Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics.

Among the more promising treatments proposed for Alzheimer's disease (AD) and Parkinson's disease (PD) are those reducing brain insulin resistance. The antidiabetics in the class of incretin receptor agonists (IRAs) reduce symptoms and brain pathology in animal models of AD and PD, as well as glucose utilization in AD cases and clinical symptoms in PD cases after their systemic administration. At least 9 different IRAs are showing promise as AD and PD therapeutics, but we still lack quantitative data on their relative ability to cross the blood-brain barrier (BBB) reaching the brain parenchyma. We consequently compared brain uptake pharmacokinetics of intravenous 125I-labeled IRAs in adult CD-1 mice over the course of 60 min. We tested single IRAs (exendin-4, liraglutide, lixisenatide, and semaglutide), which bind receptors for one incretin (glucagon-like peptide-1 [GLP-1]), and dual IRAs, which bind receptors for two incretins (GLP-1 and glucose-dependent insulinotropic polypeptide [GIP]), including unbranched, acylated, PEGylated, or C-terminally modified forms (Finan/Ma Peptides 17, 18, and 20 and Hölscher peptides DA3-CH and DA-JC4). The non-acylated and non-PEGylated IRAs (exendin-4, lixisenatide, Peptide 17, DA3-CH and DA-JC4) had significant rates of blood-to-brain influx (Ki), but the acylated IRAs (liraglutide, semaglutide, and Peptide 18) did not measurably cross the BBB. The brain influx of the non-acylated, non-PEGylated IRAs were not saturable up to 1 µg of these drugs and was most likely mediated by adsorptive transcytosis across brain endothelial cells, as observed for exendin-4. Of the non-acylated, non-PEGylated IRAs tested, exendin-4 and DA-JC4 were best able to cross the BBB based on their rate of brain influx, percentage reaching the brain that accumulated in brain parenchyma, and percentage of the systemic dose taken up per gram of brain tissue. Exendin-4 and DA-JC4 thus merit special attention as IRAs well-suited to enter the central nervous system (CNS), thus reaching areas pathologic in AD and PD.

Mi experiencia con liraglutida en pacientes con diabetes mellitus de tipo 2 frente a otros agonistas del receptor del GLP-1 / My experience with liraglutide vs. other GLP-1 receptor agonists in patients with DM2

Liraglutida es un agonista del receptor del péptido similar al glucagón de tipo 1 (ARGLP-1) aprobado para el tratamiento de la diabetes mellitus de tipo 2 (DM2), que mejora el control glucémico con bajo riesgo de hipoglucemias, reducción del peso corporal, un efecto favorable sobre otros factores de riesgo cardiovascular y un potencial efecto protector sobre la función de la célula b. En este artículo se revisan los ensayos clínicos comparativos directos con otros ARGLP-1, en los cuales liraglutida ha mostrado superioridad o no inferioridad en el descenso de HbA1c y un efecto similar o superior en términos de reducción del peso, con un buen perfil de seguridad. Además, se presentan varios estudios del autor con liraglutida en la vida real que corroboran los resultados de los ensayos clínicos y amplían el espectro de posibilidades de indicación, como la nefroprotección o el tratamiento de la DM2 tras cirugía bariátrica

Liraglutide is a GLP-1 receptor agonist (GLP-1-RA) approved for the treatment of type 2 diabetes mellitus (T2DM), which improves glycemic control with a low risk of hypoglycaemia, aids weight reduction, and has a favourable effect on other cardiovascular risk factors and a potential protective effect on beta cell function. This article reviews head-to-head comparisons with other GLP-1-RAs. In those trials, liraglutide has been shown to be superior or non-inferior in reducing HbA1c and to have a similar or greater effect in terms of weight reduction, with a good safety profile. In addition, several real-life studies with liraglutide undertaken by the author of this article are presented which corroborate the results of clinical trials and broaden the spectrum of possibilities of indication, such as renal protection or management of type 2 diabetes after bariatric surgery