There is an emerging consensus that situations of acute or chronic imbalance between the antioxidative capacity of cells and tissues, and the production of pro oxidative species, is associated with the development of a number of human diseases
Current dual agonists under investigation also include efinopegdutide and cotadutide.144,145,146,147 Triple agonist Triple agonists go even further.148 These drugs act by simultaneously targeting three different agonists GLP-1R, the GIPR, and the GCGR.149,150,151 These receptors each have independent yet complementary roles in the treatment of diabetes and obesity.150,152,153 Activation of the GLP-1R can enhance insulin secretion, reduce glucagon secretion, delay gastric emptying,154 and suppress appetite.155,156 GIPR activation also promotes insulin release, especially after meals, helping to improve glucose utilization.157,158 Activation of the insulin or Insulin-like Growth Factor 1 (IGF-1) receptor can enhance insulin sensitivity, improve glucose absorption and utilization by cells, and potentially have positive effects on cardiovascular health and long-term energy balance.159 As of now, GLP-1-related triple agonists are primarily still in the development stage and have not been widely approved for use.159 These drugs are not yet widely available on the market but have shown some potential in clinical trials.160,161 For example, HM15211, a triple agonist developed by Hanmi Pharmaceutical in South Korea that activates GLP-1R, GIPR and GCGR has entered early clinical trials for the treatment of obesity and non-alcoholic steatohepatitis (NASH).162,163 Retatrutide (LY-3437943), a novel triple agonist developed by Eli Lilly that targets GLP-1R, GIPR and GCGR, has shown potential in preliminary clinical data for providing excellent blood sugar control and significant weight reduction.158,161,164,165 However, activating multiple receptors may lead to more complex side effects, and in some experiments, dual and triple agonists have indeed shown more severe side effects.165,166 Retatrutide has now entered Phase III clinical trials.161 The results of the Phase II clinical trials of retatrutide were published in The Lancet in 2023.161 The trials involved adult participants with T2DM aged 18 to 75, conducted across 42 research and medical centers in the United States.161 Over a period of 24 weeks, all dosage groups of retatrutide showed significant improvements in reducing glycated hemoglobin (HbA1c) and body weight compared to the placebo group, especially in the higher dosage groups
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The idea is not that DSIP replaces opioids, but that it might support the body during the withdrawal phase
