SanyouBio Express| Lower Blood Sugar and Lose Weight, Learn about GLP-1
Diabetes is categorized into four types: type 1 diabetes, type 2 diabetes, gestational diabetes, and specific types of diabetes caused by other factors. Type 1 diabetes, also known as insulin-dependent diabetes, is caused by genetic and environmental triggers that lead to autoimmune damage to pancreatic β-cells. The resulting decrease in insulin production and absolute insulin deficiency in the body leads to sustained high blood glucose levels and the development of diabetes. Type 1 diabetes accounts for less than 10% of total diabetes patients, while type 2 diabetes is the most common type of diabetes. Insulin resistance or insufficient insulin secretion induced by various triggers, including genetic factors, obesity, lack of exercise, and a high-fat diet, causes clinical symptoms due to glucose metabolic disturbance and results in type 2 diabetes. High blood sugar levels can result in various complications, including but not limited to diabetic retinopathy, peripheral neuropathy, cardiovascular and cerebrovascular diseases, renal failure, diabetic foot, and other related conditions.
Obesity is a chronic metabolic disease characterized by an excessive total body fat content and/or a localized increase in fat content and abnormal distribution, mainly caused by multiple factors such as genetics, dietary habits, lifestyle, psychology, and environment. Individuals with a body mass index (BMI) between 25.0-29.9 are considered overweight, while those with a BMI over 30.0 (BMI=weight/kg/height2/m2) are classified as obese, according to the World Health Organization (WHO). Being overweight and obese is associated with increased risks of various diseases, such as endocrine disorders, lipid metabolism disorders, cerebrovascular diseases, hypertension, cardiac load, fatty liver, diabetes, tumors, and bone and joint conditions.
Type 2 diabetes and obesity are the most significant metabolic diseases threatening human health. According to reports from the International Diabetes Federation (IDF) and the World Health Organization (WHO), there are currently approximately 537 million adults worldwide with diabetes and over one billion people with obesity (including 650 million adults, 340 million adolescents, and nearly 40 million children with obesity).
According to the Informa database (Figure 1), there are currently 165 marketed drugs for type 2 diabetes worldwide, mainly including glucagon-like peptide-1 (GLP-1) analogs and insulin and its analogs, with many drugs in clinical and preclinical stages of development. The main research targets for type 2 diabetes are the glucagon-like peptide-1 receptor (GLP-1R), insulin receptor (INSR), and dipeptidyl peptidase-4 (DPP-4) (Figure 2). In comparison, there are few marketed drugs for the treatment of obesity. The glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR), and glucose-dependent insulinotropic polypeptide receptor (GIPR) are the most popular targets for therapeutic drug discovery for obesity (Figure 3). Therefore, GLP-1R, GCGR, and GIPR are currently the most promising targets for the therapeutic drug discovery of both diabetes and obesity.
The market and prospects of GLP-1 drugs
In 2022, the total sales of diabetes drugs were approximately $60 billion. The GLP-1 market is growing rapidly, with sales reaching $22.6 billion in 2022, accounting for nearly 38% of the hypoglycemic drug market. This scale far exceeds insulin's $15.3 billion, making it the most significant driving force in the current diabetes market (Table 1). Moreover, GLP-1 drugs have substantial effects in the clinical treatment of obesity and are being explored for the treatment of non-alcoholic fatty liver, Alzheimer's disease, and other diseases, indicating broad prospects.
The Mechanism of Action of GLP-1
Glucagon-like peptide-1 (GLP-1) is a natural incretin hormone composed of 37 amino acids. It is primarily secreted by L cells in the intestines. Natural GLP-1 can stimulate insulin secretion by pancreatic beta cells and regulate blood glucose balance in the human body while inhibiting the generation and secretion of glucagon.
GLP-1 exists in two active forms in the human body: GLP-1 (7-36) and GLP-1 (7-37), with the former being more abundant. Due to the easy recognition of alanine at the eighth position of GLP-1 by DPP-4, it is degraded into inactive GLP-1 (9-36) and quickly cleared by the kidneys, resulting in a very short half-life.
GLP-1R, which belong to the seven-transmembrane G protein-coupled receptor family, are primarily bound by GLP-1 and located on specific tissues. These receptors are widely distributed in organs such as the pancreas, lungs, heart, kidneys, stomach, and intestines (Figure 4). The N-terminal extracellular domain of GLP-1R is closely associated with GLP-1 binding, while the third intracellular loop is crucial in regulating intracellular signaling pathways.
When GLP-1 binds to GLP-1R on pancreatic beta cells, it activates adenylate cyclase activity and increases the production of intracellular second messenger cAMP. This, in turn, triggers the cAMP-dependent PKA signaling pathway, which closes ATP-dependent K+ channels, depolarizes the cell membrane, and activates voltage-dependent Ca2+ channels. This process causes Ca2+ influx and generates an action potential, or releases Ca2+ through the activation of inositol triphosphate (IP3), ultimately leading to an increase in intracellular Ca2+ concentration. The increase in intracellular Ca2+ concentration then triggers insulin exocytosis [5, 9].
Comparison of GLP-1 representative drugs
Among the top 10 diabetes drugs with the highest sales in 2022, Novo Nordisk's GLP-1 analog Semaglutide ranked first, followed by Eli Lilly's dulaglutide, far exceeding insulin and its analogs (Table 2).
In the GLP-1 market, Novo Nordisk and Eli Lilly are the two major companies competing fiercely, making it difficult to distinguish between them. In 2009, Novo Nordisk launched the short-acting peptide liraglutide. Then in 2014, Eli Lilly launched dulaglutide, which had significantly better glucose-lowering effects than liraglutide and had a higher frequency of use per week than liraglutide's usage per day. Not to be outdone, Novo Nordisk modified liraglutide and launched Semaglutide in 2017, which became a sensation overnight due to its unique weight loss effect, with sales reaching nearly $10.9 billion in 2022. Eli Lilly then launched the GIPR/GLP-1R dual-target agonist Tirzepatide in 2022, which garnered sales of $483 million within nine months of its launch (Table 2).
Semaglutide shares a homology of 94% with the GLP-1 sequence (see Figure 5) and is resistant to DPP-4 degradation due to substituting the 8th amino acid of GLP-1 with α-amino isobutyric acid. Also, lysine at position 26 is linked to a C18 fatty acid side chain via a spacer, which enhances its binding to albumin. The substitution of arginine at position 34 with lysine prevents the C18 fatty acid from binding in the incorrect position. Modifications made to liraglutide have significantly extended the half-life of Semaglutide to one week.
Semaglutide binds and activates the intracellular signaling pathways mediated by GLP-1R, which promotes insulin secretion, inhibits glucagon secretion, and delays gastric emptying. It achieves dual effects of hypoglycemia and weight reduction. In addition, it lowers the risk of major cardiovascular events (MACE) in patients with type 2 diabetes and is one of the most successful GLP-1 drugs currently available.
Tirzepatide is a peptide made up of 39 amino acids with a fatty acid attached at position 20 and bound to albumin to make it last longer in the body. It binds strongly to both GIPR and GLP-1R ( Figure 5). In clinical trials for type 2 diabetes, Tirzepatide was found to be more effective than Semaglutide in lowering blood sugar levels (see Figure 6). Semaglutide reduced body weight by 15% in clinical trials for obesity after 68 weeks of treatment (Figure 7). However, Tirzepatide's high-dose group achieved a 22.5% reduction in body weight after 72 weeks of treatment, which was significantly more effective than Semaglutide. Therefore, Tirzepatide is currently Semaglutide's main competitor.
Potential rising stars in the GLP-1 drug market
Apart from the GLP-1 analogs discussed above, other innovative multi-target molecules are undergoing rigorous testing in clinical trials.
Recommended by LinkedIn
One such molecule is AMG133, developed by Amgen, an antibody-peptide conjugate that links the GLP-1 peptide to the heavy chain of a GIPR antibody. This compound inhibits GIPR while activating the GLP-1R-mediated intracellular signaling pathway. Phase I clinical trials demonstrated excellent weight loss efficacy, with a weight loss of -14.52% in the high-dose group compared to +1.49% in the placebo group after only 12 weeks of treatment. Additionally, AMG133 considerably extended the dosing interval to once every four weeks, and its Phase II clinical trial is currently enrolling participants. Notably, both AMG133 and Tirzepatide are dual-target drugs that target both GIPR and GLP-1R, but they employ different mechanisms because the mechanism of action of GIP is unclear. Further research and observation are necessary to determine the clinical efficacy of GIP-targeted drugs.
Mazdutide (IBI362), a GLP-1R/GCGR dual agonist jointly developed by Innovent Biologics and Eli Lilly, has entered Phase III clinical trials. Based on GCG as a pro-catabolic hormone, it uses GCG to increase energy consumption while suppressing appetite through GLP-1, thereby achieving better weight loss results. Its Phase II clinical trial data showed that continuous use of 6.0mg Mazdutide for 24 weeks resulted in an 11.57% decrease in weight. Compared to a placebo, it can bring about a weight reduction of 12.6%, which exceeds the injection effect of Semaglutide for 68 weeks. Lilly's Retatrutide, a GLP-1R/GCGR/GIPR triple agonist, has completed Phase II clinical trials. Hengrui Medicine's GMA-106, a GLP-1R/GIPR bispecific antibody, is currently in Phase I clinical trials, with the dosing frequency expected to be extended to once every 2 or 4 weeks. Additionally, the development of single-target/bispecific/triple-target drugs targeting GLP-1R, GCGR, and GIPR is unstoppable and is also being laid out in clinical trials (Figure 9).
Summary
In conclusion, the continuous accumulation of adverse effects from contemporary lifestyles and dietary structures on the human body has led to a rise in the number of patients with diabetes and obesity. The impressive therapeutic effects of Semaglutide and Tirzepatide in treating type 2 diabetes and obesity have also pushed the GLP-1 market to a climax in drug development, with the development of single/multi-target agonists targeting GLP-1R, GIPR, GCGR, FGF21 (fibroblast growth factor 21), DDP-4, and other related targets. The molecular form of drugs is not limited to peptide drugs, and innovative molecular forms such as antibody-peptide conjugates and bispecific antibodies have entered clinical trials. While breakthroughs in treating diabetes and obesity are expected to benefit many patients, adjusting unhealthy lifestyles and dietary structures is the fundamental premise for controlling blood sugar and maintaining a stable weight.
SanyouBio's multi-trillion phage-display peptide library platform:
Based on a super trillion-molecule discovery platform verified by more than 600 projects, SanyouBiol has independently developed a phage-display peptide library with a capacity of up to 1.21E+12 trillion (a single-ring peptide library of 4-17 amino acids) and will soon launch exclusive screening and drug development services for peptide libraries. The platform offers:
1. Unique peptide molecules with sequence obtained in just 3 weeks;
2. Integrated service for peptide drug screening and in vitro and in vivo pharmacological evaluation;
3. Exclusive access to multi-target peptide platform screening services.
We welcome everyone to inquire and make an appointment.
About SanyouBio
Sanyou Biopharmaceuticals Co., Ltd. is a world-leading biotechnology and high-tech enterprise focusing on innovative antibody drug research and development (R&D) and services. The company is committed to establishing a leading, high-quality, high-throughput, and integrated R&D and value transformation platform for innovative antibody drugs internationally. It aims to construct a business ecosystem that involves therapy, R&D, and diagnostic products and services. SanyouBio also collaborates with global biopharmaceutical, diagnostic, and drug R&D companies to make new progress in diagnosing and treating human diseases.
SanyouBio has established an integrated, innovative antibody drug R&D laboratory that covers over 20,000 square meters and has advanced facilities. The laboratory has a range of advanced technologies called super-trillion phage technologies, consisting of over 40 innovative core technological platforms. These platforms exhibit antibody libraries and integrated systems that cover various aspects of antibody drug development, such as creative discovery, optimization, production cell line construction, upstream and downstream process development, preclinical research and development, and industrial development. SanyouBio has built a business system that integrates "differentiated CRO, innovative CPO, and characteristic CRS." The company continues to launch new technologies, products, services, and scenarios with "the best quality, the fastest speed, and the highest cost performance." Additionally, SanyouBio has established friendly business cooperation relations with more than 400 pharmaceutical companies, drug R&D institutions, and diagnostic reagent and product companies worldwide.
Reference:
1. Navarria A, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6(4):275-86.
2. Bergman BK, et al. Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. N Engl J Med. 2021;385(6):503-15.
3. Juan P. Frías, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2021
4. John P.H. Wilding, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021
5. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007 May;132(6):2131-57. doi: 10.1053/j.gastro.2007.03.054. PMID: 17498508.
7. Wang L. Designing a Dual GLP-1R/GIPR Agonist from Tirzepatide: Comparing Residues Between Tirzepatide, GLP-1, and GIP. Drug Des Devel Ther. 2022 May 25;16:1547-1559. doi: 10.2147/DDDT.S358989.
8. Kalra S, Sahay R. A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus. Diabetes Ther. 2020 Sep;11(9):1965-1982. doi: 10.1007/s13300-020-00894-y. Epub 2020 Jul 28.
9. Zhao X, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne). 2021 Aug 23;12:721135. doi: 10.3389/fendo.2021.721135.