Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells after eating. It lowers blood glucose levels by increasing insulin secretion and inhibiting glucagon (GCG) release which prolong gastric emptying and reduce calorie intake. Since GLP-1 increases insulin release only when blood sugar levels are high, it does not cause hypoglycemia.

GLP-1 receptors (GLP-1R) are distributed across various organs in the human body. When GLP-1 binds to GLP-1R, it has several effects, including reducing appetite, promoting insulin secretion, delaying gastric emptying, increasing glucose uptake in skeletal muscle, and enhancing glycogen storage in the liver, etc.

Figure 1. Reported pleiotropic effects of GLP-1 or GLP-1 receptor agonists on various tissues and organs under experimental conditions. [1]

Native GLP-1 is a peptide chain composed of 31 amino acids and has a very short half-life in the body, about 2 minutes, before it is degraded by the enzyme DPP-4. To improve its resistance to DPP-4 and extend its half-life, GLP-1 analogs have been developed by optimizing and modifying the amino acid structure of GLP-1. GLP-1 analogs and other drugs that target and activate GLP-1 receptors are collectively known as GLP-1 receptor agonists (GLP-1RAs).

The FDA has approved a total of 9 GLP-1RAs, with approved indications including type 2 diabetes and weight loss. Other potential indications under investigation include metabolic dysfunction-associated steatohepatitis (MASH/NASH) and cardiovascular diseases. Among the marketed products, the most recently approved is tirzepatide, a dual GIP/GLP-1 RA, while the others are single agonists. Trzepatide has experienced rapid growth since its approval, generating nearly $500 million in its first year. In 2023, sales of Mounjaro reached $5.163 billion, a 970% increase, far surpassing the initial performance of semaglutide, which had sales of $286 million in 2018 and $1.686 billion in 2019, a 490% increase. After the approval for the weight loss indication, Zepbound achieved $176 million in revenue in less than two months on the market. The success of tirzepatide has made GLP-1 dual/triple agonists a hot area of competition.

Table 1. FDA approved GLP-1 RAs

Dual/Triple GLP-1 RAs

Currently, most multi receptor agonists under development worldwide are focused on dual GLP-1/GIP RAs, dual GLP-1R/GCG RAs, and triple GLP-1R/GIPR/GCGR RAs. Tirzepatide is the first and only dual GLP-1/GIP RA received FDA approval. The advantage of dual/triple agonists lies in their ability to activate multiple signaling pathways in the body simultaneously, leading to better glucose-lowering effects while reducing side effects.

GLP-1R/GIPR Dual Agonists

GIP (Glucose-dependent insulinotropic polypeptide) was the first incretin discovered. In healthy individuals, the incretin effect stimulates insulin secretion, accounting for about 70% of total insulin secretion, with GIP contributing two-thirds of this effect, which is higher than that of GLP-1. In the presence of elevated blood glucose levels, GIP can increase the levels of cyclic adenosine monophosphate (cAMP) in β-cells, promoting glucose-dependent insulin secretion. Therefore, GIP receptor agonists are an important supplement to glucose-lowering therapies.

Tirzepatide

Tirzepatide is a drug made up of 39 amino acids, created by fusing and modifying the structures of GIP and GLP-1. It is amidated at the C- terminal and conjugates a C20 fatty diacid attached to Lys20 in the GIP structure. Additionally, the substitution of arginine at positions 2 and 13 with 2-aminoisobutyric acid (Aib) increases its resistance to DPP-4 and enhances its ability to bind to albumin, thereby improving its stability and half-life.

Figure 2. Tirzepatide Structure

Tirzepatide has an uneven affinity for its two targets; its affinity for GIPR is similar to that of native GIP, while its affinity for GLP-1R is about five times weaker than that of native GLP-1.

Tirzepatide (Mounjaro) was approved by the FDA in May 2022 for use in combination with diet and exercise to improve blood sugar control in adults with type 2 diabetes. In November 2023, tirzepatide (Zepbound) received another FDA approval for helping adults who are obese or overweight to lose weight and maintain weight loss.

In addition to its glucose-lowering and weight-loss effects, tirzepatide is currently undergoing Phase 3 or 4 clinical trials for other conditions, including obesity with osteoarthritis, atherosclerosis in T2DM patients, lipid metabolism and brain function in T2DM patients, and obstructive sleep apnea. It is also being studied in Phase 2 clinical trials for major indications such as MASH and chronic kidney disease.

GLP-1R/GCGR Dual Agonists

Glucagon (GCG) is a 29-amino acid peptide that is proteolytically cleaved from proglucagon by the proprotein convertase PC2. It is primarily secreted  from pancreatic alpha cells and acts to increase blood glucose concentration by stimulating glycogen breakdown and activating gluconeogenesis within the liver. Additionally, glucagon stimulates insulin release from pancreatic β cells and suppresses further glucagon secretion from α cells, helping to prevent hyperglycemia.

Mazdutide

Mazdutide (IBI362), co-developed by Innovent Biologics and Eli Lilly, is a long-acting synthetic peptide similar to mammalian oxyntomodulin (OXM)  with a fatty acid side chain attached thereto. Mazdutide is thought to exert its biological effects by activating the GLP-1R and GCGR in human beings, which improves glucose tolerance and induces weight loss, mimicking the effects of endogenous OXM. 

Mazdutide achieved its primary endpoint and all key secondary endpoints in the first Phase III clinical study (GLORY-1) conducted in overweight or obese adults in China. In addition, the Phase III clinical study (DREAMS-1) for patients with type 2 diabetes was also successful, demonstrating significant benefits in lowering blood sugar and body weight, as well as improving cardiovascular and renal metabolic parameters.

On June 14, 2024, detailed data from the Phase III GLORY-1 trial of Mazdutide for the treatment of overweight and obesity were presented at the American Diabetes Association (ADA) Annual Meeting. In the GLORY-1 study, Mazdutide not only resulted in an average weight reduction of 11.58% to 14.37% among participants but also significantly lowered cardiovascular risk factors such as blood pressure, triglycerides, total cholesterol, LDL-C, and serum uric acid over the 48-week treatment period.

Figure 3. Primary endpoint and key secondary endpoints of GLORY-1 [2]

GLP-1/GIP/GCG Triple Agonists 

Given the metabolic regulatory effects of GLP-1, GCG, and GIP, and their distinct synergistic actions, several pharmaceutical companies have started developing GLP-1/GCG/GIP triple receptor agonists.

Retatrutide

Retatrutide (LY3437943) is a triple agonist (GLP-1R/GIPR/GCGR) developed by Eli Lilly, based on the GIP structure, and is composed of 39 amino acids. In terms of activity at the three targets, Retatrutide is 2.9 times less potent at activating GCGR compared to human glucagon, 8.9 times more potent at activating GIPR compared to GIP, and 2.5 times less potent at activating GLP-1R compared to GLP-1. Retatrutide is currently in Phase 3 clinical trials.

Data from a Phase 2 clinical trial (n=338), published in August 2023, showed that in obese patients, 48 weeks of treatment resulted in an average weight reduction of 22.8% in the 8 mg group and 24.2% in the 12 mg group. In another Phase 2 trial for T2DM patients, also published at the same time, Retatrutide was observed to improve fasting blood lipids in a dose-dependent manner after 36 weeks of treatment, with total cholesterol reduction reaching up to 16.67% and triglyceride reduction up to 35.02% in the 8 mg and 12 mg increasing dose groups. Both the weight loss and lipid improvement data were highly promising.

References:
[1] Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012 Dec;8(12):728-42. doi: 10.1038/nrendo.2012.140. Epub 2012 Sep 4. PMID: 22945360.
[2] LINONG JI, HONGWEI JIANG, HUA LI, JUNHANG TIAN, DEXUE LIU, YUZHU ZHAO, JIEYU GU, ZIHAN LIU, HUAN DENG, YANQI WANG, LI LI, LEI QIAN, THE GLORY-1 INVESTIGATORS; 1856-LB: Efficacy and Safety of Mazdutide in Chinese Participants with Overweight or Obesity (GLORY-1). Diabetes 14 June 2024; 73 (Supplement_1): 1856–LB. https://doi.org/10.2337/db24-1856-LB
[3] Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023 Aug 10;389(6):514-526. doi: 10.1056/NEJMoa2301972. Epub 2023 Jun 26. PMID: 37366315.
[4] Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, Thomas MK, Hartman ML, Haupt A, Milicevic Z, Coskun T. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023 Aug 12;402(10401):529-544. doi: 10.1016/S0140-6736(23)01053-X. Epub 2023 Jun 26. PMID: 37385280.