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A physiologically-based quantitative systems pharmacology model for mechanistic understanding of the response to alogliptin and its application in patients with renal impairment.
J Pharmacokinet Pharmacodyn
January 2025
Department of Clinical Pharmacy and Pharmacy Administration, West China school of Pharmacy, Sichuan University, Chengdu, 610064, China.
Alogliptin is a highly selective inhibitor of dipeptidyl peptidase-4 and primarily excreted as unchanged drug in the urine, and differences in clinical outcomes in renal impairment patients increase the risk of serious adverse reactions. In this study, we developed a comprehensive physiologically-based quantitative systematic pharmacology model of the alogliptin-glucose control system to predict plasma exposure and use glucose as a clinical endpoint to prospectively understand its therapeutic outcomes with varying renal function. Our model incorporates a PBPK model for alogliptin, DPP-4 activity described by receptor occupancy theory, and the crosstalk and feedback loops for GLP-1-GIP-glucagon, insulin, and glucose.
View Article and Find Full Text PDFOnce-weekly IcoSema versus once-weekly semaglutide in adults with type 2 diabetes: the COMBINE 2 randomised clinical trial.
Diabetologia
January 2025
Internal Medicine Department, Endocrine Division (SEMPR), Universidade Federal do Paraná, Curitiba, Brazil.
Aims/hypothesis: COMBINE 2 assessed the efficacy and safety of once-weekly IcoSema (a combination therapy of basal insulin icodec and semaglutide) vs once-weekly semaglutide (a glucagon-like peptide-1 analogue) 1.0 mg in individuals with type 2 diabetes inadequately managed with GLP-1 receptor agonist (GLP-1 RA) therapy, with or without additional oral glucose-lowering medications.
Methods: This 52 week, randomised, multicentre, open-label, parallel group, Phase IIIa trial was conducted across 121 sites in 13 countries/regions.
Effects of tryptophan-selective lipidated GLP-1 peptides on the GLP-1 receptor.
J Endocrinol
January 2025
N Inagaki, Department of Diabetes, Endocrinology and Nutrition, Kyoto University, Kyoto, Japan.
Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) are widely used as antidiabetic and anti-obesity agents. Although conventional GLP-1 RAs such as liraglutide and semaglutide are acylated with fatty acids to delay their degradation by dipeptidylpeptidase-4 (DPP-4), the manufacturing process is challenging. We previously developed selectively lipidated GLP-1 peptides at their only tryptophan residue (peptide A having one 8-amino-3,6-dioxaoctanoic acid (miniPEG) linker and peptide B having three miniPEG linkers).
View Article and Find Full Text PDFExploring associations between the FTO rs9939609 genotype and plasma concentrations of appetite-related hormones in adults with obesity.
PLoS One
January 2025
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
Associations between variants in the FTO locus and plasma concentrations of appetite related hormones are inconsistent, and might not work in a dose dependent fashion in people with obesity. Moreover, it is relevant to report meal related plasma concentrations of these hormones in persons with obesity given the growing interest in their pharmacological potential in obesity therapy. We find it clinically relevant to examine associations between the SNP rs9939609 genotypes and homeostatic appetite regulation in individuals with BMI ≥35 kg/m2.
View Article and Find Full Text PDFDose-related effects of calcium to enhance the effects of L-tryptophan on gut hormones and energy intake in obesity.
J Clin Endocrinol Metab
January 2025
Adelaide Medical School, University of Adelaide, Adelaide, Australia.
Context: In males of normal weight, intraduodenal administration of calcium enhances the effects of the amino acid, L-tryptophan (Trp), to suppress energy intake, associated with greater stimulation of cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1) and peptide tyrosine-tyrosine (PYY) secretion (key mechanisms underlying the regulation of pyloric motility and gastric emptying), but not gastrin or glucose-dependent insulinotropic polypeptide (GIP).
Objective: Given the implications for the management of obesity, the current study evaluated the effects of calcium, when administered alone and in combination with Trp, on gut hormone secretion, antropyloroduodenal motility and energy intake in males with obesity.
Methods: Fifteen males with obesity and without type 2 diabetes (mean±SD; age: 27±8 years; body mass index: 30±2 kg/m2; HbA1c: 5.
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