1. Introduction

As the rates of type 2 diabetes and obesity continue to rise, traditional treatment methods are facing growing challenges in both efficacy and patient adherence [1]. Semaglutide, a new GLP-1 receptor agonist, has proven highly effective in controlling blood glucose levels and promoting weight loss, making it a key treatment option for type 2 diabetes and obesity [2]. Through multiple mechanisms such as promoting insulin secretion, inhibiting glucagon release, delaying gastric emptying, and regulating appetite, it helps patients control their weight and blood sugar levels, achieving positive results in clinical trials [3]. However, the clinical application of Semaglutide still faces challenges, such as incomplete research on its side effects, drug interactions, and long-term safety [4]. Thus, a thorough understanding of Semaglutide’s mechanism of action, efficacy, side effects, and potential drug interactions is key to optimizing its clinical use and ensuring the best possible outcomes for patients. This paper reviews the existing literature, analyzes the practical effects and limitations of Semaglutide in treating type 2 diabetes and obesity, and offers recommendations for its future optimization. The research provides a theoretical foundation for Semaglutide’s clinical application, aiding in the enhancement of patient adherence, while also offering valuable insights for future drug improvements and the exploration of potential new therapeutic uses.

2. Synthesis methods and mechanism of action of semaglutide

2.1. Synthesis methods

The synthesis of Semaglutide integrates biotechnological fermentation with chemical synthesis. GLP-1 (11-37) fragments are initially produced through biotechnological fermentation, which are subsequently subjected to chemical modification. However, this approach is associated with certain limitations [5]. In the synthesis of the GLP-1 fragment, the amino terminus and hydroxyl groups on the side chains of amino acids such as serine, threonine, and tyrosine are not protected, which may result in non-specific reactions with certain reagents, such as OSu esters, leading to impurities that affect the overall purity of the product. This increases the difficulty of subsequent separation and purification processes, ultimately lowering the yield. Thus, while this method enables the successful synthesis of Semaglutide in the laboratory, improving both yield and purity continues to present a significant challenge.

Moreover, Semaglutide can be synthesized using traditional solid-phase peptide synthesis (SPPS) and fragment coupling methods [6]. Solid-phase peptide synthesis technology is well-established and capable of synthesizing high-purity peptide fragments while minimizing impurity generation by precisely controlling reaction conditions. However, in large-scale production, solid-phase peptide synthesis encounters challenges such as low yield and poor purification efficiency, especially when synthesizing long peptide chains. The lengthy reaction cycles and complex process contribute to high production costs. Fragment coupling methods, which involve linking shorter peptide segments to form a complete polypeptide chain, offer an effective solution to the challenges of synthesizing long peptide chains. However, this approach also presents strict reaction conditions, the potential for impurity formation, and the risk of structural isomer issues, all of which could impact the quality and biological activity of the final product.

2.2. Mechanism of action

Semaglutide helps lower blood glucose and reduce weight through several mechanisms, including boosting insulin secretion, inhibiting glucagon release, slowing gastric emptying, and controlling appetite.

2.2.1. Promotion of insulin secretion

As a GLP-1 receptor agonist, Semaglutide binds to the GLP-1 receptors on the surface of pancreatic \( β \) -cells, thereby activating the receptor and initiating a cascade of intracellular signaling events. Receptor activation triggers G-proteins, which subsequently activate adenylate cyclase (AC), thus leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. As a key second messenger, cAMP regulates insulin secretion through the activation of protein kinase A (PKA). The ways in which PKA exerts its effects are outlined below. PKA promotes cell membrane depolarization, activating calcium ion channels that allow calcium ions to enter \( β \) -cells, thus raising intracellular calcium concentrations. This increase in calcium triggers the fusion of insulin vesicles with the cell membrane, facilitating insulin secretion. Furthermore, PKA regulates the transcription factors responsible for insulin gene expression, thus boosting insulin synthesis. Also, PKA plays a crucial role in regulating the cytoskeleton and vesicle transport proteins, which can facilitate the transport and fusion of insulin vesicles, further optimizing the efficiency of insulin secretion. Related research has shown that Semaglutide enhances insulin secretion efficiency through these multiple pathways, with a particularly pronounced effect in cases of postprandial hyperglycemia [7].

2.2.2. Inhibition of glucagon secretion

Semaglutide inhibits the secretion of glucagon from pancreatic \( α \) -cells, thereby reducing hepatic glucose production and further stabilizing blood glucose levels. Glucagon is normally released when blood glucose levels are low, stimulating the liver to produce and release glucose to maintain blood glucose homeostasis. However, in the context of postprandial hyperglycemia, Semaglutide binds to GLP-1 receptors on \( α \) -cells, significantly inhibiting glucagon secretion and thus reducing excessive hepatic glucose production [8]. This mechanism helps prevent postprandial blood glucose spikes and contributes to overall blood glucose balance, which is particularly clinically relevant for diabetic patients. Through this inhibitory effect, Semaglutide effectively alleviates postprandial glucose fluctuations and improves blood glucose control.

2.2.3. Regulation of appetite and weight management

Semaglutide mediates appetite regulation and promotes weight management through the activation of GLP-1 receptors in both the gastrointestinal tract and central nervous system. By influencing the contractility of smooth muscle in the gastrointestinal tract, it prolongs gastric emptying, while simultaneously relaying signals to the brain through the vagus nerve, thus regulating gastric motility and promoting satiety. This mechanism alleviates hunger and amplifies sensations of fullness, thereby contributing to a reduction in food intake. In addition, Semaglutide increases the secretion of gastrointestinal hormones, such as glucagon-like peptide-1 (GLP-1), further enhancing satiety. Its impact on the gastrointestinal tract also helps control eating speed and prevent overeating. Besides, by influencing multiple components of the neuroendocrine system, the drug alters the transmission of appetite signals, thus promoting weight loss. Clinical studies have demonstrated that Semaglutide significantly alleviates both pre-meal and post-meal hunger, while enhancing satiety. These effects, along with its capacity to improve energy metabolism and promote fat oxidation, support effective weight management. Furthermore, clinical trials highlight its particular efficacy in weight reduction, especially among obese and diabetic patients, offering substantial benefits in both weight loss and blood glucose control. [9].

3. Clinical applications and challenges of semaglutide

3.1. The clinical trials on blood glucose control

As a GLP-1 receptor agonist, Semaglutide has demonstrated significant efficacy in controlling blood glucose levels in patients with type 2 diabetes, as evidenced by the PIONEER series of studies. The PIONEER series is a large-scale, global, multi-center clinical trial, and the results indicate that Semaglutide significantly reduces HbA1c levels in type 2 diabetes patients. Compared to traditional therapies, it also exhibits better tolerability and control of side effects. For example, the PIONEER 4 study showed that when used in combination with other antihyperglycemic agents, Semaglutide significantly improves blood glucose control and has good tolerability, particularly in avoiding increased hypoglycemia risks while effectively reducing HbA1c levels. Furthermore, the PIONEER 6 study revealed that Semaglutide significantly attenuates mortality rates attributable to cardiovascular diseases. The research findings also revealed that, in Chinese patients, Semaglutide monotherapy achieved an HbA1c target rate of 92.3%, underscoring the drug’s broad applicability and effectiveness across diverse populations. Thus, the PIONEER series provides a solid foundation for the widespread clinical application of Semaglutide in the treatment of type 2 diabetes [10,11].

3.2. The clinical trials on weight loss

In the area of weight management, the STEP series of trials further validated the efficacy of Semaglutide in promoting weight loss. The STEP 1 study showed that Semaglutide significantly reduced patients’ body weight by an average of 14.9%, with over one-third of patients achieving a weight loss of more than 20%, which far surpasses traditional weight loss medications [12]. The STEP 5 study showed that with long-term treatment (lasting 108 weeks), Semaglutide resulted in a sustained 15.2% weight loss, with even more pronounced effects when combined with a low-calorie diet and moderate exercise. The STEP 8 study further compared the efficacy of Semaglutide with liraglutide, and the results showed that Semaglutide had a distinct advantage in non-diabetic obese populations, with 38.5% of patients achieving more than 20% weight loss and 55.6% losing more than 15% of their weight [12]. These findings not only confirm its effectiveness as a weight loss treatment but also highlight its long-term potential and role in managing obesity. The drug therefore provides a new therapeutic option for obesity management and paves the way for future weight loss therapies.

3.3. The clinical trials on cardiovascular and renal protection

Semaglutide has demonstrated not only efficacy in blood glucose control and weight management but also substantial benefits in cardiovascular and renal protection. The FLOW trial revealed that Semaglutide significantly reduces the risk of cardiovascular events and mortality in patients with chronic kidney disease and type 2 diabetes. In this study, the incidence of cardiovascular events was reduced by 18%, and overall mortality risk decreased by 20% in the Semaglutide treatment group. Furthermore, a dedicated trial in chronic kidney disease patients showed that the drug effectively slows the progression of kidney function decline and reduces the urinary albumin-to-creatinine ratio (UACR) [13]. The findings further reinforce its potential to protect cardiovascular and renal health, particularly in patients with diabetic kidney disease, offering a promising new treatment option .

3.4. Common side effects and contraindications

Despite the positive clinical outcomes, the potential side effects of Semaglutide remain an important factor to consider in its clinical application. And the most frequently reported adverse effects are gastrointestinal in nature, including nausea, vomiting, diarrhea, and constipation. These side effects are typically more pronounced during the early stages of treatment, though most patients gradually acclimate as treatment progresses. The STEP series of studies suggest that, in most cases, these side effects are mild and transient, with their intensity diminishing as treatment continues. To manage these effects, clinical guidelines recommend a gradual dose escalation, tailored adjustments to the treatment regimen, and complementary dietary interventions. Also, Semaglutide is contraindicated in individuals with known hypersensitivity to its components, as well as those with a family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2). Thus, a thorough evaluation is essential before initiating treatment to ensure patient safety [14].

3.5. Major challenges in clinical application

Semaglutide;s clinical application is constrained by two factors: its high cost and gastrointestinal side effects, both of which can adversely affect long-term patient adherence. Though the medication provides significant therapeutic benefits, its high cost restricts access, particularly for low-income populations and in resource-limited settings. Additionally, gastrointestinal issues such as nausea and vomiting may compromise patient compliance, making it difficult for some individuals to maintain consistent use. To overcome these challenges, it is essential to reduce production costs to enhance accessibility, while also developing personalized treatment strategies tailored to individual patient needs. Such strategies may involve dose adjustments, modifications to treatment regimens, and the incorporation of lifestyle interventions to alleviate side effects and improve patient adherence. And ongoing research is critical to optimizing its therapeutic efficacy and expanding its availability, thereby ensuring broader access to this treatment [12].

4. Conclusion

Semaglutide has demonstrated significant efficacy in the treatment of type 2 diabetes and obesity, becoming an important therapeutic option in this field. However, its application still faces certain limitations, particularly gastrointestinal discomfort, which may affect patient adherence and pose challenges to long-term safety. Existing studies indicate that Semaglutide has clear advantages in blood glucose control and promoting weight loss, but managing side effects remains a key issue in its clinical application. Future research should focus on improving the management of side effects, exploring new formulations or administration methods to alleviate gastrointestinal discomfort and enhance patient treatment tolerance. Personalized treatment will be key to improving therapeutic outcomes, with future research focusing on tailoring plans to individual patient needs. Additionally, the long-term safety of Semaglutide, particularly its impact on the pancreas and thyroid, needs confirmation through larger clinical trials. In the future, Semaglutide’s indications may be expanded, as research explores its potential in cardiovascular diseases, non-alcoholic fatty liver disease, and cognitive function. As such, long-term, large-scale clinical studies will be crucial to thoroughly assess its efficacy and safety, supporting its broader use in various metabolic disorders.