In the phase III TRIUMP-2 trial, retatrutide improves glycaemic control and reduces body weight in adults with type 2 diabetes (T2D) who are overweight or have obesity, potentially expanding weight-loss options for this population.
Participants taking retatrutide—an investigational triple hormone receptor agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon—achieved a mean body weight loss of 18.8 percent (45.6 lb) at 80 weeks when randomized to the highest dose (12 mg). Corresponding reductions were 16.8 percent (40.3 lb) with the 9 mg dose and 11.9 percent (28.5 lb) with the 4 mg dose, compared with 5.1 percent (12.8 lb) with placebo. [Lancet 2026;doi:10.1016/ S0140-6736(26)01861-1]
On top of background diabetes therapy, the mean change in HbA1c from baseline to week 80 was −1.45 percent with the 12-mg dose, −1.50 percent with the 9-mg dose, and −1.38 percent with the 4-mg dose, compared with −0.45 percent with placebo. Up to 40 percent of retatrutide-treated participants achieved normoglycaemia (HbA1c <5.7 percent).
Weight reduction challenging
“Findings from TRIUMPH-2 suggest that retatrutide could advance treatment for people with obesity and T2D, a population in which weight reduction has been challenging,” said Dr Virginia Bellido of Virgen del Rocío University Hospital in Seville, Spain.
“We know that people with T2D lose less weight than those without diabetes. We see this irrespective of the weight-loss method, whether it’s pharmacotherapy or metabolic surgery," said Dr Juan Frias of the Los Angeles Institute for Metabolic Research in Los Angeles, California, US, who presented the findings at EASD 2026.
Interestingly, he said the weight loss observed in TRIUMPH-2 had previously been seen only in patients without diabetes (13.2 percent with semaglutide and 15.7 percent with tirzepatide in previous clinical data).
In the efficacy estimand (which assumes all participants take the study medication as intended, without intercurrent events), weight loss reached 20.8 percent with the highest retatrutide dose. “We’re reaching that threshold … over 50 percent of patients had >15 percent weight loss,” reported Frias.
The more, the better?
“The reason we’re seeing more robust weight loss than with selective GLP-1 RAs and dual agonists is that we’re engaging another system,” Frias explained. “We have GIP, GLP-1, and glucagon. These three hormones act centrally to reduce appetite through both distinct and overlapping mechanisms. In T2D, it appears that you need to engage as many of these pathways as possible.”
“However, the weight loss we observed in TRIUMP-2 was still lower than the 28.3 percent achieved in TRIUMPH-1, which tested retatrutide in individuals with obesity or overweight but without diabetes. Hence, there remains an unmet need for more effective weight reduction in individuals with obesity and T2D,” he added.
In an accompanying editorial, Dr Jens Juul Holst of the University of Copenhagen in Denmark noted that despite the overall good results, weight loss and HbA1c changes with retatrutide in TRIUMPH-2 were comparable to those in TRANSCEND-T2D-1. This suggests that weight loss remains disproportionate among people with diabetes.
“Otherwise, the results are, of course, impressive, even when compared with those of other incretin-based agents. Thus, the inclusion of glucagon agonism in the triple agonist might be viewed as beneficial,” Holst writes. He adds, however, that long-term follow-up of patients on triple agonists will be important to ensure prolonged use does not affect amino acid or protein metabolism. [Lancet 2026;408:1398-1399]
TRIUMPH-2 population
At baseline, the average BMI was 38.2, HbA1c was 7.71 percent, median obesity duration was 21 years, and median diabetes duration was 5.6 years. Participants were on stable background glucose-lowering therapy with up to three oral agents for at least 90 days before screening and had a history of diet-based weight-loss attempts.
TRIUMPH-2 was not designed to assess hard clinical outcomes. Still, the investigators noted improvements in several cardiometabolic secondary endpoints with retratrutide, including reductions from baseline of up to 15.4 cm in waist circumference, 35.6 percent in triglycerides, 16.5 percent in non-HDL cholesterol and 56.1 percent in high-sensitivity C-reactive protein.
The trial was conducted at 92 medical and research centres across eight countries. Participants were randomized 1:1:1:1 to receive once-weekly subcutaneous injections of retatrutide 4 mg, 9 mg,12 mg, or placebo.
Overall, 3−11 percent of patients in the retatrutide groups discontinued study treatment due to adverse events, compared with 5 percent of placebo recipients. Gastrointestinal events, mainly nausea, diarrhoea, and constipation, were the most common adverse events. Discontinuation due to GI symptoms was low (0-2 percent with retatrutide vs 1 percent with placebo).