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18 days ago
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Overview of Triple Agonists
In recent years, with the deepening of research into the pathogenesis of metabolic diseases, the development of multi-target agonist drugs targeting multiple hormone receptors has become a hot topic. Retatrutid is a novel triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (GC) receptors.
(1) Physiological Basis of Hormone Receptor Functions
GIP Receptor: GIP is an intestinal insulin-secreting hormone secreted by K cells in the small intestine, released rapidly after meals. Upon binding to the GIP receptor, GIP stimulates insulin secretion, and this stimulatory effect is glucose-dependent, meaning that as blood glucose levels rise, GIP enhances its insulin-secreting effect, helping to maintain stable blood glucose levels. Additionally, GIP participates in the regulation of lipid metabolism, influencing adipocyte differentiation and lipid accumulation.
Fig. 1. RETA or SEMA treatment reduces body weight and improves fasting blood glucose.a Percent changes in body weight from baseline are reported. b, Epididymal white adipose tissue weight was quantified at the endpoint. c Fasting blood glucose was quantified at baseline and throughout the study at indicated time points until the endpoint. d Tumor engraftment or “tumor take” is reported.
GLP-1 receptor: GLP-1 is secreted by intestinal L cells and also has a glucose-dependent insulinotropic effect, enhancing insulin synthesis and release, inhibiting glucagon secretion, and reducing hepatic glucose output. GLP-1 also delays gastric emptying, increases satiety, and thereby reduces food intake. It has protective and proliferative effects on pancreatic beta cells, helping to maintain pancreatic function.
3. GC Receptor:
After binding to the GC receptor, glucagon primarily acts on the liver by promoting glycogenolysis and gluconeogenesis, thereby elevating blood glucose levels. In lipid metabolism, it promotes lipolysis, increasing the release and oxidation of fatty acids for energy. Under normal physiological conditions, glucagon secretion is inhibited when blood glucose levels rise to maintain glucose balance.
(2) Advantages of Triple Agonist Action
As a triple agonist, Retatrutid can simultaneously activate these three receptors, exerting synergistic effects. By activating GIP and GLP-1 receptors, it enhances glucose-dependent insulin secretion, more effectively lowering blood glucose levels. The increased satiety and delayed gastric emptying induced by GLP-1 receptor activation, along with the lipolysis promoted by GC receptor activation, collectively contribute to weight management. This multi-targeted mechanism of action provides a more comprehensive regulation of various pathophysiological processes associated with metabolic diseases.
Mechanism of Action of Retatrutid in Metabolic Diseases
Metabolic diseases are a class of conditions caused by disruptions in metabolic processes within the body, including common conditions such as diabetes, obesity, and non-alcoholic fatty liver disease. Retatrutid exerts its effects on these metabolic diseases through its unique triple agonist properties.
(1) Mechanism of Action in Diabetes
Glucose Regulation: Retatrutid activates GIP and GLP-1 receptors, enhancing glucose-dependent insulin secretion. When blood glucose levels rise, it more effectively stimulates pancreatic beta cells to secrete insulin, promoting glucose uptake and utilization, thereby lowering blood glucose levels. By inhibiting glucagon secretion and reducing hepatic glucose output, it further stabilizes blood glucose levels. In clinical trials involving patients with type 2 diabetes, Retatrutid treatment resulted in significant reductions in both fasting and postprandial blood glucose levels.
Protection of pancreatic beta cells: Activation of the GLP-1 receptor not only promotes insulin secretion but also has a protective and proliferative effect on pancreatic beta cells. Retatrutid may achieve this by continuously activating the GLP-1 receptor, slowing down beta cell apoptosis, increasing their number and function, thereby improving insulin secretion capacity and maintaining stable blood glucose levels over the long term.
(2) Mechanism of action in obesity
Regulation of energy intake: Retatrutid activates GLP-1 receptors, delaying gastric emptying, prolonging the retention time of food in the stomach, increasing satiety, and reducing food intake. It can act on the central nervous system to regulate appetite-related neurotransmitters, such as inhibiting the release of orexin, further reducing appetite, and thereby controlling energy intake.
Increased Energy Expenditure: Activation of the GC receptor promotes lipolysis, increasing the release and oxidation of fatty acids for energy production. The oxidation of fatty acids provides energy to the body, reduces fat storage, and aids in weight loss. Activation of the GIP receptor also participates in energy metabolism regulation, increasing energy expenditure.
Figure 2 RETA treatment reduces body weight and adiposity, improves fasting blood glucose. a Percent changes in body weight from baseline are reported. b Epididymal white adipose tissue was weighed at the endpoint and normalized to total body weight. c Fasting blood glucose was quantified at baseline and throughout the study at indicated time points until the endpoint.
(3) Mechanism of action in non-alcoholic fatty liver disease
Improved hepatic lipid metabolism: Retatrutid activates the GC receptor, promoting the breakdown and β-oxidation of fat in the liver, thereby reducing fat accumulation in the liver. Activation of the GIP and GLP-1 receptors may regulate the expression of genes related to lipid metabolism in the liver, upregulating the expression of fatty acid transporters and fatty acid oxidases, thereby promoting fatty acid uptake and oxidation, and further improving hepatic lipid metabolism.
Enhanced insulin sensitivity: While improving glucose regulation and increasing insulin secretion, Retatrutid can enhance hepatic insulin sensitivity by activating GLP-1 receptors. Enhanced insulin sensitivity enhances the liver's response to insulin, better inhibiting hepatic glucose output, reducing de novo fatty acid synthesis, and thereby alleviating hepatic steatosis.
Applications and Effects of Retatrutid in Metabolic Diseases
(1) Applications in Diabetes
lycemic Control Effects: Retatrutid demonstrates significant glycemic control effects in patients with type 2 diabetes. According to data, patients treated with Retatrutid exhibited a significant reduction in hemoglobin A1c (HbA1c) levels. In a randomized controlled trial involving 353 patients with type 2 diabetes, the HbA1c levels in the Retatrutid treatment group decreased by 1.64% from baseline, while there was no significant change in the placebo group.
Comparison with Other Drugs: Compared with traditional antidiabetic drugs such as metformin or GLP-1 receptor agonists, Retatrutid demonstrates superior blood glucose control effects.
(2) Application in obesity
Weight loss effects: Retatrutid demonstrates significant efficacy in the treatment of obesity. In clinical trials targeting adult obese patients, significant weight loss was observed after 48 weeks of treatment with different doses of Retatrutid. In one trial, patients treated with a 12mg dose of Retatrutid experienced an average weight loss of 24.2% after 48 weeks, compared to only 2.1% in the placebo group. Additionally, 83% of participants in the high-dose group achieved weight loss of 15% or more, far exceeding the 2% rate in the placebo group.
Long-Term Effects: Retatrutid maintains weight loss effects well throughout the treatment period. This suggests that long-term use may help maintain stable weight and prevent weight regain, which is beneficial for the long-term management of obesity.
(3) Application in non-alcoholic fatty liver disease
Liver fat reduction: In patients with metabolic dysfunction-associated fatty liver disease and liver fat content ≥10%, Retatrutid treatment resulted in a significant reduction in liver fat content. In a randomized, double-blind, placebo-controlled trial, at 24 weeks, liver fat content decreased by 81.4% and 82.4% from baseline in the 8 mg and 12 mg dose groups, respectively, while the placebo group increased by only 0.3%.
Advantages and Potential of the Triple Agonist
Retatrutid comprehensively regulates multiple pathophysiological pathways of metabolic diseases by simultaneously activating GIP, GLP-1, and GC receptors. From blood glucose control, weight management, to improved hepatic lipid metabolism, this multi-targeted mechanism of action theoretically offers a more comprehensive correction of metabolic disorders compared to single-target drugs, demonstrating potential to address the complex etiology of metabolic diseases. Existing clinical trial data show that Retatrutid has achieved significant effects in the treatment of metabolic diseases such as diabetes, obesity, and non-alcoholic fatty liver disease.
Conclusion
As a novel triple agonist, Retatrutid holds promise for the treatment of metabolic diseases.
Sources
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[5] Doggrell S A. Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity?[J]. Expert Opinion On Investigational Drugs, 2023,32(5):355-359.DOI:10.1080/13543784.2023.2206560.
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