▎Semaglutid Research
What is the research background of Semaglutid?
Semaglutid is a human glucagon-like peptide-1 (GLP-1) analogue, belonging to the class of GLP-1 receptor agonist drugs. GLP-1 is a naturally occurring hormone secreted by intestinal cells after eating, which promotes insulin secretion and inhibits glucagon secretion to regulate blood glucose levels. The development of Semaglutid originated from in-depth research on the physiological functions of GLP-1. GLP-1 has a short half-life in the body, about 1-2 minutes, as it is easily degraded by dipeptidyl peptidase-4 (DPP-4) enzymes in the body. To overcome this limitation, scientists modified the structure of GLP-1, introducing specific amino acid substitutions and adding protective groups to enhance its resistance to DPP-4 enzymes, thereby prolonging its duration of action in the body[1]. In the structure of Semaglutid, the alanine at position 8 is replaced by α-aminoisobutyric acid (Aib), which not only improves the stability of the drug but also enhances its binding force with GLP-1 receptors [2]. A unique fatty acid side chain is added to the C-terminus of Semaglutid, which is connected to a lysine residue via γ-glutamine, further extending the drug’s half-life and allowing it to be injected once a week or taken orally once a day [1]. Semaglutid was initially developed based on research and modification of natural GLP-1, aiming to provide a more effective treatment for patients with type 2 diabetes [1, 2]. Through these structural optimizations, Semaglutid not only retains the physiological activity of GLP-1 but also significantly improves its pharmacokinetic properties, becoming a long-acting GLP-1 receptor agonist of important clinical value. The development of Semaglutid is a significant achievement, bringing new treatment options for patients with type 2 diabetes. By optimizing the structure of natural GLP-1, it overcomes the limitation of its short half-life and improves the drug’s stability and duration of action.
What is the mechanism of action of Semaglutid?
Semaglutid is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, and its mechanism of action is mainly achieved through the following aspects:
Blood glucose regulation:
Semaglutid is a novel GLP-1 receptor agonist (GLP-1RA). Its primary mechanism is to curb food cravings by inhibiting appetite, reducing the preference for high-fat foods, and modulating the hypothalamic feeding center to decrease food intake. It also increases satiety, delays gastric emptying, and reduces gastrointestinal motility, thereby achieving weight loss. This weight reduction enhances insulin sensitivity and helps regulate blood glucose levels [3]. Semaglutid induces weight loss in rodents through distributed neural pathways. Studies show it acts on the brainstem, septal nucleus, and hypothalamus but doesn’t cross the blood-brain barrier. Instead, it interacts with the brain through circumventricular organs and ventricular-proximal areas. Semaglutid activates c-Fos in ten brain regions, including hindbrain areas directly targeted and secondary regions like the lateral parabrachial nucleus without direct GLP-1R interaction. Automatic analyses suggest activation involves lateral parabrachial nucleus neurons controlling meal termination, thus regulating blood glucose[4] .
Gastrointestinal regulation:
Semaglutid acts on GLP-1 receptors in the gut, using the vagus nerve pathway to modulate gastrointestinal motility. It suppresses antral contractions, bolsters pyloric sphincter tension, and prolongs gastric food retention, delaying duodenal entry and preventing postprandial blood glucose spikes, leading to more stable levels[5] . Additionally, Semaglutid affects central GLP-1 receptors, particularly in the hypothalamic arcuate and paraventricular nuclei. It inhibits appetite-stimulating factors like neuropeptide Y (NPY) and agouti-related protein (AgRP), while activating proopiomelanocortin (POMC) neurons to boost alpha-melanocyte-stimulating hormone (α-MSH) secretion [5]. These actions induce satiety, reduce hunger, and decrease food intake, aiding weight management and indirectly improving blood glucose control.
Cardiovascular protection:
Semaglutid promotes the release of nitric oxide (NO) and other vasodilators from vascular endothelial cells, enhancing vasodilation and blood flow. It also inhibits inflammation and oxidative stress, reducing endothelial damage and atherosclerosis risk. By curbing appetite and food intake, it aids weight loss, improves lipid metabolism, lowers triglycerides and low-density lipoprotein cholesterol (LDL-C), and raises high-density lipoprotein cholesterol (HDL-C). Moreover, it may benefit blood pressure by modulating renal hemodynamics and neuroendocrine function, lowering hypertension risk and reducing cardiovascular disease risk factors[6] .
Key experiments and research
In terms of chemical structure design and optimization, during the design of semaglutide, a method of reversible binding to albumin was adopted to prolong the duration of action of the drug. By determining the optimal combination of fatty acids and linkers, the binding capacity to albumin was maximized while maintaining the efficacy on the GLP-1 receptor (GLP-1R) (Knudsen L B, 2019).
In terms of drug application, semaglutide has superior weight loss effects. Semaglutid is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a long elimination half-life, allowing weekly subcutaneous injection. Its weight loss effect is remarkable. In patients with type 2 diabetes (T2DM), weekly subcutaneous injection of semaglutide seems more effective for weight loss than other weekly GLP-1RAs. In a phase II dose-finding trial for obese patients without T2DM, once-daily subcutaneous injection of semaglutide was more effective for weight loss than placebo and once-daily 3.0mg liraglutide. The weight loss caused by semaglutide in this study exceeded the standard for anti-obesity drugs set by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), with no safety issues, indicating that once-daily subcutaneous injection of semaglutide has the potential to be a future weight loss drug[7] .
Semaglutid can improve cardiac function and is used for the treatment of cardiovascular diseases. The results of the STEP-HFpEF trial were announced, in which high-dose antidiabetic glucagon-like peptide 1 agonist semaglutide significantly improved symptoms of heart failure with preserved ejection fraction (HFpEF) and reduced N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. The study tested the effect of acute semaglutide treatment on isolated human right atrial trabeculae and found that semaglutide increased the tension of human atrial trabeculae by more than three times in a dose-dependent manner, without increasing the tendency for arrhythmias. This effect is most likely due to increased sarcoplasmic reticulum Ca2+ uptake. High-dose semaglutide treatment in heart failure patients can improve atrial function and thus alleviate symptoms[8] .
Semaglutid is being studied for the treatment of non-alcoholic steatohepatitis (NASH). Its rational design has made great contributions to improving blood glucose control, weight, blood pressure, lipids, β-cell function, and the cardiovascular system in patients with type 2 diabetes. Moreover, the development of an oral formulation of semaglutide may offer additional benefits to patients in terms of treatment compliance[9] .
Differences in Weight Loss Effects of Semaglutid Across Populations
Weight Loss Effects in Adults with Existing Cardiovascular Disease, Overweight or Obesity without Diabetes:
In the SELECT cardiovascular outcomes trial, semaglutide reduced major adverse cardiovascular events (MACE) by 20% in 17,604 adults with existing cardiovascular disease, overweight or obesity, and no diabetes[10] . In this pre-specified analysis, researchers examined the effects of semaglutide on weight, anthropometric outcomes, safety, and tolerability by baseline body mass index (BMI). Patients receiving semaglutide experienced sustained weight loss over 65 weeks, persisting up to 4 years. At 208 weeks, semaglutide led to significantly greater mean reductions in weight (-10.2%), waist circumference (-7.7 cm), and waist-to-height ratio (-6.9%) compared to placebo (-1.5%, -1.3 cm, and -1.0%, respectively; all comparisons were statistically significant. Clinically meaningful weight loss occurred across males and females, all ethnicities, body types, and regions. Semaglutid was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40, and ≥40 kg/m²), semaglutide had lower serious adverse event rates (events per 100 person-years: 43.23, 43.54, 51.07, and 47.06 vs. 50.48, 49.66, 52.73, and 60.85 for placebo). Semaglutid was linked to increased trial product discontinuation rates, which rose with decreasing BMI categories. In the SELECT trial, semaglutide induced significant clinical weight loss and anthropometric improvements compared to placebo at 208 weeks, with weight loss sustained over 4 years.
Weight Loss Effects in Obese or Overweight Individuals without Diabetes:
A systematic review evaluated the efficacy and safety of semaglutide in obese or overweight individuals without diabetes[11] . This review synthesized results from multiple clinical trials, highlighting semaglutide’s impact on weight loss, metabolic parameters, and overall health outcomes. Findings indicated semaglutide was associated with significant weight loss and improvements in obesity-related health metrics, suggesting its potential as a valuable treatment option for obese patients.
Weight Loss Effects in Non-Diabetic Patients (Evidence from Multiple RCTs):
Four randomized controlled trials (RCTs) involving patients with baseline weights of 96–105 kg evaluated weekly 2.4 mg subcutaneous semaglutide plus lifestyle interventions (counseling, diet, physical activity) for weight loss[12]. One RCT in non-diabetic patients (N = 1,961) reported a mean weight loss of 15% (15 kg) vs. 2% (3 kg) with placebo after 68 weeks (statistically significant). The proportion of patients achieving ≥5% weight loss was 86% vs. 32% (number needed to treat [NNT] = 2), and ≥10% weight loss was 69% vs. 12% (NNT = 2). Weight loss plateaued at ~60 weeks. Gastrointestinal adverse events (AEs) occurred in 74% vs. 48% (number needed to harm [NNH] = 3). Discontinuation due to AEs was 7% vs. 3% (NNH = 25). Similar results were observed in another RCT with intensive lifestyle intervention (N = 611): semaglutide induced 16% (17 kg) vs. 6% (6 kg) weight loss. In a dose-exploration RCT in non-diabetic patients (N = 1,210), weekly 2.4 mg semaglutide, 1.0 mg semaglutide, or placebo yielded mean weight losses of 10%, 7%, and 3% after 68 weeks. Proportions achieving ≥5% weight loss were 69% (2.4 mg), 57% (1.0 mg), and 29% (placebo). For 2.4 mg vs. 1.0 mg, NNT = 9. AE profiles were similar across doses. In a weight maintenance RCT (N = 803), non-diabetic participants received 2.4 mg semaglutide weekly for 20 weeks, then were randomized to continue semaglutide or switch to placebo. After 48 weeks, continued semaglutide users lost 8% vs. placebo users gaining 7%.
In summary, semaglutide is a GLP-1 receptor agonist with multi-domain application value. In diabetes treatment, it binds to GLP-1 receptors to promote insulin secretion and inhibit glucagon release, effectively controlling blood glucose levels and providing a significant treatment option for patients with type 2 diabetes. In the field of obesity treatment, semaglutide can significantly reduce energy intake through mechanisms such as central appetite suppression and delayed gastric emptying, helping obese patients lose weight and improve their metabolic status. Additionally, semaglutide shows potential application prospects in the prevention and treatment of cardiovascular diseases, and its improvement of cardiovascular risk factors offers a new approach to reducing the incidence of cardiovascular events. The emergence of semaglutide not only enriches the treatment methods for related diseases but also brings new hope for improving patients’ quality of life and health.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Hegner P is a researcher at the University of Regensburg. His work spans Chemistry, Cardiovascular System, and Cardiology. In Chemistry, he explores reactions tied to cardiovascular health. In Cardiovascular System studies, he probes heart and vessel functions, seeking therapeutic insights. His Cardiology research focuses on heart disease prevention, diagnosis, and treatment.
Hegner’s contributions are significant. His chemical insights have spurred new cardiovascular drug development. His work on heart and vessel mechanisms has enhanced understanding of cardiovascular diseases. Clinically, his research has improved heart disease management, raising standards of patient care. Overall, Hegner’s multidisciplinary approach enriches cardiovascular medicine, offering hope for reduced disease burdens and better patient outcomes. Hegner P is listed in the reference of citation [8].
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