Class of Compound:

Peptide

Mechanism of Action:

Retatrutide is a triple receptor agonist that targets the receptors of GIP, GLP-1, and glucagon hormones. By combining the effects of native GIP and GLP-1 with glucagon receptor activation, it exerts a broad appetite-suppressing and metabolic impact. Researchers suggest that this triple mechanism may offer more effective glycemic control and weight loss compared to other incretin-based therapies.

Notable Studies:

· Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity?

· 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 - The Lancet

· Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial | New England Journal of Medicine

What is Retatrutide?

Retatrutide, a synthetic peptide created by Eli Lilly, is also known by its development code LY3437943. This peptide acts as a triple receptor agonist, targeting the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG) receptors.

Both GLP-1 and GIP are incretin hormones that stimulate insulin secretion and modulate immune responses. Moreover, the activation of GCG receptors by retatrutide is thought to boost metabolic rate and increase energy expenditure.

This cutting-edge compound is being explored for its role in controlling blood glucose levels and aiding in weight loss.

Important details for researchers:

· Developed by Eli Lilly, retatrutide is a synthetic peptide based on the structure of GIP and is composed of 39 amino acids. While it predominantly targets GIP receptors, it has been engineered to also activate GLP-1 and GCG receptors.

· Retatrutide features a structural modification with a fatty acid component, which enhances its stability and prolongs its activity in the body, allowing for once-weekly dosing.

· Currently, retatrutide is undergoing evaluation in clinical trials for its safety and effectiveness in treating obesity, both in individuals with and without type 2 diabetes (T2D), as part of Eli Lilly’s TRIUMPH phase-3 clinical program.

· Initial study results have indicated positive outcomes for both glycemic control and weight loss .

Although it has not yet been approved by regulatory authorities such as the U.S. Food and Drug Administration (FDA), retatrutide is available to qualified researchers as a reference material for studying the therapeutic potential of this triple receptor agonist.

What Does Retatrutide Do?

Retatrutide operates through a unique mechanism as a triple agonist, targeting the GIP, GLP-1, and GCG receptors, with a strong emphasis on GIP receptor activation.

Incretin hormones GLP-1 and GIP stimulate insulin secretion from pancreatic beta cells and contribute to feelings of fullness after eating, while glucagon serves a counter-regulatory function by raising blood glucose levels during fasting.

This receptor interaction leads to a comprehensive approach to metabolic regulation, significantly impacting both glycemic control and weight loss. Below is an overview of the underlying mechanisms:

· Retatrutide’s primary mechanism involves potent activation of the GIP receptor, which plays a vital role in appetite regulation by directly affecting the brain’s satiety centers. This reduces hunger, cravings, and overall food intake.

· Through GLP-1 receptor activation, retatrutide supports glycemic regulation and enhances satiety. GLP-1 also slows down gastrointestinal motility and delays gastric emptying, leading to increased feelings of fullness after meals.

· Activation of the GCG receptor by retatrutide is believed to increase energy expenditure and promote fat oxidation, largely through metabolic actions in the liver. GCG receptor stimulation encourages fat breakdown and elevates metabolic rates. Additionally, it induces “beiging” of white fat, converting it into beige fat with thermogenic properties similar to brown fat, thereby boosting calorie burning and enhancing metabolism.

These combined mechanisms make retatrutide a promising option for treating obesity and type 2 diabetes by not only curbing calorie intake but also increasing energy expenditure, offering a dual strategy for effective weight management.

Research Applications and Benefits of Retatrutide

Outlined below you can find several key clinical trials that have demonstrated the efficacy and potential research applications of retatrutide.

Retatrutide and Weight Loss Research

As of 2024, phase 3 trials within the TRIUMPH program are in progress, exploring retatrutide’s potential for weight loss. Earlier phase 1 and phase 2 studies have shown promising results, indicating that the peptide could lead to up to a 24% reduction in body weight from baseline.

The initial human trial of retatrutide, a proof-of-concept study, took place in Singapore in 2019. This phase 1 trial involved 47 participants who were administered six different dose levels, ranging from 0.1 mg to 6 mg weekly. The study suggested potential positive effects on appetite, food intake, and other metabolic markers, alongside a favorable safety profile.

Following this, a larger phase 2 trial was conducted, lasting 48 weeks and involving 338 non-diabetic adults with overweight and obesity. Participants received varying doses of retatrutide, and the trial demonstrated a dose-dependent reduction in weight and improvement in cardiometabolic risk factors. Key findings included:

· An 8.7% weight reduction in the 1 mg dose group

· A 17.1% weight reduction in the 4 mg group

· A 22.8% reduction in the 8 mg group

· A 24.2% reduction in the 12 mg group

All participants who received either 8 mg or 12 mg of retatrutide weekly experienced at least a 5% reduction in their initial body weight. In addition, significant reductions were observed in waist circumference, blood pressure, glycated hemoglobin, fasting glucose, insulin levels, and lipid levels, excluding HDL cholesterol.

Retatrutide and Type 2 Diabetes Research

Eli Lilly is conducting ongoing research on retatrutide’s potential to manage glycemic control and obesity in individuals with type 2 diabetes (T2D) as part of the phase 3 TRIUMPH clinical trials.

Earlier trials, including phase 1b and phase 2 studies, have shown encouraging outcomes. In a 12-week phase 1b trial, 72 adults aged 20-70 with T2D and baseline A1c levels between 7.0% and 10.5% were treated with either retatrutide, dulaglutide (a GLP-1 agonist approved by the FDA), or placebo.

By week 12, those receiving the highest dose of retatrutide (12 mg weekly) saw a significant decrease in A1c of up to 1.6% and a weight reduction of up to 19.7 pounds (8.96 kg). These results were markedly better than those seen with both dulaglutide and placebo.

A subsequent 36-week phase 2 trial involved 281 T2D patients receiving up to 12 mg of retatrutide weekly. Key results include .

· Participants in the 12 mg group experienced a significant HbA1c reduction of 2.02% (22.07 mmol/mol) at 24 weeks and 2.16% (23.59 mmol/mol) at 36 weeks, compared to negligible change (0.01%) in the placebo group after 24 weeks.

· By the conclusion of the 36-week trial, weight loss was dose-dependent, with the 12 mg group losing 16.94% of their body weight, compared to a 3.00% reduction in the placebo group.

· Additionally, retatrutide treatment led to improved lipid profiles, including decreases in triglycerides and non-HDL cholesterol, with the 12 mg group showing significant improvement at 36 weeks compared to both baseline and placebo.

Retatrutide is a synthetic peptide with glucose-lowering effects. It is an antidiabetic agent for type 2diabetes (T2D) that stimulates insulin and inhibits glucagon secretion in a glucose-dependent manner. Retatrutide
has also been shown to delay gastric emptying, reduce fasting and postprandial blood glucose concentrations, reduce food intake, and reduce body weight in patients with type 2 diabetes.