Retatrutide 20 mg

What is retatrutid?

Retatrutide (development designation LY3437943) is a synthetic peptide and one of the most innovative molecules in modern metabolic pharmacology. It is a triagonist — a single substance that simultaneously activates three different G protein-coupled receptors: the GLP-1 receptor, the GIP receptor (gastric inhibitory polypeptide / glucose-dependent insulinotropic polypeptide) and the glucagon receptor. The molecule is being developed by Eli Lilly and represents a structural development from the single agonists semaglutide and liraglutide and from the dual agonist tirzepatid.

The substance consists of a 39-amino acid peptide chain modified with a C20 fatty acid side chain that binds to serum albumin and extends the plasma half-life to approximately six days — weekly administration is thus possible. Retatrutide is being developed in the phase 3 TRIUMPH program for obesity, type 2 diabetes and cardiovascular outcomes. At the date of this compilation, retatrutid is not registered with any pharmaceutical authority and has no formal approved indication.

In the phase 2 program, the results of which were published in 2023 in the New England Journal of Medicine, doses between 1 mg and 12 mg per week were tested. The highest dose of 12 mg showed a weight reduction of up to 24 percent at 48 weeks, among the strongest results reported for any pharmacological treatment for obesity. Presentation 20 mg is above the highest dose formally studied in published phase 2 data — the safety and efficacy profile for doses above 12 mg is therefore incompletely characterized and based largely on extrapolation from lower dose ranges.

How does retatrutid work?

Retatrutide exerts its effect via the simultaneous activation of three receptors, all of which are G-protein coupled, and trigger increased intracellular cAMP via the Gs protein. Activation of the GLP-1 receptor causes glucose-dependent insulin secretion from the beta cells, suppresses glucagon secretion from the alpha cells, delays gastric emptying, and mediates satiety signals in the hypothalamus and brainstem. GIP receptor activation enhances glucose-dependent insulin secretion and affects adipose tissue metabolism and central appetite regulation in a complementary way.

The third component — glucagon receptor activation — is the most distinctive feature. Activation of the glucagon receptor in the liver stimulates gluconeogenesis and fat oxidation while increasing energy metabolism. In brown and beige fat, glucagon increases basal metabolism via upregulation of UCP1 expression. The paradoxical combination is balanced by GLP-1 activation counteracting the hyperglycemic tendency of the glucagon component — the net is improved glucose homeostasis.

At the highest doses studied in phase 2, gastrointestinal side effects and dose-dependent satiety effects predominate. At doses above 12 mg, which is above the range studied, it is reasonable to assume that the gastrointestinal and central nervous effects are more pronounced — but formal documentation from controlled human studies at these levels is lacking in the published literature. The half-life of approximately six days is dose-independent and makes weekly administration possible.

What can retatrutide potentially affect?

In published phase 1 and phase 2 studies as well as in preclinical research, several physiological systems return where retatrutide leaves a clear imprint. The effect size is dose-dependent and exhibits a continuous curve within the dose range studied:

• Body weight and body composition — sharp reduction in fat mass and total body weight; Phase 2 results showed up to 24 percent weight reduction at the highest studied dose of 12 mg at 48 weeks.

• Energy metabolism and thermogenesis — glucagon receptor activation increases basal metabolism via UCP1-mediated thermogenesis in brown and beige fat.

• Appetite regulation and satiety — central influence in the hypothalamus and brainstem reduces appetite, delays gastric emptying and prolongs the feeling of satiety.

• Glucose homeostasis — lowered levels of HbA1c, fasting glucose and postprandial glucose via glucose-dependent insulin secretion and attenuated glucagon secretion via the alpha cells.

• Lipid metabolism and hepatic steatosis — reduced levels of triglycerides and LDL and reduced hepatic fat deposition in exploratory analyses.

• Cardiovascular markers — lowered blood pressure and improved biomarkers of inflammation have been observed in phase 2.

Potential side effects of retatrutide

As retatrutide is in phase 3 development and is not registered as a medicinal product, the safety profile is currently limited to data from phase 1 and phase 2 trials and ongoing phase 3 studies. Long-term safety in humans is incompletely characterized and postmarketing experience is lacking. For doses above the formally studied range (≥12 mg), safety data are particularly limited. The profile below is based on published study results and on the established safety profiles of GLP-1 and GIP receptor agonists as well as on preclinical research on the glucagon component.

• Gastrointestinal — nausea, vomiting, diarrhea, constipation, and abdominal pain are the most common side effects and are dose-dependent. At high doses, the symptoms can be more pronounced and prolonged.

• Pancreatitis — acute pancreatitis is a well-known observandum for incretin-based drugs; long-term data for retatrutide are lacking, but the risk is assumed to be of the same order of magnitude as with other agonists in the class.

• Gallbladder and biliary tract — cholelithiasis and cholecystitis occur with rapid weight loss and have been reported in phase 2.

• Thyroid C cells — in animal studies of GLP-1 agonists, medullary thyroid cancer has been observed in rats; the same observandum applies to retatrutid and the human relevance has not been established.

• Heart rate — some increase in resting heart rate has been documented, an effect known from other incretin-based drugs and which at high doses may be more noticeable.

• Hypoglycaemia — the risk is low with monotherapy but increases in combination with insulin or sulfonylureas.

• Local reactions — redness, itching and skin reactions at the injection site.

• Dehydration and renal function — severe gastrointestinal side effects can cause dehydration and, in rare cases, acute renal failure, a risk that increases with dose.

The overall safety picture of retatrutide is incompletely characterized at the date of this compilation because the molecule is in phase 3 development. For doses above the range studied, the uncertainty is even greater. Long-term efficacy and safety data in humans will be established through results from the TRIUMPH program and potential subsequent postmarketing reporting. For the time being, the risk picture must be interpreted in the light of limited human data.