Retatrutide is a new entrant into the rapidly-expanding space of anti-obesity peptides. It is known as a GGG tri-agonist. This means that retatrutide works at all of the incretin receptors including GLP-1 and GIP as well as the glucagon receptor itself. Research indicates that retatrutide may be the most effective weight loss peptide yet developed, with some studies showing a rapid and sustained weight loss response as high as 24% of total body weight[1]. Retatrutide is thought to promote weight loss by increasing energy expenditure as well as decreasing energy consumption. It does the former via action at the glucagon receptor and the latter through both central and peripheral appetite control.

Secuencia: YA1QGTFTSDYSIL2LDKK4AQA1AFIEYLLEGGPSSGAPPPS3Fórmula molecular:C₂₂₃h₃₄₃F₃norte₄₆oh₇₀ Peso molecular: 4845,44 g/molPubChem SID: 474492335Número CAS: 2381089-83-2Sinónimos: LY-3437943, NOP2Y096GV

¿Qué es la retatrutida?

Retatrutida, como se mencionó, es un triagonista de GGG. La retatrutida es un péptido único acilado de ácido graso que combina las actividades GCGR, GIPR y GLP-1R. Se basa en la columna vertebral del péptido GIP que está muy modificada. La modificación de esta columna vertebral ha permitido que la retatrutida se una a la albúmina en el torrente sanguíneo. Esto, a su vez, significa que el fármaco permanece en la sangre durante un período de tiempo prolongado. Esta vida media prolongada significa que retatrutida solo debe tomarse una vez por semana[2]. Su amplio espectro de actividad permite que retatrutida se una a varios receptores de incretina diferentes y produzca efectos específicos de la siguiente manera.

• Receptor de péptido inhibidor gástrico (GIPR): también llamado receptor de polipéptido insulinotrópico dependiente de glucosa, este receptor se encuentra en el sistema nervioso central, así como en todo el tracto gastrointestinal y el cuerpo. Parece desempeñar un papel importante en los mecanismos centrales que afectan el hambre y se cree que desempeña un papel en el envío de señales de “saciedad” desde el tracto gastrointestinal al cerebro.

• Receptor 1 del péptido similar al glucagón (GLP-1R): la activación de este receptor conduce a una desaceleración del vaciado gástrico. El vaciamiento gástrico lento envía señales al cerebro para disminuir la ingesta de alimentos y, por lo tanto, puede ayudar a controlar el consumo de energía. Los péptidos dirigidos a este receptor se desarrollaron originalmente para tratar la diabetes tipo 2, pero desde entonces se ha descubierto que mejoran la pérdida de peso y disminuyen el riesgo de ciertas formas de enfermedades cardíacas. Están bajo investigación para el tratamiento de la depresión, los trastornos del sistema de recompensa (p. ej., alcoholismo, adicción), el síndrome de ovario poliquístico y la enfermedad del hígado graso no alcohólico.

• Receptor de glucagón (GCGR): El receptor de glucagón se encuentra principalmente en el hígado y el riñón. Las mutaciones en este receptor están asociadas con ciertas formas de diabetes tipo 2. Al unirse a este receptor, la retatrutida aumenta la producción de glucagón, lo que estimula la descomposición de formas almacenadas de energía como la grasa y el glucógeno. Esto conduce a un aumento del metabolismo basal (incluso durante el sueño) que aumenta la pérdida de peso en general y de grasa en particular.

¿Cómo actúa la retatrutida?

In vivo research, in humans, indicates that retatrutide activates and is a full agonist of all of the incretin receptors including GIPR, GLP-1R, and GCGR. Retatrutide was specifically designed to be highly potent at the GIPR and GLP-1R locations. As a result, retatrutide is one of the most potent incretins available and thus has strong effects on both gastric emptying and the central control of hunger/satiety. Research shows that the bulk of retatrutide’s effects are driven by loss of fat mass that is probably the result of a larger and more prolonged reduction in food intake compared to similar peptides. Decreased food intake, especially as occurs early in the use of the peptide, jump starts fat oxidation. This sets the stage for prolonged weight loss by altering basal metabolism and overcoming the hormonal forces that perpetuate obesity[2]. The bulk of retatrutide’s benefit is a result of its ability to decrease energy intake via delayed gastric emptying and increased control of hunger signals in the central nervous system. That said, the ability of the peptide to increase energy expenditure is also statistically significant and should not be discounted.Efecto GIPR:(glucose-dependent insulinotropic polypeptide receptor) Agonism of the GIPR leads to decreased gastric acid secretion and gastrin release. Gastrin is a peptide hormone that stimulates the release hydrochloric acid and histamine in the stomach. These effects help to slow digestion and reduce transit through the GI tract. As a result, action on the GIPR can lead to increased feelings of fullness.Efectos del GLP-1R:(glucagon-like peptide-1 receptor) Agonism of the GLP-1R is well known to delay gastric emptying. Research in both rodents and humans supports this. Gastric emptying (GE) is an important determinant of the glycemic response following food intake. Research indicates that slowing GE can reduce food intake and thus impact weight loss. Research in mice reveals that GLP-1R is the only receptor of the three to affect GE, and thus the delay of GE caused by retatrutide is no greater than the delay caused by semaglutide, tirzepatide, liraglutide, or any of the other GLP-1R agonists. Interestingly, however, is the difference in dose to achieve full effect on GE. Research shows that retatrutide has the same efficacy as semaglutide at a dose that is more than 30 times smaller[3]. As with semaglutide, however, the effects of retatrutide on GE wane over time. This decrease in effect of a therapeutic over time is referred to as tachyphylaxis and may, in some cases, necessitate a drug holiday to help restore effects.Efectos del GCGR:(G-protein-coupled receptor) It wasn’t fully understood until relatively recently that glucagon plays an important role in regulating hunger and energy expenditure. Research now reveals that glucagon signals the brain from the gut via the vagal nerve. This signaling promotes feelings of fullness and is regulated by glucagon concentrations in the portal circulation of the liver. In mouse models, the administration of glucagon has resulted in a 20% weight loss[4]. Additional research has shown that glucagon can increase energy expenditure. This effect has been observed in both animal and human trials. This particular effect is not mediated through the GCGR, but rather through via FGF21. FGF21 is a protein secrete by the liver that regulated sugar intake and preferences for sweet foods, among a host of other functions. Mutations in this protein have been identified in those with a “sweet tooth” [5]. FGF21 regulates the uptake of glucose by adipocytes (fat cells). Treatment of animals with FGF21 results in increased energy expenditure, fat utilization and lipid excretion. Studies in mice show that activation of FGF21 can lead to a 20% weight reduction primarily via increased fat loss[6]. This occurs without a change in total calorie intake, indicating a change in metabolic rate. Mice given an FGF21 infusion have demonstrated higher energy expenditure both during wakefulness and during sleep. This is likely mediated through effects on mitochondrial activity.

¿Qué tan efectiva es la retatrutida para bajar de peso?

Research indicates that retatrutide is likely the most effect incretin-based peptide for weight loss yet developed. In a study in rodents, for instance, just 10 days of retatrutide treatment leads to decreases in total body weight greater than those seen with semaglutide. This occurs when the peptides are administered at the same doses. If retatrutide is given at a lower dose that semaglutide, then it produces similar weight loss effects but with decreased risk of side effects[3]. Thus, retatrutide may offer an alternative treatment option for those who are somewhat intolerant of the side effects of semaglutide. A phase 2 study in humans has showed that retatrutide can produced significant reductions in body weight. In fact, trial participants given the highest dose of the peptide lose approximately 20 pounds in just 12 weeks[1]. In another trial, individuals treated for 26 weeks showed changes in waist circumference ranging from -2.1 cm to -10.2 cm[7]. In other words, people taking retatrutide in this trial lost anywhere from 1 inch to ~5 inches off of their waist in just 6 months. Finally, in a trial published in the New England Journal of Medicine, weight loss from retatrutide varied in a dose-dependent manner over the 48 weeks of the trial. Individuals given the lowest dose of the peptide lost 8.7% of their total body weight while those given the highest dose lost more than 24% of their total body weight[8]. Similar results were published in a JAMA article as well[9].

Retatrutida y diabetes

En los ensayos de fase 2, retatrutida ha producido reducciones significativas en los niveles de hemoglobina glucosilada (hemoglobina A1c)[10]. La hemoglobina es el compuesto de la sangre que transporta oxígeno. La hemoglobina glucosilada es hemoglobina que se ha unido químicamente a un azúcar. Los niveles altos de hemoglobina glucosilada son causados ​​por niveles crónicamente altos de azúcar en sangre y están asociados con la diabetes. De hecho, los niveles de HBA1c se pueden utilizar para controlar el control del azúcar en sangre a largo plazo en personas que padecen diabetes. Mantener estos niveles bajos es fundamental no sólo para un buen control del azúcar en sangre, sino también para prevenir los efectos a largo plazo de la diabetes, incluidas enfermedades cardiovasculares, daño a los nervios, lesiones renales y problemas oculares.

Retatrutida y salud del corazón

It has long been known that infusing elevated doses of glucagon into those with heart failure can augment heart rate and cardiac contractility. Pharmacological administration of glucagon, typically in milligram quantities, is commonly employed in addressing acute cardiac depression resulting from overdoses of calcium channel antagonists or beta-blockers, despite limited research in this area. Interestingly, glucagon concentrations within the normal physiological range seem to have no discernible impact on heart rate or contractility[11]. The impact of retatrutide on heart health has not been directly assessed in humans, but it has been assessed in cynomolgus monkeys. In the past, it was thought that elevated actions of glucagon were associated with diabetes. That is to say, scientists thought that lower glucagon would lead to improved outcomes in diabetes. Thus, monoclonal glucagon antibodies, glucagon receptor antagonists (peptide and non-peptide) and molecules targeting the expression of GCGR have all been tested as potential treatments. Research on these agents, however, revealed a number of major obstacles including limited efficacy, the risk of iatrogenic hypoglycemia, and other safety issues related to lack of specificity of glucagon blockade, immunogenicity and toxicity. This really should not have come as any surprise as the rise in glucagon levels in diabetes is likely a consequence of the disease and not a cause of it. Research also indicates that incretins have beneficial effects on the cardiovascular system by decreasing blood pressure, improving left ventricular function, endothelium-dependent vasodilation, and by increasing endothelial progenitor cells. In other words, glucagon and related molecules appear to improve heart health[12]. Supporting this notion is the fact that a number of incretin agonists (e.g. semaglutide, liraglutide) have been associated with improvements in cardiovascular outcomes in diabetes. As a result, these peptides are now under investigation for direct use in heart disease. Retatrutide is likely to show improved results given its more extensive effects on glucagon levels, but the exact effects will have to await more detailed clinical and benchtop trials. These findings indicate that retatrutide and similar molecules may be beneficial to regeneration in the cardiovascular as well as helping to prevent cardiovascular disease in the first place. As mentioned, a limited, non-clinical cardiovascular study of retatrutide in monkeys has been undertaken. This study revealed higher heart rates at all dose levels with a dose dependent effect overall. At the same time retatrutide was increasing heart rate, it was decreasing blood pressure in the monkeys. Unfortunately, this study was limited in both duration and number of individuals under investigation. Thus, while it can offer some foundation on which to ground speculation, it cannot provide any definitive information about retatrutide and its long-term effects on cardiovascular health.

Resumen de retatrutida

Retatrutide is an incretin mimetic and GGG agonist. It binds to glucagon receptors, gastric inhibitory peptide receptors, and glucagon-like peptide-1 receptors. This triple activity has been associated with significant weight loss (24% of body weight at 6 months) in clinical trials. This outcome makes retatrutide the most effective of incretin peptides to date and thus it is under intense investigation as a weight loss agent. There is some hope that retatrutide may also have beneficial cardiovascular effects and might therefore be useful in the treatment of heart disease complicated by diabetes as well as heart disease in general.

William C. Roell, PhD. Recibió su licenciatura en microbiología y bioquímica de la Universidad de Miami. Obtuvo su doctorado en Fisiología Celular e Integrativa de la Facultad de Medicina de la Universidad de Indiana trabajando en terapia celular y estudiando los cambios metabólicos asociados con la maduración de los adipocitos. Uniéndose a Lilly en 2000,Guillermoworked with multiple drug discovery groups providing innovative approaches to translate therapeutic concepts from bench to bedside. More recently, he has supported efforts in diabetes biomarker discovery and target identification/advancement, impacting discovery and development efforts across Lilly’s Diabetes and Complications portfolio. William and his lab currently are active in drug discovery with a focus on diabetes and obesity. He has a particular interest in mechanisms by which incretin receptor modulation contributes to the profound benefits observed clinically with existing and emerging therapeutics. Dr. William C. Roell is being referenced as one of the leading scientists involved in the research and development of Retatrutide. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between

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