Semaglutide: Diabetes Treatment and Weight Management

By Cocer Peptides      13 days ago

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Overview of Semaglutide

Semaglutide is a novel glucagon-like peptide-1 receptor agonist (GLP-1 RA). Glucagon-like peptide-1 (GLP-1) is a hormone naturally secreted by the human body that plays a crucial role in blood glucose regulation. When blood glucose levels rise, GLP-1 is secreted and regulates blood glucose levels through various mechanisms. However, in diabetic patients, GLP-1 secretion is often insufficient or its effects are inadequate. Semaglutide binds to GLP-1 receptors, mimicking the physiological effects of GLP-1, thereby exerting therapeutic effects for diabetes and weight management.

Figure 1 Treatments for obesity and their impact on weight loss

The Role of Semaglutide in Diabetes Treatment

Promoting Insulin Secretion

Under physiological conditions, when blood glucose levels rise, enteroendocrine cells in the intestine secrete GLP-1. GLP-1 binds to GLP-1 receptors on the surface of pancreatic β cells, activating a series of signaling pathways to increase insulin secretion. Semaglutide can also specifically bind to GLP-1 receptors on the surface of pancreatic β cells, stimulating insulin secretion in a glucose concentration-dependent manner. This means that when blood glucose levels rise, Semaglutide effectively promotes insulin release to lower blood glucose levels; when blood glucose levels are within the normal range, its effect on promoting insulin secretion is weak, thereby reducing the risk of hypoglycemia. Studies have shown that after treatment with Semaglutide, patients' insulin secretion levels improve significantly, and blood glucose levels can be effectively controlled.

Figure 2: An upstream weight-centric approach versus more downstream, glucose-centric, and cardiometabolic approaches. Incretin-based therapies are already active at the most upstream step.

Unlike traditional insulin secretagogues, such as sulfonylureas, which continuously stimulate insulin secretion regardless of blood glucose levels and may increase the risk of hypoglycemia, Semaglutide's glucose-concentration-dependent insulin secretion properties enable it to effectively lower blood glucose levels while significantly reducing the incidence of hypoglycemia, providing a safer and more effective blood glucose control option for diabetes patients.

Inhibition of glucagon secretion

Glucagon is a hormone secreted by pancreatic α cells that elevates blood glucose levels, acting oppositely to insulin. In diabetic patients, glucagon secretion often remains uninhibited even when blood glucose levels are elevated. Semaglutide acts on GLP-1 receptors on pancreatic α cells to inhibit glucagon secretion. When glucagon secretion decreases, the liver's glycogenolysis and gluconeogenesis processes are inhibited, reducing endogenous glucose production and further lowering blood glucose levels. Scientists have confirmed that in type 2 diabetes patients treated with Semaglutide, plasma glucagon levels significantly decrease, effectively reducing hepatic glucose output and playing a crucial role in stabilizing blood glucose levels.

Delaying gastric emptying

Semaglutide acts on GLP-1 receptors in the gastrointestinal tract to slow gastric emptying. Rapid gastric emptying causes food to enter the small intestine quickly, leading to a rapid rise in blood glucose levels. By delaying gastric emptying, food remains in the stomach longer and enters the small intestine more slowly, resulting in a more gradual absorption of glucose and preventing a sharp postprandial rise in blood glucose levels. This effect helps maintain stable postprandial blood glucose levels and reduce blood glucose fluctuations. In some clinical trials, patients treated with Semaglutide experienced a significant reduction in postprandial blood glucose peaks and smaller blood glucose fluctuations, improving overall blood glucose control quality. Additionally, the delayed gastric emptying can induce a sense of fullness, helping to reduce food intake and thereby assist in blood glucose control and weight management from another angle.  

Figure 3: Mechanism of Semaglutide for the Management of Obesity  

Improving β-Cell Function

Chronic hyperglycemia can damage pancreatic β cells, leading to gradual functional decline. Semaglutide not only lowers blood sugar by promoting insulin secretion but also protects and repairs pancreatic β cells, thereby improving β cell function. Scientific studies have shown that semaglutide may activate certain intracellular signaling pathways to promote β-cell proliferation, inhibit β-cell apoptosis, thereby increasing the number and function of β-cells. In animal experiments and some clinical studies, it was observed that after using Semaglutide, the insulin secretion capacity of β cells was enhanced, and insulin resistance was improved. This is of great significance for the long-term treatment of type 2 diabetes, as it helps slow the progression of the disease and reduce the risk of diabetic complications.

Applications of Semaglutide in Diabetes Treatment

Semaglutide has different application methods in diabetes treatment. For newly diagnosed type 2 diabetes patients, if blood glucose levels are not severely elevated and there are no obvious acute complications or other severe comorbidities, monotherapy with Semaglutide can be considered. Clinical studies show that some newly diagnosed patients experienced a significant decrease in hemoglobin A1c (HbA1c) levels and weight loss after a period of monotherapy. For example, in the PIONEER series of studies, patients treated with oral Semaglutide monotherapy experienced a significant reduction in HbA1c levels compared to the placebo group, with good safety and tolerability. The advantage of monotherapy is that it avoids the risk of drug interactions associated with combination therapy, and its relatively simple administration helps improve patient adherence to treatment.

Semaglutide can also be used in combination with other medications. When combined with metformin, which is a first-line medication for type 2 diabetes, it improves insulin resistance and reduces hepatic glucose output. The two medications have complementary mechanisms of action, enabling more effective blood glucose control. Studies have shown that this combination regimen further lowers HbA1c levels and results in more pronounced weight loss. For example, in some clinical trials, patients treated with metformin who added Semaglutide experienced greater reductions in HbA1c levels compared to those who continued metformin monotherapy, along with additional weight loss, without a significant increase in hypoglycemia risk. This regimen is suitable for patients whose blood glucose levels are not adequately controlled with metformin monotherapy.

For patients with type 2 diabetes who have high blood glucose levels and require insulin therapy, adding Semaglutide to insulin therapy can reduce insulin dosage. In insulin therapy, patients often face issues such as weight gain and increased risk of hypoglycemia. When used in combination, Semaglutide's effects of promoting insulin secretion and inhibiting glucagon secretion can optimize insulin use, reduce dosage, and thereby lower the risks of weight gain and hypoglycemia. For example, in some clinical studies, patients who added Semaglutide to their insulin therapy experienced an average reduction in insulin dosage, along with further decreases in HbA1c levels, weight loss, and a reduction in the frequency of hypoglycemia episodes.

Semaglutide can also be used in combination with other antidiabetic drugs such as SGLT2 inhibitors. SGLT2 inhibitors lower blood glucose by promoting glucose excretion in urine. The combination of the two can further improve blood glucose control through different mechanisms and may also have synergistic effects in weight management.

The role of Semaglutide in weight management

Appetite suppression

Semaglutide acts on GLP-1 receptors in the central nervous system, particularly in the hypothalamus. The hypothalamus is a key region in the body for regulating appetite and energy balance. After binding to GLP-1 receptors in the hypothalamus, semaglutide can regulate the release of neuropeptides, such as reducing the secretion of neuropeptide Y (NPY), which is a strong appetite-stimulating factor. Additionally, Semaglutide may increase the activity of proopiomelanocortin (POMC) neurons, whose activation generates satiety signals. Through these mechanisms, Semaglutide effectively suppresses appetite, leading patients to reduce their food intake. In clinical trials, obese or overweight patients using Semaglutide reported reduced appetite and decreased food intake, laying the foundation for weight loss.

Increasing energy expenditure

In addition to suppressing appetite, Semaglutide may also influence energy metabolism, increasing energy expenditure. Research suggests that Semaglutide may increase energy expenditure by regulating the activity of brown adipose tissue. Brown adipose tissue is a special type of fat tissue whose primary function is to consume energy through thermogenesis. Semaglutide may activate certain signaling pathways in brown adipose tissue, promoting fatty acid oxidation and thermogenesis. Additionally, Semaglutide may influence energy metabolism in tissues such as muscle, increasing energy expenditure even at rest. For example, in animal experiments, after administration of Semaglutide, the animals' energy metabolism rates increased, and their body weights decreased even when food intake remained the same, indicating that Semaglutide plays a positive role in weight management by increasing energy expenditure.

Regulation of fat metabolism

Semaglutide also has a regulatory effect on fat metabolism. It can promote the breakdown of fat, reduce fat synthesis, and inhibit fat storage. In the liver, Semaglutide may inhibit the activity of enzymes such as fatty acid synthase, thereby reducing fatty acid synthesis. Additionally, in adipose tissue, Semaglutide may promote fat breakdown, increase the release of free fatty acids, and facilitate their entry into mitochondria for oxidative breakdown, thereby reducing fat storage. Clinical studies have shown that after a period of treatment with Semaglutide, patients' body fat content, especially visceral fat content, decreases. This not only aids in weight loss but also has significant implications for improving metabolic syndrome and reducing the risk of cardiovascular disease.

Application of Semaglutide in Weight Management

For patients with obesity or overweight accompanied by related diseases

Semaglutide has a clear target population for weight management. For obese patients with a BMI ≥30 kg/m² or overweight patients with a BMI ≥27 kg/m² and at least one weight-related condition (such as hypertension, type 2 diabetes, or hypercholesterolemia), it is an effective weight management medication. The STEP series of clinical trials demonstrated significant weight loss in treated patients. In the STEP 1 study, treated patients achieved an average weight loss of approximately 15% over 68 weeks, while the placebo group lost only about 2.4%. These results indicate that it can help obese or overweight patients with related conditions achieve significant and sustained weight loss, improve health outcomes, and reduce the risk of obesity-related diseases.

Combined with lifestyle interventions

In weight management, Semaglutide is typically used in combination with lifestyle interventions, including reducing calorie intake and increasing physical activity. If weight loss relies solely on medication without changing unhealthy lifestyle habits, the effects are often not sustainable. The combination of both approaches has a synergistic effect: the medication suppresses appetite and increases energy expenditure, while dietary control reduces calorie intake and increased physical activity further boosts energy expenditure, leading to more significant and sustained weight loss. For example, in some clinical practices, patients who follow a low-calorie diet plan developed by a nutritionist and increase their weekly aerobic exercise time while receiving treatment achieve significantly better weight loss outcomes than those who rely solely on medication or lifestyle interventions. This combined approach emphasizes the importance of comprehensive management in weight management, helping patients establish healthy lifestyles and achieve long-term weight control.

Conclusion

Semaglutide demonstrates significant potential in both diabetes treatment and weight management. In diabetes treatment, it effectively controls blood glucose through multiple mechanisms, improves β-cell function, and can be used as monotherapy or in combination with other antidiabetic medications. In weight management, it suppresses appetite, increases energy expenditure, and regulates fat metabolism, making it suitable for obese or overweight patients with associated conditions. When combined with lifestyle interventions, it yields even better results.

Sources

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