12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study

Obesity and type 2 diabetes (T2D) are metabolic diseases with shared pathophysiology. Traditional polygenic risk scores (PRS) have focused on these conditions individually, yet the single disease approach falls short in capturing the full dimension of metabolic dysfunction. We derived biologically enriched metabolic PRS (MetPRS), a composite score that uses multi-ancestry genome-wide association studies of 22 metabolic traits from over 10 million people. MetPRS, optimized to predict obesity (O-MetPRS) and T2D (D-MetPRS), was validated in the UK Biobank (UKB, n=15,000), and tested in UKB hold-out set (n=49,377), then externally tested in 3 cohorts: All of Us (n=245,394), Mass General Brigham (MGB) Biobank (n=53,306), and a King Faisal Specialist Hospital and Research Center cohort (n=6,416). O-MetPRS and D-MetPRS outperformed existing PRSs in predicting obesity and T2D across 6 ancestries (European, African, East Asian, South Asian, Latino/admixed American, and Middle Eastern). O-MetPRS and D-MetPRS also predicted morbidities and downstream complications of obesity and T2D, as well as the use of GLP-1 receptor agonists in contemporary practice. Among 37,329 MGB participants free of T2D and obesity at baseline, those in the top decile of O-MetPRS had a 103% relatively higher chance, and those in the top decile of D-MetPRS had an 80% relatively higher chance of receiving a GLP-1 receptor agonist prescription compared to individuals at the population median of MetPRS. The biologically enriched MetPRS is poised to have an impact across all layers of clinical utility, from predicting morbidities to informing management decisions.

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Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer’s disease

Abdulhameed,

Babin,

Hansen

et al. 2024

Alz Res Therapy

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Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer’s disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.

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12-month neurological and psychiatric outcomes of semaglutide use for type 2 diabetes: a propensity-score matched cohort study

Cited by 5 publications

References 26 publications

The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice

The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice

Metabolic Polygenic Risk Scores for Prediction of Obesity, Type 2 Diabetes, and Related Morbidities

Comparing regional brain uptake of incretin receptor agonists after intranasal delivery in CD-1 mice and the APP/PS1 mouse model of Alzheimer’s disease

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