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Globally, obesity has become an increasingly serious public health issue, closely linked to various chronic diseases such as cardiovascular disease and type 2 diabetes, making the search for effective weight loss methods a key focus of medical research. Survodutide, as a novel drug, has demonstrated potential efficacy in weight loss.
Overview of Survodutide
Survodutide is an investigational long-acting dual agonist that simultaneously targets the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR). It requires only once-weekly administration, offering patients greater convenience and improving adherence to long-term treatment.
Mechanism of Survodutide in Weight Loss
Regulating Energy Intake
Appetite Suppression: After activating GLP-1R and GIPR, Survodutide interacts with the central nervous system to regulate the hypothalamic appetite control center. Activation of GLP-1R acts on vagal afferent fibers to transmit signals to the arcuate nucleus of the hypothalamus, inhibiting the activity of agrep protein (AgRP) neurons, It can also activate proopiomelanocortin (POMC) neurons, thereby inducing a sense of satiety and reducing food intake. Activation of GIPR may also enhance this appetite-suppressing effect through similar or synergistic neural pathways, thereby reducing the body's desire for food and consequently decreasing energy intake.
Altering food preferences: In a hamster model of obesity and dyslipidemia induced by free-choice diet, Survodutide exerted a unique effect on food preferences. Compared with the control group, Survodutide significantly reduced the intake of high-fat diet and fructose-rich water during the 5-week treatment period, while having no obvious effect on the intake of regular feed and normal water. This regulatory effect on food selection helps reduce the intake of high-calorie foods, controlling excessive energy accumulation at its source and laying the foundation for weight loss.
Regulating energy expenditure
Promoting fat oxidation: Survodutide exhibits significant regulatory effects on fat metabolism. By activating GLP-1R and GIPR, it influences fat cell metabolism through multiple signaling pathways. It promotes lipolysis within adipocytes, increasing the release of fatty acids; these released fatty acids are transported to mitochondria for oxidation, thereby increasing energy expenditure. Studies have shown that in an in vitro adipocyte model, following Survodutide treatment, key enzymes involved in lipolysis and fatty acid oxidation, such as hormone-sensitive lipase (HSL), carnitine palmitoyltransferase-1 (CPT-1), indicating that its mechanism of action in promoting fat oxidation involves regulating key enzymes in fat metabolism.
Increasing energy expenditure: In addition to directly acting on fat cells to promote fat oxidation, Survodutide may also increase energy expenditure by influencing systemic energy metabolism. In animal experiments, it was observed that while the activity levels of animals did not change significantly after Survodutide administration, their basal metabolic rate increased. This is due to the drug's comprehensive effects on multiple tissues and organs, enhancing metabolic activity in the liver and skeletal muscle, thereby increasing energy consumption in a resting state and achieving an energy deficit, which promotes weight loss.
Regulation of glucose metabolism and insulin sensitivity
Improving insulin resistance: Obese patients often have insulin resistance, which affects normal energy metabolism and utilization. Survodutide activates GLP-1R to stimulate insulin secretion while enhancing insulin sensitivity, thereby increasing the body's responsiveness to insulin. In studies of patients with type 2 diabetes, after 16 weeks of Survodutide treatment, plasma insulin levels and the insulin resistance index (HOMA-IR) were significantly reduced, indicating that the drug can improve insulin resistance, enabling better cellular uptake and utilization of glucose, reducing its conversion to fat, and aiding in weight control.
Regulating blood glucose levels: Survodutide's dual receptor agonist action gives it a unique advantage in regulating blood glucose levels. GLP-1R agonism promotes insulin secretion while inhibiting glucagon release, thereby lowering blood glucose levels. GIPR agonism also promotes insulin secretion under physiological conditions. Through synergistic effects, it can better maintain stable blood glucose levels. Stable blood sugar levels help reduce hunger and increased energy storage caused by blood sugar fluctuations, indirectly exerting a positive effect on weight control.
The Role of Survodutide in Weight Loss
Significant weight loss effects: In a randomized, double-blind, placebo-controlled Phase 2 dose-finding trial targeting obese patients, 387 adults aged 18–75 years old with with a body mass index (BMI) ≥27 kg/m² and no diabetes were randomly assigned to five groups, receiving weekly subcutaneous injections of Survodutide (0.6, 2.4, 3.6, or 4.8 mg) or placebo for a 46-week treatment period. The results showed that at week 46, patients treated with 4.8 mg of Survodutide experienced an average weight loss of 18.7% compared to the placebo group, with a statistically significant difference in weight reduction. In another study targeting patients with type 2 diabetes and obesity, Survodutide treatment resulted in weight loss that was dose-dependent after 16 weeks, with a maximum reduction of 8.7%. Additionally, Survodutide at a dose of ≥1.8 mg once weekly produced greater weight loss than the commonly used GLP-1 receptor agonist Semaglutid, which resulted in a weight reduction of 5.3%.
Gender and BMI differences: Further subgroup analyses indicated that the weight-loss effects of Survodutide varied across different genders and BMI levels. In the aforementioned trial targeting obese patients, at week 46, the average weight loss percentage (17.0%) in the 4.8 mg Survodutide group was higher in women than in men (11.9%); across different BMI subgroups, patients with BMI < 30 kg/m² had a relatively higher weight loss percentage (19.1%), but the absolute weight loss values were not significantly different across BMI subgroups. This suggests that in clinical practice, physicians can more accurately estimate the weight loss effects of Survodutide based on factors such as patient gender and BMI.
Body Fat Distribution and Metabolic Improvement
Reducing visceral fat: Survodutide not only reduces total body weight but also has a positive impact on body fat distribution. Excessive accumulation of visceral fat is closely associated with the development of various metabolic diseases. In relevant studies, after receiving Survodutide treatment for a period of time, patients experienced a significant reduction in visceral fat area. This is because the drug promotes the breakdown and oxidation of visceral fat, improving its metabolism and thereby reducing the metabolic risks associated with excessive visceral fat.
Improving lipid abnormalities: Obese patients often have lipid abnormalities, such as hypercholesterolemia and hypertriglyceridemia. Survodutide not only aids in weight loss but also improves lipid parameters. In animal experiments, obese hamsters treated with Survodutide showed a significant reduction in plasma total cholesterol levels, with a 41% decrease in the Survodutide group and a 24% decrease in the semaglutide group. Similar results were observed in human trials, where Survodutide treatment led to a significant decrease in triglyceride levels. It also exerted varying degrees of regulatory effects on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), helping to correct dyslipidemia and reduce the risk of cardiovascular disease.
Effects on cardiovascular risk factors
Lowering blood pressure: Obesity is one of the major risk factors for hypertension. In clinical trials targeting obese patients, after 46 weeks of Survodutide treatment, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) showed significant reductions. Compared with the placebo group, the 4.8 mg Survodutide group showed a maximum average reduction of 10.2 mmHg in SBP and 4.8 mmHg in DBP. This blood pressure-lowering effect may be related to multiple factors, including Survodutide's improvement of vascular endothelial function, reduction of sympathetic nerve activity, and weight loss, which collectively help reduce the risk of cardiovascular disease.
Improving vascular function: Survodutide may also exert protective effects on the cardiovascular system by improving the function of vascular endothelial cells. Following Survodutide administration, the release of nitric oxide (NO) by vascular endothelial cells increases. NO is an important vasodilator that dilates blood vessels, reduces vascular resistance, and improves blood circulation. The drug may also inhibit inflammatory responses and oxidative stress, thereby reducing vascular wall damage and further maintaining vascular health.
Application of Survodutide in Weight Loss
Target Population
Obese and Overweight Individuals: For obese or overweight individuals with a BMI ≥ 27 kg/m², Survodutide has demonstrated good weight loss effects. Both patients with simple obesity and those with obesity accompanied by other metabolic disorders such as type 2 diabetes or dyslipidemia may benefit from Survodutide treatment. In clinical trials, obese patients across different age groups (18–75 years) demonstrated good responses to Survodutide, indicating a broad range of eligible populations.
Patients with obesity related to specific diseases: In addition to general obesity populations, Survodutide is also a treatment option for obesity caused by specific diseases, such as polycystic ovary syndrome (PCOS), where obesity and metabolic disorders often coexist.
To further enhance weight loss effects and improve metabolic status, Survodutide can be used in combination with other treatment methods. When combined with lifestyle interventions (dietary control and exercise), synergistic effects can be achieved. In clinical trials, patients who received Survodutide treatment combined with regular exercise and a balanced diet experienced greater weight loss and more significant improvements in metabolic markers. Additionally, for patients with type 2 diabetes and obesity, Survodutide can be used in combination with other antidiabetic medications such as metformin to control blood sugar levels while achieving better weight management.
Conclusion
In summary, Survodutide, as a novel dual receptor agonist, is beneficial for weight loss. Its unique mechanism of action not only effectively reduces weight but also improves body fat distribution, regulates glucose and lipid metabolism, and reduces cardiovascular risk factors.
Sources
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[7] Lawitz E J, Fraessdorf M, Neff G W, et al. OS-119 Survodutide (BI 456906), a glucagon receptor/glucagon-like peptide-1 receptor (GCGR/GLP-1R) dual agonist, in people with compensated and decompensated cirrhosis: a multinational, open-label, phase 1 trial[J]. Journal of Hepatology, 2024. https://api.semanticscholar.org/CorpusID:270457365
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