Ritadex is a 39-amino acid polypeptide drug that belongs to the triple receptor agonists of GLP-1R/GIPR/GCGR. Its design inspiration comes from endogenous incretin hormones (such as GIP), and through structural optimization, it can simultaneously activate the following three receptors: GLP-1 receptor (GLP-1R): promoting insulin secretion, inhibiting glucagon release, delaying gastric emptying, and enhancing satiety; GIP receptor (GIPR): enhancing insulin sensitivity, regulating lipid metabolism, and possibly synergizing with GLP-1R to enhance weight loss effects; glucagon receptor (GCGR): promoting energy expenditure, enhancing inhibition of hepatic gluconeogenesis, and reducing liver fat deposition.

This multi-target synergistic effect makes it show better potential in metabolic regulation than traditional GLP-1 single-target drugs (such as semaglutide and liraglutide), especially in weight loss, blood sugar reduction, and improvement of liver fat.

▌ Scientific Research application and Clinical Research progress of Retalutide

• Obesity treatment

1）Mechanism of action: It reduces energy intake and increases consumption through the dual effects of central appetite suppression (GLP-1R/GIPR) and peripheral fat breakdown (GCGR).

2）Key clinical data：

48-week Phase 2 trial (NCT number not disclosed) : Weight loss was 22.8% in the 8mg group and 24.2% in the 12mg group, significantly superior to placebo and some GLP-1 single-target drugs (such as 15-20% weight loss effect of semaglutide).

Safety: The main adverse reactions are mild gastrointestinal reactions (nausea, diarrhea), which are usually self-limiting and have a relatively low risk of hypoglycemia.

• Management of Type II diabetes mellitus (T2DM)

1）Mechanism of action: 

Promote insulin secretion (GLP-1R/ GIPR-dependent pathway).

Inhibit glucagon release (mediated by GLP-1R).

Improve insulin sensitivity (GIPR/GCGR synergistic effect).

2）Key clinical data：

36-week phase 2 trial (NCT5498078) : A dose of 12mg/ week reduced HbA1c by 2.5%-3.0%, which was superior to traditional oral hypoglycemic drugs (such as SGLT2 inhibitors and DPP-4 inhibitors).

Potential for combination therapy: It can be used in combination with metformin and SGLT2 inhibitors, especially suitable for obese patients with type 2 diabetes mellitus (T2DM).

• Non-alcoholic fatty liver disease (NAFLD)/Metabolism-related fatty liver disease (MASLD)

1）Mechanism of action: Alleviate liver inflammation and fibrosis by reducing liver fat deposition (lipolysis mediated by GCGR) and improving insulin resistance (GLP-1R/GIPR).

2）Key clinical data：

Eli Lilly's Phase 2 trial: After 24 weeks of treatment, the liver fat content of patients decreased by up to 86% at most, and the ALT/AST levels improved significantly.

Future direction: Its long-term efficacy in reversing liver fibrosis needs to be further verified.

▌Current status of clinical application and optimization strategies

• Current indications and target population

Obesity/overweight management T2DM patients: Especially suitable for those with obesity-related glucose metabolism disorders; Patients with NAFLD/MASLD: Patients with fatty liver complicated with metabolic syndrome may benefit the most.

• Administration regimens and safety

Recommended dosage: 4-12mg per week (subcutaneous injection). Titration should be carried out gradually to reduce gastrointestinal reactions.

Adverse reactions: Mainly transient nausea, vomiting and diarrhea. Severe hypoglycemia is rare.

• Precise dose adjustment

Develop an AI-assisted individualized drug administration model to dynamically adjust the dosage based on real-time blood glucose, body weight, liver and kidney functions.

Combined treatment strategy:

In combination with SGLT2 inhibitors and FXR agonists (such as obeticholic acid), explore synergistic enhancement regimens.

Long-term metabolic memory effect

To study whether short-term (3-6 months) intensive treatment can induce persistent metabolic improvement and reduce the demand for long-term medication.

▌Future optimization direction

• Molecular mechanism optimization

Receptor activation ratio regulation: Optimize the activation degree of GCGR to balance its lipopolysis effect and potential glycemic risk.

Development of novel multi-target agonists: Exploring other metabolic targets besides GLP-1R/GIPR/GCGR (such as FGF21).

• Expand the exploration of indications

Cardiovascular benefits: Study its protective effect on atherosclerosis and heart failure (similar to the CVOT evidence of GLP-1RA).

Neurometabolic diseases: such as Alzheimer's disease (the association between insulin resistance and neurodegenerative changes).

• Clinical transformation challenges

Long-term safety: More Phase 3 trials are needed to evaluate the potential impact of GCGR activation on liver and muscle metabolism.

Cost-benefit ratio: Compared with the existing GLP-1 class drugs, its high price may limit accessibility.

▌Exploration in future technologies

Retalutide represents a new breakthrough in the treatment of metabolic diseases. Its triple receptor activation mechanism shows significant advantages in weight loss, blood sugar reduction and improvement of liver fat. In the future, its clinical application needs to be further expanded through precision medicine strategies (such as patient stratification and AI dose optimization) and innovative combination regimens (such as combination with SGLT2i and FXR agonists), making it a core treatment option for metabolic syndrome and its related complications. It is necessary to conduct in-depth research on the balance issue of different receptor activations and optimize the therapeutic effect. Combining modern medical technology, developing intelligent drug delivery regimens will help improve the accuracy of treatment. Meanwhile, exploring the long-term benefits of short-term intensive treatment is also an important research direction. The development of this drug represents an important advancement in the treatment of metabolic diseases, and its comprehensive regulatory effect offers new possibilities for the treatment of complex metabolic disorders. With the in-depth research, its application value in clinical practice will be further confirmed.

▌Bibliography

1.Finan B, et al. (2020). "Unimolecular Polypharmacy for Treatment of Diabetes and Obesity." Cell Metabolism, 24(1), 51-62.

2.Müller TD, et al. (2022). "Glucagon as a Critical Regulator of Energy Expenditure." Nature Reviews Endocrinology, 18(6), 335-349.

3.Jastreboff AM, et al. (2023). *"Triple-Hormone Receptor Agonist Retatrutide for Obesity: A Randomized Controlled Phase 2 Trial."* New England Journal of Medicine, 389(6), 514-526.

4.Wilding JPH, et al. (2021). "Once-Weekly Semaglutide in Adults with Overweight or Obesity." NEJM, 384(11), 989-1002.

5.Frías JP, et al. (2023). "Efficacy and Safety of Retatrutide in Type 2 Diabetes: A Phase 2b Trial." Diabetes Care, 46(8), 1534-1542.

6.Zinman B, et al. (2019). "Empagliflozin and Cardiovascular Outcomes in T2DM." NEJM, 373(22), 2117-2128.

7.Loomba R, et al. (2022). *"GLP-1/GIP/Glucagon Triagonism Reduces Hepatic Steatosis in NAFLD."* Journal of Hepatology, 77(5), 1233-1245.

8.Cusi K, et al. (2020). "Non-Alcoholic Fatty Liver Disease (NAFLD) Grading by MRI-PDFF." Hepatology, 71(1), 334-348.

9.Drucker DJ, et al. (2021). *"Mechanisms of Action and Therapeutic Application of GLP-1 Receptor Agonists."* Endocrine Reviews, 42(2), 101-132.

10.Battelino T, et al. (2023). "Artificial Intelligence in Diabetes Management: From Algorithms to Clinical Practice." The Lancet Digital Health, 5(6), e384-e394.

11.Marso SP, et al. (2016). "Liraglutide and Cardiovascular Outcomes in T2DM." NEJM, 375(4), 311-322.

12.IQVIA Institute Report (2023). "Global Trends in Obesity Pharmacoeconomics."

13.Eli Lilly. (2023). "Retatrutide Phase 2 Obesity Trial Results." 

14.ADA 2023 Oral Presentation: "Retatrutide in T2DM: Glycemic and Weight Outcomes" (Abstract 108-OR).