NEW ORLEANS — Monotherapy with once-weekly retatrutide, an investigational triple hormone receptor agonist, improved glycemic control and body weight in adults with type 2 diabetes, the phase III TRANSCEND-T2D-1 trial showed.
Among 537 adults, average change from baseline in HbA1c concentration was -1.69% with retatrutide 4 mg, -1.86% with 9 mg, and -1.94% with 12 mg compared with -0.81% with placebo by week 40 in the treatment regimen estimand (all P<0.0001), reported Harpreet S. Bajaj, MD, MPH, of LMC Diabetes and Endocrinology in Ontario, Canada.
Retatrutide-treated participants ended with an HbA1c between 5.9% to 6.2% compared with 7.2% in those given placebo, he said at the American Diabetes Association (ADA) Scientific Sessions.
“HbA1c levels of less than 5.7%, representing a normal value for HbA1c, were reached by 35-40% of participants treated with retatrutide, without any case of severe hypoglycemia,” the authors wrote in The Lancet, where the findings were simultaneously published. “Reductions in HbA1c did not appear to reach a plateau by the end of the 40-week treatment period in the retatrutide 9 mg and 12 mg groups.”
The HbA1c reduction is similar to that of dual GLP-1 and GIP agonists, Bajaj noted during a press conference. For example, tirzepatide (Mounjaro) was associated with a 1.5% reduction in HbA1c when used as a standalone therapy in a trial.
Retatrutide is not only a GLP-1 and GIP agonist, but is also an agonist of glucagon. “Traditional thinking is maybe glucagon agonism may increase the glucose, but that’s not what we see in these study results,” said Bajaj. “On the other hand, the benefit of glucagon agonism is on weight reduction.”
Meeting a key secondary endpoint, participants lost 11.5% of body weight with retatrutide 4 mg, 13.9% with 9 mg, and 15.3% with 12 mg versus 2.6% with placebo; weight reduction had not yet plateaued by the end of the treatment period.
This level of weight loss is “staggering,” said Bajaj, who noted it had never been seen before in a phase III diabetes trial. “We know that people with diabetes lose on average less weight compared to people without diabetes.”
In an accompanying commentary, Shuyao Zhang, MD, and Ildiko Lingvay, MD, MPH, both of University of Texas Southwestern Medical Center in Dallas, noted that retatrutide’s “principal advantage” is greater weight reduction rather than glycemic control.
“Whether this incremental weight loss translates into improved clinical outcomes, enhanced quality of life, or other patient-reported benefits remains uncertain,” they continued. “GLP-1 receptor mono-agonists have already shown benefits to weight, glycemia, cardiovascular risk factors, cardiorenal outcomes, liver health, and some obesity-related complications such as osteoarthritis.”
“As a plethora of multireceptor modulators are being developed, the question is not merely whether they will have the same benefits but whether broader receptor engagement confers distinct metabolic advantages (such as improvements in bone health or muscle strength), disease-modifying effects for either diabetes (such as β-cell preservation) or obesity (such as resetting the defended weight), and improved tolerability resulting from the additional mechanism(s) of action,” the duo noted.
“For retatrutide and other multireceptor modulators to warrant a distinct role in treatment algorithms, they must show clinically meaningful benefits beyond what is already attributed to GLP-1 receptor agonism, with advantages that clearly outweigh any additional tolerability concerns or treatment burden,” wrote Zhang and Lingvay.
For the double-blind TRANSCEND-T2D-1 trial, 537 adults with type 2 diabetes inadequately controlled by diet and exercise were randomized between April 2024 and April 2025. All had an HbA1c between 7% and 9.5% and a body mass index (BMI) of at least 23. The average age was 48.8, HbA1c was 7.9%, duration of diabetes was 2.5 years, and BMI was 35.8.
As expected, the most frequent adverse events with retatrutide were gastrointestinal, but were mild to moderate and subsided over time. No participants on placebo discontinued due to adverse events, while 2-5% of those on retatrutide did.
Two deaths occurred — both among those taking retatrutide — but were deemed unrelated to the study drug.
Since the population was largely medication-naïve, the findings may not be generalizable to patients who are already on an antihyperglycemic or insulin regimen, Bajaj’s team noted.
However, some lingering questions may be resolved by the additional ongoing TRANSCEND-T2D trials, they noted. TRANSCEND-T2D-2 is investigating retatrutide compared with semaglutide (Ozempic) over 80 weeks in participants with type 2 diabetes using metformin with or without an SGLT2 inhibitor, and TRANSCEND-T2D-3 is investigating retatrutide compared with placebo over 52 weeks in participants with type 2 diabetes and renal impairment.
