▎GLP-1 Research
What is the research background of GLP-1?
GLP-1 is a human glucagon-like peptide-1 (GLP-1) analog, classified as a GLP-1 receptor agonist. GLP-1 is a natural hormone secreted by intestinal cells after eating. It plays a role in promoting insulin secretion and inhibiting glucagon secretion, thereby regulating blood glucose levels. The development of GLP-1 originated from in-depth explorations of the physiological functions of GLP-1. However, GLP-1 has an extremely short half-life in the body, lasting only about 1 to 2 minutes, which is attributed to its susceptibility to degradation by dipeptidyl peptidase-4 (DPP-4) enzymes in the body. To overcome this limitation, scientists modified the structure of GLP-1 through specific amino acid substitutions and the addition of protective groups, enhancing its resistance to DPP-4 enzymes and thus prolonging its duration of action[1]. In the structure of GLP-1, alanine at the 8th position is replaced by α-aminoisobutyric acid (Aib). This change not only improves the stability of the drug but also strengthens its binding to the GLP-1 receptor (Ma H, 2020). Additionally, a unique fatty acid side chain connected to its C-terminus, linked via γ-glutamine to lysine residues, further extends the half-life, enabling once-weekly injection or once-daily oral administration[1]. Initially based on the research and modification of natural GLP-1, GLP-1 aims to provide more effective treatment options for patients with type 2 diabetes[1, 2]. After structural optimization, it retains the physiological activity of GLP-1 while significantly improving its pharmacokinetic properties, becoming an important long-acting GLP-1 receptor agonist. The research and development of GLP-1 are of great significance for the treatment of type 2 diabetes, offering new choices to patients. By optimizing the structure, it overcomes the problem of the short half-life of natural GLP-1, enhancing the drug's stability and duration of action.
What is the mechanism of action of GLP-1?
GLP-1 is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, and its mechanism of action is as follows:
Blood Glucose Regulation: As a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), GLP-1 mainly reduces patients' cravings for food and decreases their preference for high-fat foods by suppressing appetite. It regulates the feeding center in the hypothalamus, reducing food intake, increasing satiety, inhibiting gastric emptying, and decreasing gastrointestinal motility, thus achieving the goal of weight loss. Weight loss helps improve insulin resistance and further regulates blood glucose levels[3] (Kim H S, 2021). GLP-1 induces weight loss in rodents through the distributed neural pathways. Studies have shown that GLP-1 acts directly on areas such as the brainstem, septal nucleus, and hypothalamus. Although it does not cross the blood-brain barrier, it interacts with the brain through circumventricular organs and specific regions near the ventricles. It induces central c-Fos activation in 10 brain regions, including the hindbrain regions directly targeted by GLP-1 and secondary regions without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automatic analysis indicates that the activation may be related to the termination of meals controlled by neurons in the lateral parabrachial nucleus, thereby regulating blood glucose levels[4].
Gastrointestinal Regulation: GLP-1 acts on GLP-1 receptors in the gastrointestinal tract. Through the afferent pathway of the vagus nerve, it acts on areas in the brain such as the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve to regulate gastrointestinal motility. It can inhibit the contraction of the gastric antrum, enhance the tension of the pyloric sphincter, prolong the residence time of food in the stomach, and delay its entry into the duodenum, preventing a rapid rise in postprandial blood glucose and making blood glucose changes more stable[5] (Katsurada K, 2016). In addition, GLP-1 acts on GLP-1 receptors in the central nervous system, mainly in areas such as the arcuate nucleus and paraventricular nucleus of the hypothalamus. It inhibits the release of appetite-stimulating factors such as neuropeptide Y (NPY) and agouti-related protein (AgRP), and at the same time activates pro-opiomelanocortin (POMC) neurons, promoting the secretion of α-melanocyte-stimulating hormone (α-MSH) [5]. These effects generate a feeling of satiety, reduce hunger, and decrease food intake, indirectly having a positive impact on blood glucose control.
Cardiovascular Protection: GLP-1 can promote vascular endothelial cells to release vasodilatory factors such as nitric oxide (NO), enhancing vascular dilation ability and improving blood flow perfusion. At the same time, it inhibits inflammatory responses and oxidative stress, reduces damage to vascular endothelial cells, and lowers the risk of atherosclerosis. Moreover, by reducing appetite and food intake, GLP-1 helps with weight loss, improves lipid diabetes disorders, reduces the levels of triglycerides and low-density lipoprotein cholesterol (LDL-C), and increases the level of high-density lipoprotein cholesterol (HDL-C). It may also have beneficial effects on blood pressure by regulating renal hemodynamics and neuroendocrine functions, reducing the risk of hypertension and cardiovascular disease risk factors [6].
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GLP-1 and transcriptional regulation of WAT to BAT conversion and BAT activation.
Source: PubMed[12]
What are the key experiments and studies?
Design and Optimization of Chemical Structure: When designing GLP-1, a method of reversible binding to albumin was adopted to extend the drug's duration of action. By determining the optimal combination of fatty acids and linkers, while maintaining the efficacy of the GLP-1 receptor (GLP-1R), the binding capacity to albumin was maximized [7].
Drug Application: GLP-1 is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a relatively long elimination half-life, allowing for once-weekly subcutaneous injection. In patients with type 2 diabetes (T2DM), the weight loss effect of once-weekly subcutaneous injection of GLP-1 is superior to that of other once-weekly GLP-1RAs. In a phase II dose-exploration trial for obese patients without T2DM, once-daily subcutaneous injection of GLP-1 showed a better weight loss effect than placebo and once-daily 3.0 mg liraglutide. The degree of weight loss caused by GLP-1 in this study exceeded the standards for weight loss drugs set by the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), and it is safe, indicating that once-daily subcutaneous injection of GLP-1 has the potential to become a future weight loss drug [8].
Treatment of Cardiovascular Diseases by Improving Cardiac Function: The results of the STEP-HFpEF trial showed that high-dose antidiabetic glucagon-like peptide 1 agonist GLP-1 significantly improved the symptoms related to heart failure with preserved ejection fraction (HFpEF) and reduced the level of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Research tests have found that acute treatment with GLP-1 can increase the tension of human atrial trabeculae by more than three times in a dose-dependent manner, without an increased tendency for arrhythmia. This effect may be due to an increase in the uptake of Ca2+ by the sarcoplasmic reticulum. Treatment with high-dose GLP-1 in patients with heart failure can improve atrial function, thereby relieving symptoms [9].
GLP-1 is under investigation for the treatment of non-alcoholic steatohepatitis (NASH): The rational design of GLP-1 has made great contributions to improving blood glucose control, body weight, blood pressure, blood lipids, β-cell function, and the cardiovascular system in patients with type 2 diabetes. In addition, the development of an oral formulation of GLP-1 may provide an additional advantage in terms of patients' treatment compliance [7].
What are the differences in the weight loss effects of GLP-1 among different populations?
Adults with pre-existing cardiovascular diseases, overweight or obesity but without diabetes: In the SELECT cardiovascular outcomes trial, GLP-1 reduced major adverse cardiovascular events by 20% in 17,604 adults with pre-existing cardiovascular diseases, overweight or obesity, and without diabetes [10](Ryan D H, 2024). In this pre-specified analysis, researchers examined the effects of GLP-1 on body weight, anthropometric outcomes, safety, and tolerability according to the baseline body mass index (BMI). Patients receiving GLP-1 experienced a continuous decrease in body weight within 65 weeks, lasting up to 4 years. At 208 weeks, compared with the placebo group, GLP-1 led to an average reduction in body weight (-10.2%), waist circumference (-7.7 cm), and waist-to-height ratio (-6.9%), while the placebo group had reductions of (-1.5%, -1.3 cm, and -1.0%) respectively, and all comparisons with the placebo were statistically significant. Clinically meaningful weight loss occurred in both men and women, all ethnic groups, body types, and regions. GLP-1 was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40, and ≥40 kg/m²), the incidence of serious adverse events of GLP-1 (number of events observed per 100 person-years) was lower (43.23, 43.54, 51.07, and 47.06 for GLP-1, and 50.48, 49.66, 52.73, and 60.85 for the placebo). GLP-1 was associated with an increased rate of discontinuation of the trial product. As the BMI category decreased, the discontinuation rate increased. In the SELECT trial, at 208 weeks, GLP-1 produced significant clinical weight loss and improvements in anthropometric values compared with the placebo, and the weight loss persisted for 4 years.
Individuals who are obese or overweight but without diabetes: A systematic review evaluated the efficacy and safety of GLP-1 in individuals who are obese or overweight but without diabetes[11]. This review synthesized the results of multiple clinical trials, emphasizing the effects of GLP-1 on weight loss, metabolic parameters, and overall health outcomes. The results showed that GLP-1 was associated with significant weight loss and improvements in obesity-related health indicators, and it may be a valuable treatment option for obese patients.
Non-diabetic patients (evidence from multiple RCTs): In 4 randomized controlled trials, patients with a baseline body weight of 96 to 105 kg received weekly subcutaneous injection of 2.4 mg of GLP-1 and lifestyle interventions (counseling, diet, and physical activity) for weight loss treatment. One randomized controlled trial for non-diabetic patients (N = 1961) showed that after 68 weeks, the average weight loss was 15% (15 kg), which was statistically significantly different from the 2% (3 kg) in the placebo group. The proportion of patients with a weight loss of ≥5% was 86% compared with 32% in the placebo group, and the number needed to treat (NNT) = 2; the proportion of patients with a weight loss of ≥10% was 69% compared with 12% in the placebo group, and NNT = 2. The weight loss leveled off at about 60 weeks. The incidence of gastrointestinal adverse events (AEs) was 74% compared with 48% in the placebo group, and the number needed to harm (NNH) = 3. The proportion of patients discontinuing the treatment due to adverse events was 7% compared with 3% in the placebo group, and NNH = 25. In another randomized controlled trial with intensive lifestyle intervention (N = 611), the weight loss in the GLP-1 group was 16% (17 kg), which was statistically significantly different from the 6% (6 kg) in the placebo group. In a dose-exploration randomized controlled trial for diabetic patients (N = 1210), patients were given weekly 2.4 mg of GLP-1, weekly 1.0 mg of GLP-1, or placebo. After 68 weeks, the average weight losses were 10% (2.4 mg), 7% (1.0 mg), and 3% (placebo) respectively. The proportion of patients with a weight loss of ≥5% was 69% (2.4 mg), 57% (1.0 mg) compared with 29% in the placebo group. For the 2.4 mg and 1.0 mg doses, NNT = 9. The adverse events were similar among different doses. In a weight maintenance randomized controlled trial (N = 803), non-diabetic participants received weekly treatment with 2.4 mg of GLP-1 for 20 weeks, and then were randomly divided into a group continuing GLP-1 treatment or a placebo group. After 48 weeks, the group continuing GLP-1 treatment lost 8% of their body weight, while the placebo group gained 7% of their body weight.
In conclusion, GLP-1 is a GLP-1 receptor agonist drug with application value in multiple fields. In the field of diabetes treatment, it effectively controls blood glucose levels by binding to GLP-1 receptors, promoting insulin secretion, and inhibiting glucagon release, providing an important treatment option for patients with type 2 diabetes. In the aspect of obesity treatment, GLP-1 significantly reduces energy intake through mechanisms such as central appetite suppression and delayed gastric emptying, helping obese patients lose weight and improve their metabolic status. In addition, GLP-1 also shows potential application prospects in the prevention and treatment of cardiovascular diseases. Its improvement of cardiovascular risk factors provides a new approach to reducing the incidence of cardiovascular events.
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 [9].
