What is the drug retatrutide used for?

Obesity and overweight have become global health crises, with millions struggling to manage their weight and the associated health risks. As the prevalence of these conditions continues to rise, the search for effective and safe treatment options has become increasingly crucial. Enter retatrutide, a novel drug manufactured by Eli Lilly and Company that has shown promising results in clinical trials for significant weight reduction.

In this article, we will look into the world of retatrutide, exploring its mechanism of action, clinical trial findings, and the potential it holds in the battle against obesity and overweight.

Understanding obesity and overweight

Obesity and overweight are characterised by excessive accumulation of fat in the body, leading to a range of health complications. The World Health Organization (WHO) defines overweight as a body mass index (BMI) greater than 25 kg/m², and obesity as a BMI exceeding 30 kg/m².

These conditions are not simply the result of excessive food intake. Rather, they are influenced by a complex connection of biological, genetic, and psychosocial factors. Rare genetic disorders, such as Prader-Willi syndrome, have also been identified as contributors to obesity.

The consequences of obesity and overweight are far-reaching, including an increased risk of cardiovascular disease, diabetes, stroke, and pregnancy-related complications. Even modest weight reductions of 5-10% can bring about significant cardiovascular and metabolic benefits, highlighting the importance of effective weight management strategies.

How does retatrutide work?

Retatrutide works as a powerful tri-agonist on three key receptors:

• The human glucagon receptor (GCGR)
• The glucose-dependent insulinotropic polypeptide receptor (GIP)
• The glucagon-like peptide-1 receptor (GLP-1)

This unique receptor profile allows retatrutide to effectively regulate appetite, feelings of fullness, and gastric emptying, ultimately leading to weight reduction. In comparison, Wegovy and Ozempic only work on the GLP-1 and GIP receptors.

Results from clinical trials

The promising potential of retatrutide has been demonstrated in several clinical trials, showcasing its remarkable efficacy in driving substantial weight loss and improving cardiometabolic outcomes.

Phase 2 clinical trial

A phase 2, randomised, double-blind, placebo-controlled trial involving 338 adults with obesity or overweight (BMI ≥ 30 or BMI ≥ 27 with at least one weight-related condition) provides strong evidence for retatrutide’s efficacy.

Key findings:

• People who received retatrutide at doses ranging from 1 mg to 12 mg experienced significant weight loss compared to the placebo group
• At 24 weeks, the percentage change in body weight ranged from -7.2% in the 1 mg group to -17.5% in the 12 mg group, compared to -1.6% in the placebo group
• At 48 weeks, the percentage change in body weight ranged from -8.7% in the 1 mg group to -24.2% in the 12 mg group, compared to -2.1% in the placebo group
• A large proportion of people receiving retatrutide (64% to 100%) achieved a weight reduction of 5% or more, with some participants even losing 30% or more of their baseline weight
• Retatrutide treatment showed improvements in cardiometabolic measures, including reductions in glycated haemoglobin (HbA1c), fasting glucose, insulin, blood pressure, and lipid levels

Safety and tolerability

The safety profile was generally favourable, with the most common side effects of retatrutide being mild to moderate gastrointestinal issues, such as nausea, vomiting, diarrhoea, and constipation. These side effects were more frequent in the higher-dose groups and were partially reduced by starting with a lower initial dose.

Importantly, no serious safety concerns were reported, and the incidence of serious adverse events was similar between the retatrutide and placebo groups. Additionally, there were no cases of clinically significant hypoglycemia, medullary thyroid cancer, or C-cell hyperplasia observed during the trials.

Retatrutide’s potential impact on obesity and cardiometabolic health

The significant weight loss achieved with retatrutide, along with its favourable safety profile, suggests that this triple-receptor agonist could be a good option for the treatment of obesity and related cardiometabolic conditions such as fatty liver disease, diabetes mellitus, and high cholesterol.

Weight loss

The clinical trial data indicate that retatrutide has the potential to be a weight loss drug, with some participants achieving reductions of 30% or more of their baseline weight. This amount of weight loss is rarely observed with other approved drugs, making retatrutide a promising candidate for the management of severe obesity.

Cardiometabolic benefits

The improvements in cardiometabolic markers, such as HbA1c, fasting glucose, insulin, blood pressure, and lipid profiles, seen in the retatrutide trials suggest that retatrutide may have the power to address the underlying metabolic dysregulation associated with obesity.

Implications for clinical practice

Healthcare providers may consider setting more ambitious targets for weight reduction, as the great losses observed with retatrutide could potentially mean greater improvements in overall health and quality of life for patients.

Future research

The promising results from the phase 2 trials mean retatrutide can move forward into larger, phase 3 clinical studies. The Triumph trials, currently underway, are designed to further investigate the long-term safety and efficacy of retatrutide in individuals with obesity, overweight, or type 2 diabetes. Additionally, the exploration of other GIP-GCG-GLP-1 receptor agonists, such as HM15211 and SAR441255, may offer further advancements in the field of obesity pharmacotherapy.

Comparing retatrutide to other weight loss medications

Retatrutide belongs to a class of drugs known as incretin mimetic agents, which also includes medications like liraglutide and semaglutide. These drugs work by targeting the incretin system, which plays a role in regulating appetite, glucose regulation, and weight management.

In comparison to other FDA-approved (Food and Drug Administration) weight loss medications, such as orlistat, phentermine-topiramate, and naltrexone-bupropion, retatrutide has demonstrated superior weight loss efficacy. While most of these drugs typically achieve a weight reduction of less than 15%, the clinical trials on retatrutide have reported weight losses of up to 24.2% at the 48-week mark.

Retatrutide’s unique mechanism of action, which targets multiple receptors (GCGR, GIPR, and GLP-1R), sets it apart from the more selective agonists like semaglutide, which primarily targets the GLP-1R.

Conclusion

Retatrutide, a novel triple-receptor agonist, has emerged as a promising solution in the fight against the global obesity epidemic. Its unique mechanism of action, targeting the GIP, GLP-1, and GCG receptors, has demonstrated remarkable potential for driving substantial and sustained weight loss, as well as improving cardiometabolic health.

The clinical evidence from phase 2 trials has been highly encouraging, with retatrutide showing superior weight loss efficacy and a favourable safety profile compared to existing obesity treatments. As research continues to unfold, the potential of retatrutide to change the management of obesity and related conditions is becoming increasingly promising.

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