I want to talk to you about a new drug that is making waves in the management of both obesity and type 2 diabetes. It is called Retatrutide. 

Retatrutide is an investigational drug developed by Eli Lily. Currently, it is in Phase 3 clinical trials. It is unique because it simultaneously activates three important receptors involved in energy metabolism – Glucagon-like Peptide-1, Glucose-dependent Insulinotropic Polypeptide and Glucagon receptor. 

This triple agonism reduces appetite, increases insulin secretion, and boosts energy expenditure by enhancing fat oxidation. 

How does it work is:

The GLP-1 component enhances insulin secretion in a glucose-dependent manner while suppressing glucagon release, which means better glycaemic control with reduced hypoglycemia risk. The GIP receptor activation provides complementary metabolic benefits, including improved insulin sensitivity and additional appetite suppression. Glucagon receptor agonism, which seems counterintuitive, promotes energy expenditure and fatty acid oxidation, contributing significantly to weight loss. 

A cryo-electron microscopy study has revealed how Retratrutide binds to its target receptors, providing insights into its potent efficacy. The structural data highlight the peptide’s ability to engage multiple receptors simultaneously, offering a blueprint for designing future multi-agonist therapies. 

What does research say?

In a 48-week phase 2 study, there was a weight reduction of up to 24.2% in participants who received the medication. 

In patients with type 2 diabetes, Retatrutide showed HbA1c reductions up to 2.02% and weight loss up to 16.94% over 36 weeks. 

Retatrutide significantly reduced liver fat content in patients with metabolic dysfunction-associated steatotic liver disease. A 1mg dose showed 42.9%, at a 4mg dose, a 57% and at an 8mg dose showed an 81.4% reduction, and a 12mg dose showed an 82.4% reduction of liver fat at 24 weeks. At 24 weeks, normal liver fat that is <5% was achieved by 27% in patients at 1mg, 52% at 4mg, 79% at 8mg, and 86% at 12mg doses. This reduction in liver fat was related to changes in body weight, abdominal fat, and metabolic measures associated with improved insulin sensitivity and lipid metabolism. 

Side Effects:

The most common side effects mirror what we see with other GLP-1 agonists, primarily gastrointestinal symptoms including nausea, vomiting, and diarrhoea. However, the trial data suggest these effects are generally manageable with appropriate dose titration and patient education.

The key to successful implementation will be proper patient selection and monitoring. We are looking at patients with a BMI over 30, or over 27 with comorbidities, who haven’t achieved adequate results with lifestyle interventions alone. 

Conclusion

We are moving beyond treating symptoms to addressing fundamental metabolic dysfunction. The degree of weight loss we are seeing could potentially reduce the need for bariatric surgery in many patients, while the metabolic improvements suggest we might be able to induce diabetes remission more consistently than ever before. 

The phase 3 trials are currently underway, and if the results continue to mirror what we have seen, it represents not just another treatment option but potentially a new standard of care for patients with obesity and metabolic dysfunction. 

Kripa, is a Specialist Dietitian at The London Obesity & Endocrine Clinic. She has helped many patients overcome weight management barriers. ©Simplyweight

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