age groups. Our findings provide real-world evidence supporting the potential clinical benefits of semaglutide in mitigating AD initiation and development in patients with T2DM. These findings support further clinical trials to assess semaglutide's potential in delaying or preventing AD.

Keywords: Alzheimer's disease; emulation target trial; patient electronic health records; prevention; real‐world data; semaglutide; type 2 diabetes.

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; T2DM, type 2 diabetes mellitus; TUD, tobacco use disorder; TZD, thiazolidinedione. * The combined total of patients (n = 1,077,657) is not a sum of the patients from each of the seven comparison antidiabetic medication cohorts because a patient could be prescribed more than one antidiabetic medication during the study period, though there was no overlap between semaglutide and comparison medications groups. Other GLP‐1RAs included albiglutide (0.5%), dulaglutide (60.6%), exenatide (10.6%), liraglutide (35.2%), and lixisenatide (2.1%).

FIGURE 2

(A) Comparison of first‐time diagnosis of AD between propensity‐score‐matched semaglutide versus other antidiabetic medications groups in patients with T2DM and (B) cumulative AD incidences for the seven comparisons between propensity‐score‐matched semaglutide versus other antidiabetic medication groups. 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 any time up to 1 day before the index event (the first prescription of semaglutide vs comparison medication classes from December 2017 to May 2021). Outcomes were followed for 3 years after the index event for both matched exposure and comparison groups. Individuals in the matched groups were followed from the index event until the occurrence of the outcome, death, or 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 =  number of patients with outcomes during follow‐up time window/number of patients in cohort at beginning of time window. DPP‐4i, dipeptidyl‐peptidase‐4 inhibitors; SGLT2i, sodium‐glucose cotransporter‐2 inhibitors; SU, sulfonylureas; TZD, thiazolidinediones. Other GLP‐1RAs included albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide.

FIGURE 3

Comparison of AD incidence (first‐time diagnosis) between propensity‐score‐matched semaglutide versus other antidiabetic medications groups in women with T2DM and in men with T2DM. AD, Alzheimer's disease; T2DM, type 2 diabetes mellitus.

FIGURE 4

Comparison of first‐time diagnosis of AD between propensity‐score matched semaglutide versus other antidiabetic medication groups in patients with T2DM who had recent medical encounters for obesity diagnosis in the past 2 years and in those who did not. AD, Alzheimer's disease; T2DM, type 2 diabetes mellitus.