▎Survodutide Research

What is the research background of Survodutide?

Prevalence of Metabolic Diseases:

With the acceleration of the pace of life and the change of dietary structure, metabolic diseases such as obesity, type 2 diabetes mellitus, and non-alcoholic steatohepatitis (NASH) have become global public health challenges. For example, the prevalence of metabolic-associated fatty liver disease (MAFLD) exceeds 30%, and it is predicted that by 2030, metabolic dysfunction-associated steatohepatitis (MASH) will become the main cause of liver transplantation, imposing a huge burden on the healthcare system.

Limitations of Existing Drugs:

Traditional GLP-1 drugs have certain limitations in the treatment of metabolic diseases. For some patients, the weight loss effect is not satisfactory, or they may experience gastrointestinal side effects. Moreover, their ability to improve liver fat metabolism is limited, and tolerance may develop with long-term use.

Advantages of Dual Agonists:

As a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR), Survodutide can regulate metabolism from multiple dimensions. Through the GLP-1R pathway, it can suppress appetite, delay gastric emptying, and promote insulin secretion to lower blood glucose levels. Through the GCGR pathway, it can enhance fatty acid oxidation in the liver, reduce fat accumulation, and directly improve liver fibrosis, demonstrating good therapeutic effects on obesity, diabetes, and liver diseases in animal experiments.

What is the mechanism of action of Survodutide?

1. Dual Receptor Agonism

Survodutide is a dual agonist of the glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R).

GLP-1R Agonism

After activation of the GLP-1 receptor, it can enhance glucose-dependent insulin secretion and inhibit glucagon secretion, thereby reducing blood glucose levels. When Survovudutide activates GLP-1R, it can promote insulin secretion by pancreatic islet β cells and, at the same time, reduce glucagon secretion by pancreatic islet α cells, achieving fine regulation of blood glucose^[1].

In addition, GLP-1R agonism can also delay gastric emptying and increase the sense of fullness, thus helping to reduce food intake and control body weight.

GCGR Agonism

Activating the glucagon receptor can increase energy consumption and promote fat breakdown. Survodutide stimulates GCGR, increasing the body's energy metabolism level and prompting the breakdown of triglycerides in adipose tissue into fatty acids and glycerol, providing an energy source for the body^[1].

2. Effects on Metabolism

Improvement of Glucose Metabolism

Survovudutide significantly reduces the level of glycated hemoglobin (HbA1c). In clinical studies, type 2 diabetes patients treated with Survovudutide showed a significant decrease in HbA1c levels after 16 weeks of treatment. For example, compared with semaglutide, the low-dose Survovudutide (DG2) had a similar effect in reducing HbA1c. The HbA1c level in the DG2 group decreased by 15.95 mmol/mol (-1.46%), while that in the semaglutide group decreased by 16.07 mmol/mol (-1.47%) ^[1].

Its mechanism of action may be achieved by enhancing insulin secretion, inhibiting glucagon secretion, and improving the uptake and utilization of glucose by peripheral tissues.

Regulation of Lipid Metabolism

Survovudutide can reduce blood lipid levels. In a study of obese patients, compared with the placebo, Survodutide significantly reduced the triglyceride (TG) level, and also decreased the levels of low-density lipoprotein (LDL), total cholesterol (TC), and non-high-density lipoprotein cholesterol (non-HDL-C) in some dose groups^[2].

At the same time, Survodutide can also reduce liver fat content. In a study of patients with metabolic dysfunction-associated steatohepatitis (MASH), the proportion of patients treated with Survovudutide whose liver fat content decreased by at least 30% was significantly higher than that in the placebo group. For example, 63%, 67%, and 57% of patients in the Survovudutide 2.4mg, 4.8mg, and 6.0mg groups, respectively, reached this indicator, while only 14% in the placebo group^[3].

3. Effects on the Cardiovascular System

Improvement of Cardiovascular Risk Factors

Survovudutide can lower blood pressure. In obese patients, compared with the placebo, both systolic blood pressure (SBP) and diastolic blood pressure (DBP) significantly decreased after treatment with Survodutide. In actual treatment, Survodutide can reduce SBP by up to 10.2 mmHg and DBP by 4.8 mmHg, and the blood pressure-lowering effect is similar regardless of whether the patient had hypertension before screening ^[2].

In addition, Survodutide can also reduce waist circumference. In obese patients, the waist circumferences of patients in all Survodutide dose groups decreased, and the 4.8mg group had the largest average reduction, which was 16.6 cm^[2].

Effects on Markers of Non-alcoholic Steatohepatitis (NASH)

Survovudutide may have an improving effect on certain markers of non-alcoholic steatohepatitis (NASH). Current studies suggest that Survodutide may play a role in inhibiting the development of NASH by improving liver fat metabolism and the inflammatory state^[4].

What are the applications of Survodutide?

1. Treatment of Type 2 Diabetes Mellitus and Obesity

As a long-acting dual agonist, Survodutide is administered once a week and has shown significant effects in the treatment of type 2 diabetes mellitus (T2DM) and obesity.

Reduction of Glycated Hemoglobin (HbA1c):

Multiple clinical trials have shown that Survodutide can effectively reduce the HbA1c level in patients. For example, in a study of T2DM patients, after 16 weeks of treatment, the HbA1c level decreased by up to 1.7% ^[4]. HbA1c is an important indicator reflecting long-term blood glucose control, and its decrease means that the patient's blood glucose control has been improved.

Significant Weight Loss:

For patients with both T2DM and obesity, Survodutide can achieve a weight loss of up to 14.9% during 46 weeks of treatment^[4]. This is an important breakthrough for patients who are troubled by the weight gain often caused by traditional antidiabetic drugs. Weight loss not only helps improve the patient's appearance and quality of life but also reduces the risk of complications such as cardiovascular diseases.

2. Improvement of Cardiovascular Risk Factors

Survodutide also has a positive impact on cardiovascular risk factors.

Blood Pressure Reduction:

In a clinical trial of obese patients, compared with the placebo, Survodutide can reduce systolic blood pressure by up to 10.2 mmHg and diastolic blood pressure by 4.8 mmHg ^[2]. The reduction of blood pressure is of great significance for the prevention of cardiovascular diseases, especially for patients with both obesity and hypertension.

Improvement of Blood Lipid Parameters:

Survodutide can reduce the triglyceride (TG) level and also has a certain improving effect on blood lipid parameters such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (TC), and non-high-density lipoprotein cholesterol (non-HDL-C)^[2]. For example, in the planned treatment, the average TG in all Survodutide groups decreased significantly.

3. Treatment of Non-alcoholic Steatohepatitis (NASH)

Survodutide also shows potential in the treatment of non-alcoholic steatohepatitis (NASH).

Improvement of Liver Histology:

In a 48-week, phase 2 clinical trial of adult patients with MASH (metabolic dysfunction-associated steatohepatitis) and liver fibrosis, Survodutide was superior to the placebo in improving MASH without aggravating liver fibrosis. Specifically, among patients treated with different doses of Survodutide, 47% of patients in the 2.4mg group, 62% of patients in the 4.8mg group, and 43% of patients in the 6.0mg group showed improvement in MASH, while only 14% in the placebo group^[3].

Reduction of Liver Fat Content:

Survodutide can also reduce liver fat content. In the above-mentioned clinical trial, 63%, 67%, and 57% of patients treated with 2.4mg, 4.8mg, and 6.0mg doses of Survodutide, respectively, had a reduction in liver fat content of at least 30%, while only 14% in the placebo group^[3].

Improvement of Liver Fibrosis:

In addition, it has improved liver fibrosis to a certain extent. In this trial, 34%, 36%, and 34% of patients treated with 2.4mg, 4.8mg, and 6.0mg doses of Survodutide, respectively, showed an improvement in liver fibrosis of at least one stage, while it was 22% in the placebo group^[3].

4. Influence on Food Preferences and Improvement of Dyslipidemia

In an obese hamster model, both Survodutide and another drug, Semaglutid, can induce weight loss and reduce the insulin resistance index (HOMA-IR), but they have different effects on food preferences and dyslipidemia.

Effect on Food Intake:

Semaglutid significantly reduced the intake of regular feed and high-fat feed in the first week of treatment but then returned to the baseline value. At the same time, it significantly increased the intake of normal water and reduced the intake of fructose-rich water. In contrast, Survodutide did not change the intake of regular feed and normal water but significantly reduced the intake of high-fat feed and fructose-rich water during the 5-week treatment period^[5].

Effect on Blood Lipids:

Both Semaglutid and Survodutide can significantly reduce the plasma total cholesterol level, with a reduction of 24% and 41%, respectively. The reduction of the total cholesterol level by Semaglutid led to a 25% decrease in the high-density lipoprotein cholesterol level, but the low-density lipoprotein cholesterol level did not change. The cholesterol-lowering effect of Survodutide was observed in all lipoprotein components, including a 39% reduction in low-density lipoprotein cholesterol^[5].

In conclusion, as a dual receptor agonist, Survodutide can regulate metabolism, lower blood glucose, reduce body weight, improve cardiovascular risk factors, and improve markers of non-alcoholic steatohepatitis. It provides new ideas for the treatment of related diseases and is of great significance for improving the health level of patients.

About The Author

The above-mentioned materials are all researched, edited and compiled by Peptisource.

Scientific Journal Author

Le Roux C is a researcher affiliated with a number of organizations. These include University College Dublin, St Vincents Uni Hosp, Ulster University, Saint Vincent's University Hospital, St Vincents Hosp Grp, KU Leuven, University Hospital Leuven, Conway Inst Univ Coll, Ctr Diabet, Inst Conway, University of Gothenburg, Imperial College London, ICL, Univ Dublin, Istituto per la Sintesi Organica e la Fotoreattivita (ISOF-CNR), Maastricht University, King's College Hospital, King's College Hospital NHS Foundation Trust, Musgrove Park Hospital and National Hospital for Neurology & Neurosurgery.

His research interests are wide - ranging, covering Surgery, Endocrinology & Metabolism, Nutrition & Dietetics, Oncology, and Biochemistry & Molecular Biology. His work in these areas demonstrates his extensive expertise and the significant contributions he has made to the advancement of medical science. Le Roux C is listed in the reference of citation [2].

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