What are the side effects of retatrutide?

Obesity has emerged as a global health crisis, with the World Obesity Federation projecting that over 4 billion individuals will be either obese or overweight by 2035. In the quest to combat this epidemic, researchers have been exploring new drugs, including retatrutide, a novel triple agonist targeting the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (GCG) receptors.

Retatrutide has shown promising results in clinical trials, showcasing significant body weight reduction potential. However, as with any medication, understanding the potential side effects is crucial for healthcare providers and individuals considering this treatment option. This article looks into retatrutide side effects, drawing insights from the latest clinical research to empower informed decision-making.

How does retatrutide work?

Retatrutide, also known as LY3437943 is manufactured by Eli Lilly. It is a unique molecule that acts as a tri-agonist for the GIP, GLP-1, and GCG receptors. This triple-hormone receptor activation is thought to enhance the medication’s efficacy in promoting weight loss by targeting multiple pathways involved in energy balance and appetite regulation.

Gastrointestinal side effects

The most frequently reported side effects associated with retatrutide treatment are gastrointestinal, including nausea, vomiting, diarrhea, and constipation. These events are often dose-dependent, with higher doses of retatrutide generally resulting in a higher incidence of gastrointestinal adverse events.

Clinical trials have shown that the use of a lower starting dose (2 mg) compared to a higher starting dose (4 mg) can partially reduce the frequency and severity of gastrointestinal side effects. This suggests that a gradual dose increase may be beneficial in managing these adverse events.

Cardiovascular side effects

Another area of concern with retatrutide is its potential impact on the cardiovascular system. Clinical trials have reported dose-dependent increases in heart rate, which peaked at 24 weeks and then declined after that point.

Cardiac arrhythmias

Trials also reported a small number of cases of cardiac arrhythmias, including supraventricular arrhythmias and prolonged QT syndrome. Importantly, these events were generally mild to moderate in severity, except for one severe case of prolonged QT syndrome associated with the use of the antiemetic medication, ondansetron.

Monitoring cardiovascular effects

Given the potential cardiovascular effects of retatrutide, close monitoring of heart rate and rhythm is recommended during treatment. Healthcare providers should be vigilant in identifying any signs of cardiac abnormalities.

Increase in liver enzymes

Clinical trials have also reported a small percentage of participants (1%) experiencing short-lived increases in alanine aminotransferase (ALT) levels to more than 3 times the upper limit of the normal range. However, it is important to note that mean ALT and aspartate aminotransferase (AST) levels remained stable or even decreased by the end of the 48-week treatment period.

While these liver enzyme level increases were generally without symptoms, healthcare providers must monitor liver function tests in individuals receiving retatrutide.

Skin-related side effects

Another side effect reported in the clinical trials was skin sensitivity to touch, pain, pressure and heat. These events were reported in approximately 7% of the participants receiving retatrutide, compared to 1% in the placebo group.

Importantly, these skin-related side effects were generally mild to moderate in severity and did not result in the discontinuation of retatrutide or placebo.

Serious side effects

While the majority of the reported side effects with retatrutide were mild to moderate in severity, clinical trials also recorded a small number of serious adverse events. These events affected approximately 4% of the participants in both the retatrutide and placebo groups, indicating that the incidence was similar between the treatment and control arms.

The serious adverse events reported in the trials included a range of medical conditions, such as acute pancreatitis and prolonged QT syndrome. Importantly, the researchers did not identify any relationship between these serious adverse events and the use of retatrutide.

Favourable side effects

Improvements in lipid and blood sugar levels

The trials have demonstrated that treatment with retatrutide was associated with significant improvements in measures such as glycated hemoglobin (HbA1c), fasting glucose, insulin levels, and cholesterol levels. These findings suggest that retatrutide may have a favourable impact on metabolic health, potentially offering additional benefits beyond weight loss.

While these cardiometabolic improvements are encouraging, healthcare providers should still closely monitor any changes in blood glucose, insulin, or lipid levels will be crucial to ensure the overall health and well-being of the patient.

Future research

The clinical development of retatrutide is ongoing, with several phase 3 trials, collectively known as the TRIUMPH program, currently underway. These trials are designed to further investigate the long-term safety, efficacy, and side effect profiles of retatrutide in diverse populations, including individuals with obesity, those overweight, with type 2 diabetes, obstructive sleep apnea, or osteoarthritis.

Expanding the understanding of side effects

The TRIUMPH trials are expected to provide valuable insights into the long-term side effect profile of retatrutide, as well as potential strategies to reduce any adverse events. Additionally, including participants from diverse backgrounds and with various comorbidities will help to shine a light on the side effect findings.

Benefit-risk profile

As the research on retatrutide continues to evolve, healthcare providers and individuals considering this treatment option can expect a deeper understanding of the medication’s side effect profile. This knowledge will be crucial in optimising the benefit-risk profile and guiding informed decision-making regarding the use of retatrutide in the management of obesity and related conditions.

Conclusion

The development of retatrutide, a novel triple-hormone receptor agonist, has generated significant interest in weight management. While the medication has demonstrated impressive weight loss results, understanding the potential side effects is essential for ensuring this treatment’s safe and effective use.

The available clinical trial data has revealed that the most commonly reported side effects of retatrutide are gastrointestinal, including nausea, vomiting, diarrhoea, and constipation. These events appear to be dose-dependent but can be partially mitigated through a gradual dose escalation approach.

Additionally, the trials have reported potential cardiovascular effects, such as dose-dependent increases in heart rate and a small number of cardiac arrhythmia cases. An increase in liver enzymes, and skin-related side effects, such as cutaneous hyperesthesia, have also been observed.

The ongoing TRIUMPH trials are expected to provide further insights into the long-term safety and side effect profiles of this innovative treatment of obesity.

Sources

• Unleashing the power of retatrutide: A possible triumph over obesity and overweight: A correspondence – PMC
• Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial – New England Journal of Medicine
• Lilly’s phase 2 retatrutide