GLP-1/GIP/GCGR (Retatrutide)

The Cardiovascular Health Promoter

Support Heart Health: Discover the Cardio Benefits of Retatrutide

GLP-1/GIP/GCGR (Glucagon-Like Peptide-1/Glucose-Dependent Insulinotropic Polypeptide/Glucagon Receptor) also called Retetrutide is peptide acts as an agonist to three different receptors: glucagon-like peptide-1 (GLP-1), glucagon (GCGR), and glucose-dependent insulinotropic polypeptide (GIP) receptors. This multi-receptor targeting approach is designed to harness the beneficial effects of each receptor pathway to improve glucose metabolism, reduce weight, and possibly provide direct benefits to the liver.

In essence, retetrutide is being explored for its ability to improve metabolic health and provide a therapeutic option for conditions related to insulin resistance, metabolic dysfunction, and direct liver health issues.

Potential Benefits Under Research

• Improved Glucose Metabolism: By acting on GLP-1 receptors, retetrutide may enhance the body’s ability to regulate blood sugar levels, which is crucial for managing diabetes.
• Weight Reduction: Through its action on multiple receptors, including GLP-1 and GIP, retetrutide may help reduce body weight, which is beneficial for obesity management and associated metabolic disorders.
• Liver Health: Targeting the GCGR and other receptors, retetrutide might have protective effects on the liver, potentially reducing liver inflammation and fibrosis in conditions like non-alcoholic steatohepatitis (NASH).
• Cardiovascular Benefits: Although primarily focused on metabolic and liver health, the improvements in body weight and glucose metabolism could indirectly benefit cardiovascular health.

Dosing Protocol for Research Purposes

• The initial dose of GLP-1/GIP/GCGR is 0.5 mg, which is injected subcutaneously once weekly. The dose of the drug can be increased to 1 mg, 2 mg, or 4 mg after 4 weeks, depending on the patient’s response. The maximum dose is 12 mg per week.
• The initial dose of GLP-1/GIP/GCGR is important because it helps to minimize the risk of side effects. If the patient tolerates the initial dose well, the dose can be increased gradually. However, if the patient experiences any serious side effects, the dose of the drug should be reduced or discontinued.

Overview

GLP-1/GIP/GCGR also called Retetrutide is a new entrant into the rapidly-expanding space of anti-obesity peptides. It is known as a GGG tri-agonist. This means that retetrutide works at all of the incretin receptors including GLP-1 and GIP as well as the glucagon receptor itself. Research indicates that retetrutide may be the most effective weight loss peptide yet developed, with some studies showing a rapid and sustained weight loss response as high as 24% of total body weight. Retetrutide is thought to promote weight loss by increasing energy expenditure as well as decreasing energy consumption. It does the former via action at the glucagon receptor and the latter through both central and peripheral appetite control.

Retetrutide Structure

Sequence: YA1QGTFTSDYSIL2LDKK4AQA1AFIEYLLEGGPSSGAPPPS3 Molecular Formula: C223H343F3N45O10
Molecular Weight: 4845.44 g/mol
PubChem SID: 474492335
CAS Number: 2381089-83-2
Synonyms: L Y-3437943, NOP2Y096GV

Most Recent Research

On this  study on retetrutide reports significant findings from a 48-week phase 2 trial, focusing on patients with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). Here are the key takeaways from the research:

• High Resolution Rate of Fatty Liver Disease: Over 85% of the participants treated with retetrutide showed resolution of fatty liver disease. This result was consistent across various dosages of the drug, particularly the 8 mg and 12 mg weekly subcutaneous doses.
• Significant Reduction in Liver Fat: The study highlighted dramatic reductions in liver fat content. Specifically, those receiving 8 mg and 12 mg doses experienced mean relative liver fat changes of approximately -81.4% and -82.4% from baseline at 24 weeks, respectively, compared to a negligible increase in the placebo group.
• Effective Across Multiple Dosages: By week 48, those taking the 12 mg dose achieved an 86% reduction in liver fat, and a significant percentage of patients (93% in the 12 mg group) reached a liver fat level of less than 5%.
• Correlation with Weight Loss and Metabolic Improvements: The study also found significant correlations between the reduction in liver fat and improvements in body weight, waist circumference, and fasting metabolic biomarkers.
• Potential for Early Intervention: According to the lead researcher Dr. Arun J. Sanyal, retetrutide could represent a leading approach in managing early-stage fatty liver disease linked to obesity, suggesting that treating the underlying obesity could also address associated liver fat issues.

Source: HCPLive

Additional Research

What is Retetrutide? 

Retetrutide, as mentioned, is a GGG tri-agonist. Retetrutide is a fatty acid acylated single peptide that combines GCGR, GIPR, and GLP-1R activities. It is based on the GIP peptide backbone that is heavily modified. Modification of this backbone has allowed retetrutide to bind to albumin in the bloodstream. This, in turn, means that the drug remains in the blood for a prolonged period of time. This extended half-life means that retetrutide only needs to be taken once per week. Its wide spectrum of activity allows retetrutide to bind to several different incretin receptors and produce specific effects as follows.

• Gastric Inhibitor Peptide Receptor (GIPR): Also called the glucose­-dependent insulinotropic polypeptide receptor, this receptor is found in the central nervous system as well as throughout the GI tract and body. It appears to play important roles in the central mechanisms that affect hunger and is thought to play a role in sending “fullness” signals from the GI tract to the brain.
• Glucagon-like Peptide Receptor-1 (GLP-1R): Activation of this receptor leads to slowing of gastric emptying. Slowed gastric emptying sends signals to the brain to decrease food intake and can therefore help to control energy consumption. Peptides targeting this receptor were originally developed to treat type 2 diabetes, but have since been found to improve weight loss and decrease the risk of certain forms of heart disease. They are under investigation for the treatment of depression, reward system disorders (e.g., alcoholism, addiction), polycystic ovarian syndrome, and non-alcoholic fatty liver disease.
• Glucagon Receptor (GCGR): The glucagon receptor is found mainly in the liver and kidney. Mutations in this receptor are associated with certain forms of type 2 diabetes. By binding to this receptor, retetrutide increases glucagon production, which stimulates the breakdown of stored forms of energy like fat and glycogen. This leads to an increase in basal metabolism (even during sleep) that increases weight loss in general and fat loss specifically.

How Does Retetrutide Work? 

In vivo research, in humans, indicates that retetrutide activates and is a full agonist of all of the incretin receptors including GIPR, GLP-1R, and GCGR. Retetrutide was specifically designed to be highly potent at the GIPR and GLP-1R locations. As a result, retetrutide is one of the most potent incretins available and thus has strong effects on both gastric emptying and the central control of hunger/satiety. Research shows that the bulk of retetrutide’s effects are driven by loss of fat mass which is probably the result of a larger and more prolonged reduction in food intake compared to similar peptides. Decreased food intake, especially as occurs early in the use of the peptide, jump starts fat oxidation. This sets the stage for prolonged weight loss by altering basal metabolism and overcoming the hormonal forces that perpetuate obesity.

The bulk of retetrutide’s benefit is a result of its ability to decrease energy intake via delayed gastric emptying and increased control of hunger signals in the central nervous system. That said, the ability of the peptide to increase energy expenditure is also statistically significant and should not be discounted.

GIPR Effect: (glucose-dependent insulinotropic polypeptide receptor) 

Agonism of the GIPR leads to decreased gastric acid secretion and gastrin release. Gastrin is a peptide hormone that stimulates the release of hydrochloric acid and histamine in the stomach. These effects help to slow digestion and reduce transit through the GI tract. As a result, action on the GIPR can lead to increased feelings of fullness.

GLP-1R Effects: (glucagon-like peptide-1 receptor) 

Agonism of the GLP-1R is well known to delay gastric emptying. Research in both rodents and humans supports this. Gastric emptying (GE) is an important determinant of the glycemic response following food intake. Research indicates that slowing GE can reduce food intake and thus impact weight loss.

Research in mice reveals that GLP-1R is the only receptor of the three to affect GE, and thus the delay of GE caused by retetrutide is no greater than the delay caused by semeglutide, trizapatide, liraglutide, or any of the other GLP-1R agonists. Interestingly, however, is the difference in dose to achieve full effect on GE. Research shows that retetrutide has the same efficacy as semeglutide at a dose that is more than 30 times smaller[3]. As with semeglutide, however, the effects of retetrutide on GE wane over time. This decrease in the effect of a therapeutic over time is referred to as tachyphylaxis and may, in some cases, necessitate a drug holiday to help restore effects.

GCGR Effects: (G-protein-coupled receptor) 

It wasn’t fully understood until relatively recently that glucagon plays an important role in regulating hunger and energy expenditure. Research now reveals that glucagon signals the brain from the gut via the vagal nerve. This signaling promotes feelings of fullness and is regulated by glucagon concentrations in the portal circulation of the liver. In mouse models, the administration of glucagon has resulted in a 20% weight loss.

Additional research has shown that glucagon can increase energy expenditure. This effect has been observed in both animal and human trials. This particular effect is not mediated through the GCGR, but rather through via FGF21. FGF21 is a protein secreted by the liver that regulates sugar intake and preferences for sweet foods, among a host of other functions. Mutations in this protein have been identified in those with a “sweet tooth”. FGF21 regulates the uptake of glucose by adipocytes (fat cells). Treatment of animals with FGF21 results in increased energy expenditure, fat utilization, and lipid excretion. Studies in mice show that activation of FGF21 can lead to a 20% weight reduction primarily via increased fat loss. This occurs without a change in total calorie intake, indicating a change in metabolic rate. Mice given an FGF21 infusion have demonstrated higher energy expenditure both during wakefulness and during sleep. This is likely mediated through effects on mitochondrial activity.

How Effective is Retetrutide for Weight Loss? 

Research indicates that retetrutide is likely the most effective incretin-based peptide for weight loss yet developed. In a study in rodents, for instance, just 10 days of retetrutide treatment leads to decreases in total body weight greater than those seen with semeglutide. This occurs when the peptides are administered at the same doses. If retetrutide is given at a lower dose that semeglutide, then it produces similar weight loss effects but with decreased risk of side effects. Thus, retetrutide may offer an alternative treatment option for those who are somewhat intolerant of the side effects of semeglutide.

A phase 2 study in humans has shown that retetrutide can produce significant reductions in body weight. In fact, trial participants given the highest dose of the peptide lost approximately 20 pounds in just 12 weeks. In another trial, individuals treated for 26 weeks showed changes in waist circumference ranging from -2.1 cm to -10.2 cm. In other words, people taking retetrutide in this trial lost anywhere from 1 inch to -5 inches off of their waist in just 6 months. Finally, in a trial published in the New England Journal of Medicine, weight loss from retetrutide varied in a dose­-dependent manner over the 48 weeks of the trial. Individuals given the lowest dose of the peptide lost 8. 7% of their total body weight while those given the highest dose lost more than 24% of their total body weight. Similar results were published in a JAMA article as well.

Retetrutide and Diabetes 

In phase 2 trials, retetrutide has produced significant reductions in glycated hemoglobin (hemoglobin Ale) levels[l0). Hemoglobin is the compound in the blood that carries oxygen. Glycated hemoglobin is hemoglobin that has been chemically linked to a sugar. High levels of glycated hemoglobin are caused by chronically high levels of blood sugar and are associated with diabetes. In fact, HBA1c levels can be used to monitor long-term blood sugar control in those suffering from diabetes. Keeping these levels lower is critical not only to good blood sugar control, but to preventing the long-term effects of diabetes including cardiovascular disease, nerve damage, kidney injury, and eye problems.

Retetrutide and Heart Health 

It has long been known that infusing elevated doses of glucagon into those with heart failure can augment heart rate and cardiac contractility. Pharmacological administration of glucagon, typically in milligram quantities, is commonly employed in addressing acute cardiac depression resulting from overdoses of calcium channel antagonists or beta-blockers, despite limited research in this area. Interestingly, glucagon concentrations within the normal physiological range seem to have no discernible impact on heart rate or contractility.

The impact of retetrutide on heart health has not been directly assessed in humans, but it has been assessed in cynomolgus monkeys. In the past, it was thought that elevated actions of glucagon were associated with diabetes. That is to say, scientists thought that lower glucagon would lead to improved outcomes in diabetes. Thus, monoclonal glucagon antibodies, glucagon receptor antagonists (peptide and non-peptide) and molecules targeting the expression of GCGR have all been tested as potential treatments. Research on these agents, however, revealed a number of major obstacles including limited efficacy, the risk of iatrogenic hypoglycemia, and other safety issues related to the lack of specificity of glucagon blockade, immunogenicity and toxicity. This really should not have come as any surprise as the rise in glucagon levels in diabetes is likely a consequence of the disease and not a cause of it.

Research also indicates that incretins have beneficial effects on the cardiovascular system by decreasing blood pressure, improving left ventricular function, endothelium-dependent vasodilation, and by increasing endothelial progenitor cells. In other words, glucagon and related molecules appear to improve heart health[12]. Supporting this notion is the fact that a number of incretin agonists (e.g. semeglutide, liraglutide) have been associated with improvements in cardiovascular outcomes in diabetes. As a result, these peptides are now under investigation for direct use in heart disease. retetrutide is likely to show improved results given its more extensive effects on glucagon levels, but the exact effects will have to await more detailed clinical and benchtop trials. These findings indicate that retetrutide and similar molecules may be beneficial to regeneration in the cardiovascular as well as helping to prevent cardiovascular disease in the first place.

As mentioned, a limited, non-clinical cardiovascular study of retetrutide in monkeys has been undertaken. This study revealed higher heart rates at all dose levels with a dose dependent effect overall. At the same time, retetrutide was increasing heart rate, it was decreasing blood pressure in the monkeys. Unfortunately, this study was limited in both duration and number of individuals under investigation. Thus, while it can offer some foundation on which to ground speculation, it cannot provide any definitive information about retetrutide and its long-term effects on cardiovascular health.

Retetrutide Summary 

Retetrutide is an incretin mimetic and GGG agonist. It binds to glucagon receptors, gastric inhibitory peptide receptors, and glucagon-like peptide-1 receptors. This triple activity has been associated with significant weight loss (24% of body weight at 6 months) in clinical trials. This outcome makes retetrutide the most effective of incretin peptides to date and thus it is under intense investigation as a weight loss agent. There is some hope that retetrutide may also have beneficial cardiovascular effects and might therefore be useful in the treatment of heart disease complicated by diabetes as well as heart disease in general.

Article Author

The above literature was researched, edited and organized by Dr. Logan, M.D. Dr. Logan holds a doctorate degree from Case Western Reserve University School of Medicine and a B.S. in molecular biology.

Scientific Journal Author

William C. Roell, PhD. received his bachelor’s degree in microbiology and biochemistry from Miami University. He obtained his doctorate in Cellular and Integrative Physiology from Indiana University School of Medicine doing work in cellular therapy and studying metabolic changes associated with adipocyte maturation. Joining Lilly in 2000, William worked with multiple drug discovery groups providing innovative approaches to translate therapeutic concepts from bench to bedside. More recently, he has supported efforts in diabetes biomarker discovery and target identification/advancement, impacting discovery and development efforts across Lilly’s Diabetes and Complications portfolio. William and his lab currently are active in drug discovery with a focus on diabetes and obesity. He has a particular interest in mechanisms by which incretin receptor modulation contributes to the profound benefits observed clinically with existing and emerging therapeutics.

Dr. William C. Roell is being referenced as one of the leading scientists involved in the research and development of Retetrutide. In no way is this doctor/scientist endorsing or advocating the purchase, sale, or use of this product for any reason. There is no affiliation or relationship, implied or otherwise, between Guide to Peptide and this doctor. The purpose of citing the doctor is to acknowledge, recognize, and credit the exhaustive research and development efforts conducted by the scientists studying this peptide. Dr. William C. Roell is listed in [1] and [2] under the referenced citations.

Referenced Citations

1. T. Coskun et al., “LY3437943, a novel triple_glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical woof of concept,” Cell Metab., vol. 34, no. 9, RR- 1234- 1247.e9, Sep. 2022, doi: 10.1016/j.cmet.2022.07.013. 
2. T. Coskun et al., “LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery­ to clinical woof of concept,” Mo/. Metab., vol. 18, QR- 3-14, Oct. 2018, doi: 10.1016/j.molmet.2018.09.009.
3. S. Urva et al., ‘The novel GIP, GLP-1 and glucagon receptor agonist retetrutide delays….gastric em12._1Y-ingI” Diabetes Obes. Metab., vol. 25, no. 9, QR- 2784-2788, Sep. 2023, doi: 10.1111/dom.15167.
4. G. Winkler, J. T. Kis, K. A. Kiss, and L. Schandl, “A GLP1-receptor-agonistáktól a glükagonreceptor-agonizmussal kiegészített hármashormonreceptor-aktiválásig : Új távlatok a 2-es típusú diabetes és az elhízás kezelésében,” Orv. Hetil., vol. 164, no. 42, QP-:. 1656-1664, Oct. 2023, doi: 10.1556/650.2023.32894. 
5. T. M. Frayling et al., “A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Share, Lower Total Body-Fat Percentage, and Higher Blood Pressure,” Cell Rep., vol. 23, no. 2, pp. 327-3361 Aw. 2018, doi: 10.1016/j.celrep.2018.03.070.
6. T. Coskun et al., “Fibroblast Growth Factor 21 Corrects Obesity in Mice,” Endocrinology, vol. 149, no. 12, RR- 6018-6027, Dec. 2008, doi: 10.1210len.2008-0816. 
7. J. P. Frias et al., “Efficacy’.’. and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial,” Lancet Land. Engl., vol. 392, no. 10160, RR- 2180- 2193, Nov. 2018, doi: 10.1016IS0140-6736(18)32260-8. 
8. A. M. Jastreboff et al., “Triple-Hormone-Receptor Agonist Retetrutide for Obesity -A Phase 2 Trial,” N. Engl. J. Med., vol. 389, no. 61 pp 514-526, Aug. 2023, doi: 10.1056/NEJMoa2301972.
9. E. Harris, ‘Triple-Hormone Combination Retetrutide Induces 24% Body. Weight Loss,” JAMA, vol. 330, no. 4, R· 306, Jul. 2023, doi: 10.1001/jama.2023.12055.
10. A. Ray. “Retetrutide: a triple incretin receptor agonist for obesity management,” Expert De.in. lnvestig_. Drugs, vol. 32, no. 11, RR:. 1003-1008, Nov. 2023, doi: 10.1080/13543784.2023.2276754. 
11. I. Rix, C. Nex0e-Larsen1 N. C. Bergmann, A. Lund, and F. K. Knop, “Glucagon Physiology,” in Endotext, K. R. Feingold, B. Anawalt, M. R. Blackman, A. Boyce, G. Chrousos, E. Corpas, W. W. de Herder, K. Dhatariya, K. Dungan, J. Hofland, S. Kalra, G. Kaltsas, N. Kapoor, C. Koch, P. Kopp, M. Korbonits, C. S. Kovacs, W. Kuohung, B. Laferrere, M. Leyv, E. A. McGee, R. Mclachlan, M. New, J. Purnell, R. Sahay.,____& S. Shah, F. Singer, M.A. Sperlinq, C. A. Stratakis, D. L. Trence, and D. P. Wilson, Eds., South Dartmouth (MA): MDText.com, Inc., 2000. Accessed: Dec. 03, 2023. [Online].
12. A. Ceriello, S. Genovese, E. Mannucci, and E. Granda, “Glucagon and heart in type 2 diabetes: new perspectives,” Cardiovasc. Diabetol., vol. 15, no. 1, R- 123, Aug. 2016, doi: 10.1186ls12933-016- 0440-3. 

13. “Fiile:Retetrutide.png – WikiRedia.” Commons.wikimedia.org, 6 July 2023, en.wikipedia.orglwiki/File:Retetrutide.png.