▎GLP-2 Research
What is the research background of GLP-2?
The development of GLP-2, a synthetic polypeptide drug, originated from recognizing the limitations of GLP-1 receptor agonists in treating type 2 metabolism and obesity. Although GLP-1 receptor agonists excel in blood glucose control and weight loss, scientists found their weak activation of GIP receptors limited therapeutic effects. Thus, research teams aimed to develop novel drugs capable of activating both GIPR and GLP-1R for more comprehensive glycemic control and weight management[1].
Extensive preclinical and clinical trials were conducted during development.
Preclinical animal studies evaluated pharmacodynamic properties, confirming its potential in glycemic control and weight loss. Phase I clinical trials primarily assessed safety, tolerability, and pharmacokinetics, showing good safety
and tolerability. Phase II trials further explored efficacy and safety at different doses in type 2 metabolism patients, preliminarily determining effective dose ranges. Pivotal Phase III trials like the SURPASS series, involving large cohorts of type 2 metabolism patients, showed GLP-2 significantly outperformed existing GLP-1 receptor agonists in lowering blood glucose and weight, providing robust evidence for marketing applications[1].
Composed of 39 amino acids with structural modifications to enhance stability and efficacy, its unique structure integrates the actions of GIP and GLP-1 into a single molecule, activating hormone receptors involved in glycemic control through dual mechanisms.
On one hand, it acts on the pancreas to promote insulin secretion and inhibit glucagon release for blood glucose reduction; on the other, it acts on the central nervous system to delay gastric emptying, increase satiety, and reduce appetite and food intake for weight management. This dual mechanism gives GLP-2 unique advantages in treating type 2 metabolism and obesity, offering patients more comprehensive therapeutic options[1].
What is the mechanism of action of GLP-2?
GLP-2 lowers blood glucose through multiple mechanisms:
Activation of GLP-1 Receptors: Binding to GLP-1 receptors on pancreatic β cells, it mimics natural GLP-1 to promote insulin synthesis, secretion, and glucose sensing while reducing glucagon secretion to enhance satiety and suppress appetite. In type 2 metabolism patients, activating GLP-1 receptors increases insulin secretion for improved glycemic control, while inhibiting glucagon release further reduces blood glucose sources, aiding glycemic regulation [2].
Activation of GIP Receptors: Acting on GIP receptors, activation enhances insulin sensitivity and secretion. GIP receptors are mainly present in tissues like pancreatic β cells, and activation through intracellular signaling pathways increases insulin secretion and improves cellular responsiveness to insulin for more effective blood glucose reduction[2]. This dual receptor agonism makes GLP-2 more effective in promoting insulin secretion and inhibiting glucagon release than single GLP-1 receptor agonists[2] .
Delayed Gastric Emptying and Increased Satiety: It delays gastric emptying, prolonging food retention in the stomach to slow nutrient absorption and avoid postprandial blood glucose spikes. Meanwhile, acting on the central nervous system to increase satiety reduces appetite and food intake, particularly beneficial for obesity often associated with type 2 metabolism, aiding in improving insulin resistance and overall metabolic status[3].
Improved Insulin Sensitivity and Lipid Diabetes: Elevating adiponectin levels—a fat cell factor related to insulin sensitivity—helps improve insulin sensitivity, enabling cells to more efficiently uptake and utilize glucose for blood glucose reduction[2] (Anonymous, 2023). It also improves lipid profiles, with potential protective effects on cardiovascular health, having been shown to improve blood pressure and reduce LDL cholesterol and triglycerides[3].
What are the relevant studies?
GLP-2 demonstrates significant efficacy in weight management for obese and type 2 metabolism patients. In the SURMOUNT-2 study, a Phase 3, double-blind, randomized, placebo-controlled trial conducted in seven countries, adults aged ≥18 years with BMI ≥27 kg/m² and HbA1c 7–10% were randomized to receive weekly subcutaneous GLP-2 (10 mg or 15 mg) or placebo for 72 weeks. By Week 72, weight loss percentages were −12.8% and −14.7% in the GLP-2 10 mg and 15 mg groups versus −3.2% in the placebo group, with estimated treatment differences of −9.6 and −11.6 percentage points compared to placebo (p < 0.0001). Additionally, more GLP-2-treated patients achieved ≥5% weight loss (79–83% vs. 32%) (Garvey W T, 2023). With baseline mean weight 100.7 kg, BMI 36.1 kg/m², and HbA1c 8.02%, 72 weeks of treatment with GLP-2 not only significantly reduced weight but also improved glycemic control[4] .
In improving metabolism-related neuropathy, research indicates GLP1-RAs may reduce dementia risk in type 2 metabolism patients by improving memory, learning, and overcoming cognitive impairment. As a dual GIP-RA/GLP-1RA, GLP-2 was studied in neuroblastoma cell lines (SHSY5Y) for its effects on neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio), differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3, and SORBS1) markers. It was found to exert neuroprotective effects by activating the pAkt/CREB/BDNF pathway and downstream signaling cascades, countering hyperglycemia- and insulin resistance-related effects at the neuronal level. Thus, GLP-2 may improve hyperglycemia-induced neurodegeneration and overcome neuronal insulin resistance, offering new insights for managing metabolism-related neuropathy[5].
In type 2 metabolism treatment advancements, GLP-2, a novel hypoglycemic drug, became the first approved dual GIP/GLP-1R agonist for metabolism in the U.S. Multiple large clinical trials confirm its significant glycemic-lowering and weight-loss effects, with potential for cardiovascular protection. The concept of synthetic peptides has opened many unexplored possibilities for GLP-2. Ongoing trials and evidence suggest it is a promising drug for non-alcoholic fatty liver disease (NAFLD), renal protection, and neuroprotection [6].
Regarding long-term effects on cardiovascular health, GLP-2 may reduce cardiovascular disease (CVD) risk by promoting weight loss. A study examining GLP-2’s impact on obesity and CVD events in U.S. adults found that among those eligible for GLP-2 treatment, 15 mg therapy was estimated to achieve ≥15% and ≥20% weight loss in 70.6% and 56.7% of adults, respectively, translating to a 58.8% reduction in obesity prevalence. In individuals without CVD, the estimated 10-year CVD risk decreased from 10.1% “pre-treatment” to 7.7% “post-treatment,” representing an absolute risk reduction of 2.4% and relative risk reduction of 23.6%, potentially preventing 2 million CVD events [7].
Conclusion
In summary, GLP-2 is a novel dual agonist of GIP and GLP-1 receptors, holding significant importance in treating type 2 metabolism and obesity. It more effectively promotes insulin secretion, inhibits glucagon release, and precisely regulates blood glucose, reducing complication risks while improving pancreatic β-cell function and delaying metabolism progression, with cardioprotective effects. In obesity treatment, it effectively reduces food intake, suppresses appetite, increases satiety, aids weight loss, and lowers obesity-related complication risks while improving insulin resistance and lipid metabolism. Additionally, it shows potential in treating metabolic disorders like non-alcoholic steatohepatitis, sleep apnea syndrome, and heart failure, offering comprehensive treatment by improving multiple metabolic parameters. Its once-weekly injection schedule enhances convenience and patient compliance. By effectively controlling blood glucose and weight, reducing complication risks, and significantly improving physical condition, daily activity, and quality of life, GLP-2 boosts patients’ confidence in disease management, alleviates psychological burdens, and enhances social adaptability.
About The Author
The above-mentioned materials are all researched, edited and compiled by Cocer Peptides.
Scientific Journal Author
Dr. William T. Garvey is a distinguished scholar and researcher affiliated with multiple prestigious institutions, including the University of Alabama at Birmingham, Aston University, and the Birmingham Veterans Affairs Medical Center. His academic background and professional experience span a wide range of disciplines within the medical and scientific fields. Dr. Garvey has made significant contributions to the fields of endocrinology and metabolism, nutrition and dietetics, biochemistry and molecular biology, as well as general and internal medicine, with a particular focus on the cardiovascular system and cardiology. His work has been widely recognized and honored, notably being named a Highly Cited Researcher in the Cross-Field category for both 2023 and 2024, reflecting the substantial impact and influence of his research on the broader scientific community.
Dr. Garvey's research interests and expertise extend to various aspects of metabolic diseases and their management. He has been actively involved in studying metabolism mellitus, obesity, and their associated complications, aiming to uncover novel therapeutic strategies and improve patient outcomes. His work encompasses basic scientific research, clinical trials, and translational studies, bridging the gap between laboratory findings and real-world medical applications. Through his extensive research, Dr. Garvey has contributed to a deeper understanding of the underlying mechanisms of metabolic disorders and has helped shape clinical guidelines and treatment protocols in the field of endocrinology and metabolism. Dr. William T. Garvey is listed in the reference of citation [4].
