The triple hormone receptor agonist retatrutide has shown weight loss reductions of over 30% in some phase 3 trial participants – a level long associated with bariatric surgery – according to its manufacturer Eli Lilly.
The once-weekly investigational molecule activates the body’s receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. These three hormone pathways play a key role in glucose metabolism and appetite regulation.
While semaglutide activates GLP-1 receptors, and tirzepatide activates both GIP and GLP-1 receptors, retatrutide also activates a third – glucagon. By targeting this pathway, it is thought that retatrutide may help its users to consume less and the body to burn more energy.
Retatrutide efficacy
The phase 3 randomised, double‑blind, placebo‑controlled TRIUMPH-1 trial evaluated the safety and efficacy of retatrutide for the treatment of patients with obesity or overweight, moderate-to-severe obstructive sleep apnoea and obesity, and knee osteoarthritis pain.
For the master trial focusing on obesity or overweight, 2,339 eligible adults who had at least one weight-related comorbidity – but without diabetes – were randomised in a 1:1:1:1 ratio to receive retatrutide in doses of 4 mg, 9 mg, 12 mg, or a placebo.
Those randomised to retatrutide initiated treatment with 2 mg once weekly and increased the dose in a step-wise approach every four weeks until reaching the target doses for their group.
The primary endpoints was the percent change from baseline in body weight, while secondary endpoints included change from baseline in body mass index (BMI), waist circumference and systolic blood pressure.
At 80 weeks, all three doses of retatrutide met the primary and key secondary endpoints for obesity, delivering clinically meaningful weight loss.
Participants taking the highest 12 mg dose of retatrutide lost an average of 28.3% of their body weight (31.9 kg) over 80 weeks, while those on the lowest 4 mg dose lost an average of 19.0% of their body weight (21.4 kg). In contrast, participants in the placebo group lost an average of 2.2% of their body weight (2.5 kg) during the 80-week period.
A total of 45.3% of participants taking retatrutide 12 mg achieved at least a 30% weight loss, which is a level long associated with bariatric surgery.
In addition, 65.3% of participants in this highest dose group achieved a BMI of less than 30, falling under the threshold for obesity at 80 weeks. Notably, this included 37.5% of those who started with a BMI of 40 or more.
Retatrutide also showed significant improvements from baseline across cardiovascular risk factors, such as waist circumference, non-HDL cholesterol, triglycerides, systolic blood pressure and high-sensitivity C-reactive protein.
Extension study and safety
A pre-specified extension period of 104 weeks included 532 participants with a BMI of 35 or more at baseline who completed the main 80-week study and had tolerated their assigned dose of medication. They received retatrutide once weekly for an additional 24 weeks, including a blinded escalation to maximum tolerated dose of 9 mg or 12 mg.
Participants maintaining the highest 12 mg dose of retatrutide lost an average of 30.3% of their body weight (38.5 kg) at 104 weeks, while those moving from the lowest 4 mg dose to the maximum tolerated dose lost an average of 27.9% of their body weight (33.2 kg). Those moving from a 9 mg dose to the maximum tolerated dose saw an average loss of body weight of 29.5% (36.6 kg).
Participants who had received the placebo up to week 80, achieved an average of 19.2% reduction in body weight at 104 weeks after switching to the maximum tolerated dose of retatrutide.
Across the study period, adverse events were generally consistent with trials of other incretin-based therapies and typically worsened with dose escalation (4 mg, 9 mg, 12 mg, vs. placebo, respectively). The most common were nausea (28.6%, 38.4% and 42.4% vs 14.8%), diarrhoea (25.2%, 34.1% and 32.0% vs 13.5%), constipation (23.8%, 25.9% and 26.1% vs 10.9%), vomiting (10.6%, 22.8% and 25.3% vs 4.8%), and upper respiratory tract infection (14.2%, 12.2% and 13.1% vs 11.6%).
Dysesthesia occurred in 5.1% (4 mg), 12.3% (9 mg), and 12.5% (12 mg) of patients treated with retatrutide, compared to 0.9% with placebo, although this was generally mild to moderate and resolved during treatment.
Discontinuation rates due to adverse events were 4.1% (4 mg), 6.9% (9 mg) and 11.3% (12 mg), compared to 4.9% with placebo.
Potential as ‘a highly impactful future tool’
Lead investigator Dr Ania Jastreboff, professor of medicine and pediatrics (endocrinology) at the Yale School of Medicine and director of the Yale Obesity Research Center, said: ‘It was impressive to see that every dose of retatrutide resulted in clinically meaningful weight reduction for nearly all participants, and people with severe obesity on the highest dose lost on average 30% of their body weight over two years.
‘Importantly, treatment with retatrutide not only resulted in robust weight reduction, but also in clear improvements in assessed cardiometabolic health measures.
‘For patients I see in clinic, retatrutide may potentially be a highly impactful future tool to treat their obesity and transform their health trajectory.’
Commenting on the topline results, Professor Graham Finlayson, chair in psychobiology at the University of Leeds, said it was ‘striking’ to see retatrutide reaching the weight loss range ‘historically associated with bariatric surgery’ and that the ‘headline efficacy results are impressive, particularly the proportion of participants reported to achieve very large weight losses.’
He added: ‘In principle, that broader pharmacology could produce larger effects on body weight and metabolism, although the full peer-reviewed data will be needed to understand the balance between efficacy, tolerability and discontinuation.’
While this clinical trial did not examine weight regain after stopping retatrutide, other studies have found that discontinuing weight-loss medications such as semaglutide and liraglutide typically results in near-total weight regain within about 18 months.
However, a recent study has shown that a daily orforglipron pill can help to maintain weight loss after injectable use.
Results of the two basket trials for moderate-to-severe obstructive sleep apnoea and knee osteoarthritis pain are expected to be released in due course.
These phase 3 master trial results follow phase 2 trial results published in 2023.