Retatrutide 10mg (LY3437943)

Retatrutide is a new entrant into the rapidly-expanding space of anti-obesity peptides. It is known as a GGG tri-agonist. This means that retatrutide works at all of the incretin receptors including GLP-1 and GIP as well as the glucagon receptor itself. Research indicates that retatrutide 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[1]. Retatrutide 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.

Retatrutide is a fatty acid acylated single peptide that combines GCGR, GIPR, and GLP-1R activities. It is based off of the GIP peptide backbone that is heavily modified. Modification of this backbone has allowed retatrutide 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 retatrutide only needs to be taken once per week[2].

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.

Glucagon Receptor (GCGR): The glucagon receptor is found mainly in the liver and kidney. By binding to this receptor, retatrutide increases glucagon production, which stimulates the breakdown of stored forms of energy like fat and glycogen. This leads to an increase in basal metabolism that increases weight loss in general and fat loss specifically.

In vivo research, in humans, indicates that retatrutide activates and is a full agonist of all of the incretin receptors including GIPR, GLP-1R, and GCGR. Retatrutide was specifically designed to be highly potent at the GIPR and GLP-1R locations. Research shows that the bulk of retatrutide's effects are driven by loss of fat mass that is probably the result of a larger and more prolonged reduction in food intake compared to similar peptides[2].

Research in mice reveals that GLP-1R is the only receptor of the three to affect gastric emptying, and thus the delay of gastric emptying caused by retatrutide is no greater than the delay caused by semaglutide, tirzepatide, liraglutide, or any of the other GLP-1R agonists. Interestingly, however, retatrutide has the same efficacy as semaglutide at a dose that is more than 30 times smaller[3].

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 mediated through FGF21, a protein secreted by the liver that regulates sugar intake and preferences for sweet foods. Studies in mice show that activation of FGF21 can lead to a 20% weight reduction primarily via increased fat loss[6].

Research indicates that retatrutide is likely the most effective incretin-based peptide for weight loss yet developed. In a study in rodents, just 10 days of retatrutide treatment leads to decreases in total body weight greater than those seen with semaglutide at the same doses[3].

A phase 2 study in humans showed that retatrutide can produce significant reductions in body weight. Trial participants given the highest dose of the peptide lost approximately 20 pounds in just 12 weeks[1]. In another trial, individuals treated for 26 weeks showed changes in waist circumference ranging from -2.1 cm to -10.2 cm[7].

In a trial published in the New England Journal of Medicine, weight loss from retatrutide varied in a dose-dependent manner over 48 weeks. Individuals given the lowest dose lost 8.7% of their total body weight while those given the highest dose lost more than 24% of their total body weight[8]. Similar results were published in JAMA[9].

In phase 2 trials, retatrutide has produced significant reductions in glycated hemoglobin (hemoglobin A1c) levels[10]. Hemoglobin A1c 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.

It has long been known that infusing elevated doses of glucagon into those with heart failure can augment heart rate and cardiac contractility. Research 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[12].

A number of incretin agonists (e.g. semaglutide, liraglutide) have been associated with improvements in cardiovascular outcomes in diabetes. Retatrutide 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.