What is retatrutide?

Retatrutide, a new incretin mimetic agent in development, has shown promise in clinical trials for significant weight loss. It is currently undergoing phase III trials, which provide most of the safety data needed by the FDA in the medication approval process. Though not yet approved by the FDA to treat a condition, there have been a couple of successful clinical trials, with more ongoing. According to studies, “it has demonstrated dosage‐dependent pharmacokinetics with favorable safety profiles,” or rather, retatrutide has effects that change with dosage and few side observed side effects compared to other drugs in its class.

How does it work?

As mentioned, retatrutide is an incretin mimetic, which also makes it a peptide and a GLP-1 receptor agonist, like popular medications semaglutide and tirzepatide. Whereas semaglutide is a single receptor agonist and Mounjaro is a dual receptor agonist, retatrutide is a triagonist, so it works on three different types of receptors. Retatrutide uses activation of the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptors (i.e. triagonism), combining the appetite control and insulin production of GLP-1 and GIP with the energy boosting effects of glucagon.

What does the research say?

The first clinical trial was conducted between December 18, 2019, and December 28, 2020 on diabetic individuals, consist with the past development path of other incretin mimetics, like Mounjaro. Incretin mimetics are often tested separately for treatment of diabetes and weight loss, though weight loss data is collected from both. 72 individuals diagnosed with diabetes mellitus type 2, the administration of weekly subcutaneous injections of 12‐mg retatrutide led to a remarkable average weight loss of 8.96 kg (nearly 10%). In this multicenter trial, retatrutide exhibited a favorable safety profile and its pharmacokinetics indicate that it is well‐suited for weekly administration in type 2 diabetics.

A second trial, spanning from May 2021 to June 2022, also had promising results. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3.19% for the 0.5 mg group, 7.92% for the 4 mg escalation group, 10.37% for the 4 mg group, 16.81% for the 8 mg slow escalation group, 16.34% for the 8 mg fast escalation group, and 16.94% for the 12 mg escalation group

Ongoing phase 3 trials, known as Triumph trials, are evaluating the long‐term safety profile and effectiveness of retatrutide for lowering weight, osteoarthritis, and obstructive sleep apnea in obese, overweight, or type 2 diabetic individuals.

What are the side effects?

Consistent with findings from other incretin mimetic and peptide weight loss medications, the side effects of retatrutide so far have been primarily digestive. The findings from these studies unveiled that the predominant treatment‐emergent adverse events (fancy words for side effects) linked to retatrutide are mild or moderate gastrointestinal issues, like nausea, vomiting, diarrhea, and constipation. Importantly, these events demonstrated a dependency on the dosage administered. In other words, there is a strong correlation between dosage and adverse events. The lower the dose, the less frequent and less serious the side effects; the higher the dose, the less mild and more frequent the side effects.

One study found an increase in heart rate that peaked at 24 weeks of treatment then gradually returned back to normalcy, which has been seen in other GLP-1 receptor agonists. Heart rate was increased by up to 6.7 beats/min by retatrutide at its peak. However, as mentioned, most side effects are mild and digestive in nature.

Will it get approved? When will it get approved?

There is no way to know for sure if a medication will get approved by the FDA. Once all clinical trial phases are completed and Eli Lilly has collected enough data on efficacy, safety and relevant edge-cases, the process can begin. Until then, there is always the potential for new data that could suggest retatrutide does not provide benefits worth the risks. Until then, however, the medical community and individuals who struggle with weight can remain hopeful. Retatrutide has shown promising results so far, even compared to new and industry-leading medications like semaglutide and tirzepatide.

Final Notes

There's no guarantee that retatrutide will be approved by the FDA, but the results from trials so far look promising. Once all the necessary data has been collected and reviewed, the approval process can begin. It's difficult to predict exactly when this might happen, but there's hope that retatrutide could become an important option for weight loss in the future.

In the own words of the authors of this study, “it is expected that the use of retatrutide, a triple agonist, will result in significant weight loss among individuals who are obese or overweight. This medication has the potential to revolutionize pharmacotherapy for obesity and overweight in the coming years.”

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