How fast does retatrutide work?

Obesity has become a global health epidemic, affecting millions worldwide and posing significant risks to individual well-being and public health. As the prevalence of this chronic condition continues to rise, the search for effective and safe treatment options has intensified. Enter retatrutide, a novel incretin mimetic agent, a promising solution to the obesity crisis.

Retatrutide is a new weight loss drug showing promise among the popular fat loss medications Wegovy/Ozempic (semaglutide) and Zepbound/Mounjaro (tirzepatide). It is manufactured by Eli Lilly for the treatment of obesity. Retatrutide works by simultaneously targeting three key receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor, the glucagon-like peptide-1 (GLP-1) receptor, and the glucagon (GCG) receptor. This triple-agonist approach sets retatrutide apart from traditional weight loss medications, offering the potential for enhanced efficacy and a more comprehensive impact on the underlying mechanisms of obesity.

The science behind retatrutide’s rapid weight loss

The weight management potential of retatrutide can be linked to its pharmacological profile. Compared to the endogenous receptor ligands, retatrutide exhibits a reduced potency at the human GCG and GLP-1 receptors (by a factor of 0.3 and 0.4, respectively) but a significantly enhanced potency at the human GIP receptor (by a factor of 8.9). This unique balance of receptor activation is believed to play a crucial role in the drug’s ability to regulate appetite, energy expenditure, and glucose homeostasis effectively.

Appetite suppression and delayed gastric emptying

Retatrutide’s agonist effects on the GLP-1 and GCG receptors contribute to its appetite-suppressing properties. GLP-1 is known to delay gastric emptying, which slows the rate of nutrient absorption and promotes a prolonged sense of fullness. Similarly, glucagon can also slow gastric emptying, further enhancing the feeling of satiety and reducing caloric intake.

Increased energy expenditure

The GCG receptor agonism exhibited by retatrutide is thought to amplify energy expenditure, potentially through its influence on thermogenesis and substrate utilisation. Glucagon has been shown to stimulate the breakdown of stored fat (lipolysis) and increase the body’s metabolic rate, leading to a greater caloric burn and ultimately facilitating weight loss.

Improved blood glucose regulation

Retatrutide’s actions on the GIP receptor, which is known to enhance insulin secretion in a glucose-dependent manner, contributes to improved glucose homeostasis. This in turn, can help mitigate the development of obesity-related comorbidities, such as type 2 diabetes, by maintaining healthy blood sugar levels.

Rapid weight loss observed in clinical trials

The impressive weight-loss results observed in clinical trials have been a key driver of the excitement surrounding retatrutide. These studies have consistently demonstrated the drug’s ability to deliver rapid and substantial reductions in body weight, often surpassing the efficacy of other approved weight loss medications.

Phase 2 trial results

A phase 2, double-blind, randomised, placebo-controlled trial involving 338 adults with obesity or overweight revealed the potent weight-loss capabilities of retatrutide. At the 24-week mark, participants receiving the drug experienced remarkable reductions in body weight, ranging from -7.2% in the 1 mg group to -17.5% in the 12 mg group, compared to a mere -1.6% in the placebo group.

The weight-loss results continued to impressive levels at the 48-week endpoint, with the 12 mg retatrutide group achieving a mean weight reduction of -24.2%, while the placebo group only saw a -2.1% change. Notably, a substantial proportion of retatrutide recipients (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.

Rapid onset of weight loss

One of the standout features of retatrutide is the rapid onset of its weight-loss effects. In the phase 2 trial, participants began experiencing notable reductions in body weight as early as 24 weeks, with the higher-dose groups (8 mg and 12 mg) demonstrating the most pronounced changes.

This rapid weight-loss trajectory is particularly compelling, as it suggests that retatrutide may be able to deliver meaningful results in a relatively short timeframe, potentially offering a faster path to improved health outcomes for individuals struggling with obesity.

Dose-dependent efficacy and safety profile

The clinical trials have also revealed the dose-dependent nature of retatrutide’s weight-loss efficacy and safety profile, providing valuable insights for optimal therapeutic management.

Dose-dependent weight loss

The phase 2 trial demonstrated a dose-dependent relationship between retatrutide and weight loss. As the dosage increased, the magnitude of weight reduction also escalated, with the 12 mg highest dose group achieving the most substantial results. This dose-response relationship suggests that healthcare providers can tailor the retatrutide regimen to the individual needs and preferences of their patients, potentially maximising the weight-loss outcomes.

Dose-dependent side effects

While retatrutide has generally been well-tolerated, the clinical trials have also revealed a dose-dependent pattern in the occurrence of adverse events, particularly gastrointestinal (GI) side effects. Participants receiving higher doses of the drug were more likely to experience mild-to-moderate GI issues, such as nausea, vomiting, diarrhoea, and constipation. Notably, the trials also found that a lower starting dose (2 mg) during the dose-escalation phase could help mitigate the frequency and severity of these GI side effects, compared to a higher initial dose (4 mg). This suggests that healthcare providers can employ strategic dose-titration strategies to optimise the balance between weight-loss efficacy and tolerability for individual patients.

Potential for cardiometabolic benefits

In addition to its impressive weight-loss capabilities, retatrutide has also demonstrated the potential to deliver broader cardiometabolic benefits, which could have far-reaching implications for the comprehensive management of obesity and related comorbidities.

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 glycated haemoglobin (HbA1c) levels. In the phase 2 trial, a remarkable 72% of participants with prediabetes at baseline were able to revert to normoglycemia (HbA1c < 5.7%) 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 homeostasis, 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.

Notably, the improvements in blood pressure were substantial enough to result in the discontinuation of at least one antihypertensive medication in a notable proportion of retatrutide-treated participants, further highlighting the drug’s potential to mitigate obesity-related cardiovascular complications.

Ongoing and future research

As the excitement surrounding retatrutide continues to build, the research community is actively engaged in exploring the full extent of the drug’s capabilities and its long-term implications for the management of obesity and related conditions.

Phase 3 Trials: Evaluating long-term efficacy and safety

The next phase of clinical development for retatrutide is the initiation of large-scale phase 3 trials, known as the Triumph trials. These studies aim to further evaluate the long-term safety and efficacy of retatrutide in diverse patient populations, including those with obesity, overweight, and type 2 diabetes.

The Triumph trials will provide invaluable insights into the durability of retatrutide’s weight-loss effects, as well as its potential impact on obesity-related comorbidities, such as osteoarthritis and obstructive sleep apnea. Additionally, these trials will help establish the long-term safety profile of the drug, addressing any lingering concerns about potential adverse events.

Conclusion

The rapid weight-loss capabilities of retatrutide, coupled with its potential to deliver broader cardiometabolic benefits, have positioned this novel incretin mimetic agent as a promising solution in the fight against the global obesity epidemic. The dose-dependent nature of retatrutide’s efficacy and safety profile, along with the insights gained from ongoing and future research, will be instrumental in optimising its clinical application and maximising the positive impact on the health and well-being of individuals struggling with obesity and related conditions.

As the research community continues to explore the full potential of retatrutide, healthcare providers and policymakers must work together to ensure that this innovative treatment becomes a viable and accessible option for those in need. With the right strategies and collaborative efforts, retatrutide could pave the way for a new era in the management of obesity and its associated comorbidities, ultimately improving the lives of millions around the world.

Sources

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