GLP-1 Agonist Semaglutide Shows Significant Prevention of Alzheimer Disease in Emulation Target Trials

Rong Xu, PhD, a professor of biomedical informatics at Case Western University

A recently published target trial emulation of electronic healthy records from more than 1 million patients with type 2 diabetes mellitus (T2DM) showed that treatment with semaglutide (Novo Nordisk), a glucagon-like peptide receptor agonist (GLP-1RA), can delay or prevent Alzheimer disease (AD). All told, the therapy was associated with 40% to 70% reduced risks of first-time AD diagnosis in this patient population compared with other antidiabetic medications, including other GLP-1RAs.¹

Published in Alzheimer’s & Dementia, 7 trials were emulated among 1,094,761 eligible patients with T2DM who had no prior AD diagnosis by comparing semaglutide with 7 other antidiabetic medications. Of these, 17,104 were new users of semaglutide and 1,077,657 were new users of other antidiabetic medications. Led by Rong Xu, PhD, a professor of biomedical informatics at Case Western University, 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.

For each population, the investigators compared semaglutide with insulins, metformin, dipeptidyl-peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), sulfonylureas (SUs), thiazolidinediones (TZDs), and other GLP-Ras (albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide). After propensity-score matching, comparison groups were balanced. Of note, in each of the 7 target trials, the treatment strategies were the initiation of semaglutide use at baseline or the initiation of comparison antidiabetic medication use at baseline, but not both.

During the 3-year follow-up, results showed that semaglutide-treated patients had a significantly lower risk of first-time AD diagnosis, with a hazard ratio (HR) of 0.33 (0.21-0.51) compared with insulins and an HR of 0.59 (0.37-0.95) compared with other GLP-1RAs. Among older adults aged at least 60 years at the index event (average, 67.9 [±5.79]), the overall 3-year risk of first-time diagnosis of AD was twice as high as in the general population (average, 58.1 [±12.1]): 0.33% vs 0.16%.

"Our findings support further clinical evaluation of semaglutide's role in mitigating AD initiation and development in patients with T2DM," Xu et al wrote.¹ "Future research should explore its effects in mild cognitive impairment, other dementias, and neurodegenerative diseases, as well as investigate other GLP-1RAs like tirzepitide and combination therapies with other antidiabetic medications. Additional preclinical and clinical studies are needed to shed light on the mechanisms of the potential benefits of semaglutide in preventing or delaying the onset of AD and establish causal effects through randomized trials."

After propensity-score matching, there were 8881 women (average age 56.8) and 6895 men (average age 59.5) in both the semaglutide and insulin groups. Semaglutide was linked to a significantly reduced risk of first-time AD diagnosis in women, with a HR of 0.22 compared to insulin and 0.53 compared to other GLP-1 receptor agonists. Similar but weaker trends were seen in men, though with overlapping confidence intervals.

Although semaglutide had a more profound decrease in first-time diagnoses of AD in women, the study authors noted that "the characteristics of these two study populations differed, with women being younger than men (average age 56.8 vs 59.6 years) and having a higher prevalence of obesity and depression and a lower prevalence of cardiovascular diseases. This analysis demonstrates the importance of conducting separate analyses based on gender since the genders’ different characteristics may inform targeted prevention efforts. Larger, longer-term studies are needed to confirm these differences and to understand what drives the potential differential effects."

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Semaglutide was approved in the US for T2DM in 2017 and for weight loss in 2021. Both T2DM and obesity are considered significant modifiable risk factors for AD. In a subgroup of patients who were obese, semaglutide was associated with a decreased risk of first-time diagnosis of AD compared with other antidiabetic medication groups, with an HR of 0.29 compared with insulin and an HR of 0.59 compared with other GLP-1RAs. These findings remained consistent regardless of whether patients received obesity diagnosis within the last 2 years or before.

An additional analysis studied the associations of semaglutide and AD-related medication prescriptions (donepezil, rivastigmine, galantamine, memantine, aducanumab, and lecanemab). Overall, treatment with the GLP-1RA was associated with a decreased risk of AD-related medication prescriptions compared with other antidiabetic medications in patients with T2DM, with and without obesity, consistent with the main finding based on a first-time diagnosis of AD.

In recent years, the amount of research on GLP-1 analogues in the treatment of AD has steadily increased after a number of positive studies. At the recently concluded 2024 Alzheimer’s Association International Conference (AAIC), data from a phase 2b study showed that treatment with liraglutide, Novo’s other approved GLP-1RA, resulted in neuroprotective effects against AD dementia. The study, a multicenter, randomized, double-blind, placebo-controlled trial, featured 204 patients with AD from 7 cohorts in the UK who were treated with either liraglutide or placebo as a daily subcutaneous injection for 12 months. At the conclusion of the treatment period, results on MRI showed a slower decline of temporal lobe volume and total grey matter volume in liraglutide-treated patients relative to those on placebo.²

Although the primary end point of change in the cerebral glucose metabolic rate in the cortical regions of the brain was not met, the study revealed changes on secondary end points of clinical and cognitive measures and statistically significant benefits on brain volume. Overall, those on active treatment had an 18% slower decline in cognitive function at 1 year compared with placebo. Of note, the trial was not powered to assess cognitive changes.

REFERENCES
1. Wang W, Wang Q, Qi X, et al. 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. Alzheimers Dement. Published online October 24, 2024.
2. Atri A, Feldman HH, Honore JB, et al. evoke and evoke+: design of two large-scale, double-blind, placebo-controlled, phase 3 studies evaluating the neuroprotective effects of semaglutide in early Alzheimer’s disease. Presented at: AAIC 2022; ABSTRACT P3-004