For individuals with type 2 diabetes (T2D) that is inadequately controlled by diet and exercise alone, once-weekly administration of the triple hormone receptor agonist retatrutide helps improve glycaemic control, and this benefit is accompanied by substantial weight reduction, as shown in the phase III TRANSCEND-T2D-1 study.
Over 40 weeks, the mean change in HbA1c concentration was significantly greater with all retatrutide doses than with placebo: –1.69 percent with 4 mg, –1.86 percent with 9 mg, and –1.94 percent with 12 mg vs –0.81 percent (p<0.0001 for all). [Lancet 2026;doi:10.1016/S0140-6736(26)00967-0]
Among retatrutide-treated participants, 82 percent to 89 percent met the HbA1c target of <7 percent and 75 percent to 83 percent met the ≤6.5-percent target.
“Furthermore, HbA1c levels of <5.7 percent, representing a normal value for HbA1c, were reached by 35 percent to 40 percent of participants treated with retatrutide, without any case of severe hypoglycaemia,” according to first study author Dr Harpreet Bajaj from LMC Diabetes and Endocrinology, Brampton, Ontario, Canada, and colleagues.
“Reductions in HbA1c did not appear to reach a plateau by the end of the 40-week treatment period in the retatrutide 9- and 12-mg groups,” Bajaj and colleagues added.
Meaningful weight loss
“Clinically meaningful bodyweight reduction was observed with retatrutide in TRANSCEND-T2D-1,” the authors noted.
Over 40 weeks, the mean percentage reductions in bodyweight were 11.5 percent with retatrutide 4 mg, 13.9 percent with 9 mg, and 15.3 percent with 12 mg vs 2.6 percent with placebo (p<0.0001 for all).
More participants treated with retatrutide vs placebo had bodyweight reductions of ≥5 percent (75 percent to 85 percent vs 26 percent), ≥10 percent (52 percent to 70 percent vs 7 percent), and ≥15 percent (31 percent to 51 percent vs 3 percent).
“Bodyweight reduction had not plateaued by the end of the 40-week treatment period,” said Bajaj and colleagues.
Dual metabolic targets met
Notably, 41 percent to 64 percent of retatrutide-treated participants reached the composite endpoint of HbA1c ≤6.5 percent and bodyweight reduction of ≥10 percent at week 40 compared with only 3 percent of those who received placebo.
The finding demonstrates the efficacy of retatrutide in improving glycaemic control while simultaneously driving clinically meaningful weight reduction, according to Bajaj and colleagues. They highlighted the clinical implications of the composite endpoint, saying that lowering blood sugar and losing weight early on can permanently slow down or reverse T2D.
“Composite endpoints of this kind more comprehensively capture overall treatment benefit than either measure alone, and their adoption in diabetes trials should be considered,” they said.
TRANSCEND-T2D-1 study
TRANSCEND-T2D-1 was conducted at 48 sites in the US, Mexico, and India. The study involved adults with T2D that was inadequately controlled by diet and exercise alone, HbA1c between 7 percent and 9.5 percent, and BMI of at least 23 kg/m2.
A total of 537 participants (mean age 48.8 years, 55 percent female) were randomly assigned to receive retatrutide at 4 mg (n=134), 9 mg (n=133), or 12 mg (n=136) or placebo (n=134). Treatment was administered as a once-weekly subcutaneous injection for 40 weeks.
The mean duration of diabetes in the cohort was 2.5 years. At baseline, the mean HbA1c concentration was 7.9 percent, and the mean BMI was 35.8 kg/m2.
Retatrutide also improved other cardiometabolic outcomes, including lipid profile and blood pressure, over 40 weeks. Triglycerides decreased by 26.7 percent to 34.1 percent, non-high-density lipoprotein cholesterol declined by 15.5 percent to 17 percent, and systolic blood pressure dropped by 4.7–5 mm Hg.
“The safety profile was overall consistent with molecules with GLP-1 agonist activity, with the most commonly reported adverse events (AEs) being mild to moderate gastrointestinal events, which subsided over time,” Bajaj and colleagues noted.
AEs led to treatment discontinuation in 2 percent to 5 percent of participants treated with retatrutide. Two deaths were documented in the retatrutide 4-mg group, both of which were unrelated to the study drug.
Bajaj presented the TRANSCEND-T2D-1 data at the annual ADA meeting.
Manage weight in T2D
“Retatrutide, the first triple-agonist agent, may not provide incremental improvements in glycaemic control compared with existing monoagonist and dual-agonist therapies, but its principal advantage is greater weight reduction,” wrote Drs Shuyao Zhanga and Ildiko Lingvay from the University of Texas Southwestern Medical Center, Dallas, Texas, US, in an accompanying editorial. [Lancet 2026;doi:10.1016/S0140-6736(26)01136-0]
The glucose-lowering effects of retatrutide in TRANSCEND-T2D-1 were broadly similar to those reported in SUSTAIN-1 with semaglutide 1 mg (–1.53 percent) and in SURPASS-1 with tirzepatide 15 mg (–1.6 percent), noted Zhanga and Lingvay. [Lancet Diabetes Endocrinol 2017;5:251-260; Lancet 2021;398:143-155]
On the other hand, the weight loss benefit with retatrutide was greater than that achieved with semaglutide and tirzepatide in SUSTAIN-1 (–3.9 percent) and SURPASS-1 (–7.9 percent), respectively. [Lancet Diabetes Endocrinol 2017;5:251-260; Lancet 2021;398:143-155]
“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,” Zhanga and Lingvay said.
“Meanwhile, the results of the TRANSCEND-T2D-1 trial are likely to position retatrutide as a best-in-class nutrient-stimulated hormone-based therapy for reaching weight management goals in people with T2D,” they concluded.