Retatrutide (LY3437943) is an innovative peptide under development by Eli Lilly for therapy in overweight, obesity, and type 2 diabetes (T2D).

Functioning as a triple-agonist, the peptide has the ability to simultaneously engage with three key receptors: glucagon (GCGR), as well as the receptors for the incretin hormones GLP-1 (GLP-1R) and GIP (GIPR) [1].

This compound is a 39-amino-acid, single-chain peptide, meticulously crafted from a GIP peptide structure to facilitate triple agonist capabilities. It primarily favors GIPR activation, while its influence on GLP-1R and GCGR is moderately less pronounced [1].

What Should Researchers Know

The Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) is expressed in various organs, including the pancreas, adipose tissue, and brain. The hormone that activates GIPR is involved in regulating insulin production, appetite control, and fat metabolism [2].
The Glucagon-Like Peptide-1 Receptor (GLP-1R) is present in the pancreas, adipose tissue, heart, gastrointestinal system, and brain, among other organs. The hormone that binds to GLP-1R influences insulin secretion, gastric emptying, and appetite regulation [3, 4].
The Glucagon Receptor (GCGR) is located primarily in the liver and adipose tissues. Glucagon, the hormone that activates GCGR, helps prevent hypoglycemia, regulates fat metabolism, and modulates overall metabolic rate [5].

Early clinical trials, particularly phase 1b studies, have shown that retatrutide possesses favorable pharmacokinetics, allowing for once-weekly subcutaneous administration [6].

Further investigations in phase 2 trials have confirmed the compound’s safety and highlighted its effectiveness in improving metabolic health and promoting significant weight loss [7, 8].

Eli Lilly is currently advancing retatrutide as a potential treatment for obesity within the TRIUMPH phase 3 clinical program. This program includes four trials (TRIUMPH 1-4), all of which are currently in the participant recruitment phase [9].

Benefits of Retatrutide

Data from phase 1b and phase 2 trials reveal that retatrutide is notably effective in promoting weight loss and enhancing glycemic control in patients with type 2 diabetes (T2D).

Furthermore, a substudy within one of the phase 2 trials highlights its effectiveness in reducing liver fat in individuals with obesity and metabolic-dysfunction-associated steatohepatitis (MASH).

Here are more detailed insights into its key benefits:

The phase 1b and phase 2 trials involving T2D patients demonstrated that retatrutide significantly lowered triglycerides, non-HDL cholesterol, and other cardiometabolic markers when compared to baseline. These improvements surpassed those observed with both dulaglutide and placebo [7, 11].
In the 48-week phase 2 trial with 338 non-diabetic participants, retatrutide dosed at 12 mg per week led to an impressive 24.2% average weight reduction. This is the most substantial weight loss recorded in any clinical trial for a pharmacological agent. Most participants experienced at least a 10% decrease in body weight, with nearly two-thirds losing 20% or more, almost half shedding 25% or more, and about a quarter reducing their weight by 30% or more [8].

This same trial also focused on a subgroup of 98 participants diagnosed with MASH and at least 10% liver fat, measured via MRI. Within 24 weeks of receiving 12 mg per week of retatrutide, these patients saw an average reduction of 82.4% in liver fat, while the placebo group showed no improvement. Remarkably, 86% of participants achieved normal liver fat levels (<5%). In addition to liver fat reduction, there were improvements in inflammation markers, liver enzymes, triglycerides, and insulin resistance [15].

Side Effects of Retatrutide

Phase 2 trials suggest that the side effect profile of retatrutide is consistent with that of other incretin mimetics, such as the FDA-approved dulaglutide [7, 11].

In one trial comparing the two drugs, retatrutide at a dose of 12 mg per week led to side effects in 76% of participants after 36 weeks of treatment, compared to 67% in the dulaglutide group. The incidence of serious side effects was comparable between the two treatments [7].

In the largest of the two prominent studies, which included 338 non-diabetic subjects, dropout rates due to side effects ranged from 6% to 16%, depending on the dose of retatrutide. No participants in the placebo group withdrew due to adverse events [8].

Gastrointestinal issues were the most common reason for discontinuation. Among the 62 individuals who received the highest dose of 12 mg per week, the following adverse events were reported:

Pancreatitis: 1 (2%)
Hepatic disorder: 2 (3%)
Increased lipase levels: 5 (8%)
Injection-site reaction: 5 (8%)
Fatigue: 6 (10%)
Early satiety: 6 (10%)
Cardiac arrhythmia: 7 (11%)
Diarrhea: 9 (15%)
Constipation: 10 (16%)
Vomiting: 12 (19%)
Nausea: 28 participants (45%)