New research to be presented at the Annual Meeting of The European Association for the Study of Diabetes (EASD) in Milan, Italy (Sept 28 – Oct 2) and published in The Lancet shows that treatment with the new triple agonist therapy retatrutide results in substantial weight loss and improvements in blood sugar control in people living with obesity or overweight and type 2 diabetes – a population that has generally experienced less weight loss with obesity medications than people without diabetes. Study co-author Dr Juan Pablo Frías, Medical Director and Principal Investigator at Los Angeles Institute for Metabolic Research, Los Angeles, CA, USA, will present the study design and efficacy results. The study is sponsored by Eli Lilly, the manufacturer of retatrutide.
Retatrutide is an investigational triple agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors, currently under investigation for the treatment of obesity, type 2 diabetes, and other obesity-related complications, including cardiovascular disease, metabolic liver disease, knee osteoarthritis, chronic low back pain and obstructive sleep apnoea (OSA). In this 80-week trial, the authors aimed to assess the efficacy and safety of retatrutide in adults with overweight or obesity and type 2 diabetes.
This is a completed phase 3, randomised, double-blind, placebo-controlled trial conducted at 92 sites, including medical and research centres, and hospitals, across 8 countries (Argentina, Australia, Brazil, India, Mexico, Romania, Spain and the United States). The study enrolled adults (≥18 years) with a body mass index (BMI) ≥27 kg/m2 and type 2 diabetes (glycated haemoglobin HbA1c ≥6·5 to ≤10·5%).
Participants were randomly assigned 1:1:1:1 to receive once-weekly subcutaneous injections of placebo, retatrutide 4 mg, 9 mg, or 12 mg, alongside dietary counselling and guidance on physical activity. The primary endpoint was the percent change from baseline in body weight at Week 80, and change from baseline in HbA1c at Week 80 was a key secondary endpoint.
A total of 2047 participants were screened, and 1152 were randomly assigned to retatrutide 4 mg (n=292), 9 mg (n=284), 12 mg (n=287), or placebo (n=289). At baseline, the mean age was 55·1 years, 554 (48%) were female and 592 (52%) were male, mean BMI was 38·2 kg/m2, mean HbA1c was 7·71%, median duration of obesity was 21 years, and median duration of diabetes was 5·6 years. At randomisation, the percent of participants on any oral glucose lowering medication was 92%, including biguanides, SGLT-2 inhibitors, sulfonylureas, and other oral glucose lowering medications. Overall, 1046 participants (91%) completed the study, including 965 (84%) who completed it on study treatment.
The mean percent change from baseline in body weight at Week 80 was −11·9% with retatrutide 4 mg, −16·8% with retatrutide 9 mg, −18·8% with retatrutide 12 mg, and −5·1% with placebo. Estimated treatment differences (ETD) compared with placebo for percent change in body weight were −6·9% with retatrutide 4 mg, −11·8% with retatrutide 9 mg, and −13·8% with retatrutide 12 mg.
The mean change from baseline in HbA1c at Week 80 was −1·38% with retatrutide 4 mg, −1·50% with retatrutide 9 mg, −1·45% with retatrutide 12 mg, and −0·45% with placebo.
At the 12 mg dose, 47% of participants lost at least 20% of their starting weight, and 31% lost at least 25%, compared with 6% and 3%, respectively, with placebo. Additionally, 72% achieved an HbA1c of 6.5% or lower, compared with 29% with placebo (see table 2, page 10 full paper). Retatrutide also significantly improved cardiometabolic risk factors, including blood pressure and lipid profiles, and reduced high-sensitivity C-reactive protein (hsCRP), a marker of inflammation.
The most frequently reported adverse events were gastrointestinal, which were more common in the retatrutide groups. Diarrhoea occurred in 27-34% (n=80-96) of participants in the retatrutide groups compared with 13% (n=38) in the placebo group, and nausea occurred in 14-28% (n=40-80) of participants with retatrutide compared with 8% (n=23) with placebo.
Hypotension (abnormally low blood pressure), orthostatic hypotension, or decreased blood pressure occurred in 1%, 5%, and 6% of participants receiving retatrutide 4 mg, 9 mg, and 12 mg, respectively, compared with less than 1% receiving placebo. Dysesthesia (abnormal skin sensations, such as burning or discomfort) occurred in 4%, 6%, and 7% in the 4 mg, 9 mg, and 12 mg retatrutide groups, respectively, compared with 1% receiving placebo. None of the dysesthesia events were severe or serious.
Permanent treatment discontinuation due to adverse events or death was more frequent in participants treated with retatrutide 9 mg (12% [n=33]) and 12 mg (8% [n=22]) compared with retatrutide 4 mg (4% [n=11]) and placebo (5% [n=14]). Seven deaths occurred in the study: 2 in the retatrutide 4 mg group, 3 in the 9 mg group, 1 in the 12 mg group, and 1 in the placebo group, and were deemed unrelated to the study intervention by the investigator.
The authors conclude: "There is an unmet need for more efficacious weight reduction in individuals with obesity and type 2 diabetes...Findings from TRIUMPH-2 suggest that retatrutide may advance the treatment of obesity and type 2 diabetes, a population where weight reduction has been challenging to achieve. Retatrutide demonstrated substantial reduction in body weight alongside improvements in bloods sugar control and cardiometabolic risk factors, with a safety profile generally similar to other molecules with GLP-1 receptor agonist activity. These findings support obesity treatment as a strategy for people with obesity and type 2 diabetes. Further studies are required to determine whether these benefits translate to improvements in other obesity-related complications."
