Antidiabetic Effect of Abextide, a Long‐Acting Exendin‐4 Analogue in Cynomolgus Monkeys

Abstract

Abextide, synthesized by conjugating an albumin‐binding moiety—truncated Evans blue—to glucagon‐like peptide 1 receptor (GLP‐1R) agonist exendin‐4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. The aim of this study is to evaluate the pharmacodynamics of Abextide in nonhuman primates. Two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. During the whole experiment period, no abnormalities such as swelling at the injection site, lethargy, or hypoglycemia are observed in all animals. The monkeys in the Abextide group lose appetite after drug administration and then recover over time. In the single dose treatment, at day 1 and day 3 after treatment, decreased plasma glucose level is observed in the Abextide‐treated group but not in placebo or Albiglutide‐treated group. For monkeys that receive two doses of drug, the blood glucose level in all subjects in Abextide group decreases rapidly upon drug administration and return to a plateau by day 3. A similar pattern of response is seen after the second dose administration. The delayed drug release and hypoglycemic effect of Abextide make it potentially useful as an antidiabetic drug for weekly subcutaneous administration.

Predicting Hypoglycemia in Elderly Inpatients with Type 2 Diabetes: The ADOCHBIU Model

“…In the study, all of the elderly inpatients used hypoglycemic agents: 58.06% insulin, 35.16% used oral hypoglycemic agents, and 6.78% used both. Our study found that the use of oral hypoglycemic agents or insulin is a predictor of hypoglycemia, which is consistent with previous studies in which it was reported that hypoglycemia is commonly caused by insulin, sulfonylurea, and non-sulfonylurea insulin secretagogues [39][40] .…”

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

“…Due to the high expression profile of GLP-1R in pancreatic β-cells, GLP-1 analogs (such as exendin-4) have been modified by different methods (to prolong half-life, maintain receptor binding affinity and reduce renal drug accumulation) for theranostic purposes and serve as excellent templates for future cardiovascular drug development [178][179][180][181][182][183][184]. More importantly, these modified GLP-1 analogues have shown hypoglycemic [185,186] and cardiovascular protective effects [180,183] in different animal models. Further exploration of these modified agents in animal models of cardiometabolic diseases will deepen our understanding of the potential cardioprotective mechanisms of GLP-1 and GLP-1RAs and potentially provide future directions for precise therapeutic intervention [180].…”

Drug Delivery Strategies for Enhancing the Therapeutic Efficacy of Toxin-Derived Anti-Diabetic Peptides

“…The Abextide showed equivalent GLP1R binding ability to exendin-4, but an extended biological half-life (35 h; 7-fold) in Balb/c mice, and prolonged hypoglycemic effects (36 h; 3.6-fold) in db/db diabetic mice. Furthering the study of Abextide, Niu et al carried out a pharmacodynamics study in diabetic Cynomolgus monkeys [100]. The results showed that the Abextide could elicit similar levels of hypoglycemic activity with albiglutide, a clinically approved long-lasting GLP-1 agonist, and exerted hypolipidemic and anorexic activities.…”