It has been a century since Banting et al. discovered and purified insulin in 1922. Although mankind's struggle with diabetes has never stopped, and therapeutic drugs have been expanded and upgraded, diabetes continues to rage and proliferate wildly around the world and has developed into one of the four major chronic diseases worldwide.
Diabetes is spiraling out of control
The IDF Diabetes Atlas 10th edition reports a continued global increase in diabetes prevalence. In 2021, approximately 537 million adults (aged 20-79 years) worldwide are living with diabetes, accounting for 1 in 10 of the total adult population. This number is predicted to rise to 643 million by 2030 and 783 million by 2045.
Excluding the impact of the novel coronavirus, about 6.7 million adults dead from diabetes in 2021, an average of 1 diabetic death every 5 seconds.
Diabetes around the world, image source: http://diabetesatlas.org/
Antidiabetic Drugs Classification
Over the 100 years since humans used animal insulin to treat diabetes in 1922, about nine major classes of antidiabetic drugs have been developed worldwide, including sulfonylureas, biguanides, alpha-glucosidase inhibitors, insulins, thiazolidinediones (TZDs), meglitinides , GLP-1 agonists, DPP-IV inhibitors, and SGLT-2 inhibitors.
Among these nine classes of antidiabetic drugs, insulin has been around for a century, but it causes weight gain in patients and has a risk of hypoglycemia, thus its market size has been declining. Of the traditional oral medications, metformin, an entry-level product in the early stages of diabetes, is typically used in combination with other antidiabetic drugs except in the early stages of diabetes. Sulfonylureas and meglitinides have adverse effects of hypoglycemia and weight gain; α-glucosidase inhibitors lower glycosylated hemoglobin to a lesser extent; TZDS have side effects of weight gain; SGLT2 inhibitors tend to cause urinary infections. A summary of the antidiabetic drug classifications is shown in the table below.
|Method of Administration||Class||Reduction of HbA1c||Side effects|
|Injectable drugs||Insulins||~~||• Weight gain
• Blood sugar that drops too low, or hypoglycemia
• Rashes, bumps, or swelling at an injection site
|GLP-1 agonists||~~||• Nausea
• Increased risk of pancreatitis and possibly pancreatic cancer
|Oral drugs||Biguanide||0.7%~1.0%||• Lactic acidosis
• Weight loss
• Gastrointestinal complaints are common (e.g. diarrhea, abdominal cramps)
• Reduced vitamin B12 absorption
|Alpha-glucosidase inhibitors||0.50%||• Gastrointestinal complaints (flatulence, diarrhea, feeling of satiety)|
|Sulfonylureas||1%~1.5%||• Risk of hypoglycemia
• Weight gain
• Hematological changes: agranulocytosis, hemolysis
|Meglitinides||0.5%~1.5%||• Weight gain
• Risk of hypoglycemia
|Thiazolidinediones||0.7%~1.0%||• Weight gain
• Cardiac failure
• Increased risk of bone fractures (osteoporosis)
|DPP-4 inhibitors||0.4%~0.9%||• Gastrointestinal complaints
• Headache, dizziness
|SGLT-2 inhibitors||0.5%~1.0%||• Genital yeast infections and urinary tract infections
• Polyuria and dehydration
• Diabetic ketoacidosis
In 2020, insulin is nowhere to be found in the Top 20 global best-selling drugs list, replaced by GLP-1 receptor agonists, with $5.1 billion in sales of Eli Lilly's dulaglutide. This is closely followed by Novo Nordisk's semaglutide with sales of $3.5 billion and liraglutide with sales of $3.1 billion.
GLP-1 Receptor Agonists: Future Star
Looking at the current diverse selection of diabetes drugs, GLP-1 receptor agonists represent a relatively novel treatment that is not only effective in lowering glycosylated hemoglobin levels and reducing body weight, but has also been shown to have good cardiovascular outcomes and safety profiles, overcoming some of the shortcomings of traditional antidiabetic agents. Its performance in lowering glycosylated hemoglobin levels is extremely impressive among non-insulin products, and its longer half-life has allowed for once-a-week dosing and even longer periods.
The global GLP-1 drug market reached $13.1 billion in 2020, mainly held by Novo Nordisk and Eli Lilly, with a combined share of 95% by the two companies. In terms of segmentation, the market for long-acting GLP-1 drugs will expand rapidly in the future, with the global market for GLP-1 drugs expected to grow to $28.3 billion in 2025 and $40.7 billion in 2030.
Currently, there are 10 GLP RAs approved for diabetes treatment, including Exenatide, Liraglutide, Exenatide, Albiglutide, Dulaglutide, Lixisenatide, Beinaglutide, Semaglutide, Oral semaglutide, PEG-loxenatide. (More details: Overview of Long Acting GLP-1 Receptor Agonists)
In 2005, Exenatide was approved by FDA as a First-in-class GLP-1 drug. Exendin-4 is derived from giant lizards and has low similarity to human GLP-1, so it is easy to generate neutralizing antibodies. There is also no advantage in its dosing frequency, which limits the patient compliance and market expansion of the drug.
According to the data of global best-selling drugs, dulaglutide continues to dominate the GLP-1 receptor agonist market with sales of $5.068 billion in 2020, an increase of 23% over the same period of the previous year. Semaglutide sales were $3.543 billion, a rise of 88.8%, and liraglutide sales were $2.867 billion. Exenatide sales were $448 million, a decline of 18%.
Pipelines of GLP-1 RAs
Currently, there are several GLP-1RA drugs in the global pipeline, mainly in a long-acting form.
|Drug Type||Drug Name||Company||Phase||First Posted|
|Long-Acting GLP-1 RAs||Efpeglenatide||Hanmi Pharmaceutical||Ⅲ||27 Nov, 2017|
|Tirzepatide||Eli Lilly||Ⅲ||5 Nov, 2018|
|PB-119||PegBio||Ⅲ||7 Aug, 2020|
|BI 456906||Boehringer Ingelheim||Ⅱ||6 Nov, 2019|
|IBI362||Innovent Bio||Ⅰ/Ⅱ||10 Jul, 2020|
|HS-20004||Haosen Pharmaceutical||Ⅱ||12 Feb, 2019|
|LY3437943||Eli Lilly||Ⅱ||30 Apr, 2021|
|XW003||Sciwind Biosciences||Ⅱ||15 Mar, 2020|
There are many long-acting technologies that can extend the half-life of GLP-1 RAs. By connecting PEG derivatives to related GLP-1 drugs, the molecular weight of the drug can be increased, so that it is not easily degraded and filtered out by the kidney, thereby prolonging the effective concentration time of the drug in the body.
Biopharma PEG, a leading PEG derivatives supplier, has 3000+ PEG linkers in stock to empower your advanced research and drug development. These PEG derivatives are water-soluble, monodisperse, biocompatible, and almost aggregation-free, making them ideal for bioconjugation or crosslinking of proteins, antibodies, peptides, oligonucleotides, or solid surfaces to other macromolecules, therapeutic compounds or other small molecules, and dyes.
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