Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes because of pleiotropic effects, including the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-live owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics leads to 10 days of glycemic control in three different mouse models of diabetes, as well as to the reduction of glycosylated hemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.
Ticagrelor is a reversible oral P2Y12 platelet inhibitor used in patients with many forms of heart and vascular disease. Because patients receiving ticagrelor may bleed or need emergent surgery, bentracimab was studied as a ticagrelor reversal agent. In this study in 150 patients, treatment had a significant salutary impact on laboratory measured platelet function. Adjudicated hemostasis was achieved in over 90% of patients, most of whom had cardiac surgery; thrombotic events occurred in just over 5% of treated patients.
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