Is Retatrutide Safe?

Retatrutide, also known as LY3437943, is an innovative weight loss medication developed by Eli Lilly and Company. While its full safety profile is still being established in Phase 3 trials, initial data from Phase 2 trials suggest that retatrutide is generally well-tolerated. Side effects are similar to those seen with other GLP-1 receptor agonists and tend to decrease over time.

📝 What is retatrutide?

Retatrutide is an injection that is administered once-weekly for the treatment of obesity and belongs in the same drug class as semaglutide (brand names Ozempic and Wegovy) and tirzepatide (brand names Mounjaro and Zepbound).

📝 How does retatrutide work?

Retatrutide is a unique triple agonist (tri-agonist) working on three key hormone receptors:

• Glucagon-like peptide-1( GLP-1)
• GIP (glucose-dependent insulinotropic polypeptide)
• Glucagon

This triple mechanism has a significant impact on weight loss and blood sugar levels. Like other GLP-1 receptor agonists, retatrutide regulates insulin production and slows gastric emptying, which promotes satiety and reduces appetite. Activating the GIP and glucagon receptors also increases fat breakdown and energy expenditure. Retatrutide is administered as an injection once a week.

📝 Retatrutide FDA approval status

As of now, retatrutide is not FDA approved as a weight loss drug. The drug is currently in Phase 3 clinical trials, which is typically the final stage before seeking FDA approval.

📊 Clinical trial results

Weight loss results

Data from a phase 2 clinical trial, as published in The New England Journal of Medicine involving 338 adults who had obesity or were overweight with a a Body Mass Index (BMI) of ≥27 kg/m 2, showed weight management results.

At the 24-week mark, patients receiving the drug experienced average weight loss reduction ranging from 7.2% in the 1 mg group to 17.5% in the 12 mg group, compared to 1.6% in the placebo group.

The weight-loss results continued to the 48-week endpoint, with the 12 mg (highest dose) retatrutide group achieving an average body weight reduction of 24.2%, while the placebo group only saw a 2.1% change.

Also a substantial proportion of retatrutide patients (64-100%) were able to achieve a weight loss of 5% or more, a clinically significant threshold compared to just 27% in the placebo group. In addition to its impressive treatment of obesity, retatrutide has also demonstrated:

Improvements in blood glucose control

The clinical trials have shown that retatrutide treatment can lead to significant improvements in glycemic control, as evidenced by reductions in HbA1c levels. In the phase 2 trial, 72% of participants with prediabetes at baseline were able to achieve normal HbA1c levels after 48 weeks of retatrutide therapy, compared to just 22% in the placebo group.

These findings suggest that retatrutide’s actions on the GIP, GLP-1, and GCG receptors may have a positive impact on insulin sensitivity and glucose control, potentially reducing the risk of developing obesity-related conditions like type 2 diabetes.

Improvements in cardiovascular risk factors

The clinical trials have also reported favourable changes in various cardiovascular risk factors among retatrutide recipients. Participants experienced significant reductions in blood pressure, lipid profiles (except HDL cholesterol), and waist circumference, all of which are important markers of cardiometabolic health.

❗ Potential side effects

Like any treatment, retatrutide can cause side effects, especially when adjusting dosages. Common side effects include nausea, dizziness, or diarrhoea, but these gastrointestinal (GI) side effects usually go away as your body gets used to the treatment. The safety and tolerability profile of retatrutide was generally consistent with other incretin-based therapies such as semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro).

While retatrutide has generally been well-tolerated, clinical trials have also revealed a dose-dependent pattern with GI side effects. The dose of retatrutide will determine the severity of the side effects. Participants receiving higher doses of the drug were more likely to experience mild-moderate GI issues, such as nausea, vomiting, diarrhoea, and constipation.

Overall, clinical trials showed starting with a lower dose of around 2 mg can reduce the intensity and frequency of GI side effects, compared to a higher initial dose (4 mg). This suggests that healthcare providers can use a dose-titration method to achieve the balance between weight-loss efficacy and tolerability for individual patients.

While the FDA has not yet approved retatrutide, we recommend consulting with a healthcare provider.

📝 Conclusion

For healthcare professionals, the availability of retatrutide could expand their prescribing options and from the patient’s perspective, the prospect of retatrutide’s approval is particularly exciting as it is another treatment option to help achieve their weight management goals.

Phase 3 trials of retatrutide named the Triumph trials will provide invaluable insights into the long term weight-loss results of retatrutide as well as its potential impact on obesity-related conditions, such as osteoarthritis and obstructive sleep apnea. Additionally, these trials will help establish the long-term safety profile of the drug and address concerns about potential adverse events.

Sources

• Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial – New England Journal of Medicine
• American Diabetes Association Highlights Novel Agent Retatrutide which Results in Substantial Weight Reduction in People with Obesity or Type 2 Diabetes During Late Breaking Symposium | American Diabetes Association
• Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial – PMC