In topline phase 3 results, retatrutide lowered A1C more and reduced weight more than semaglutide 2 mg at 80 weeks

1. Retatrutide lowered hemoglobin A1c (A1C) by 2.2 percentage points versus 1.8 percentage points with semaglutide 2 mg at 80 weeks and produced more than double the weight loss (19.5% and 20.9% versus 9.4%).

2. Treatment discontinuation due to adverse events occurred in 4.8% and 7.9% of participants receiving retatrutide 9 mg and 12 mg, respectively, versus 2.7% with semaglutide 2 mg.

Evidence Rating Level: 2 (Good)

2MM Brief: Eli Lilly and Company reported topline results from TRANSCEND-T2D-2 (NCT06260722), a head-to-head trial comparing semaglutide with investigational retatrutide in adults with type 2 diabetes. Retatrutide is a once-weekly agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon receptors. The phase 3, randomized, open-label trial enrolled 1,298 adults whose diabetes was inadequately controlled with metformin, with or without a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Eligible participants had an A1C of 7.0% to 10.5%; at baseline, mean A1C was 8.3%, mean body weight was 225.8 lb (102.4 kg) and mean body mass index was 36.8 kg/m². Participants were randomized 2:2:1 to once-weekly retatrutide 9 mg, retatrutide 12 mg or semaglutide 2 mg; retatrutide was started at 2 mg and increased every 4 weeks to the target dose. At 80 weeks, both retatrutide doses lowered A1C by an average of 2.2 percentage points, compared with 1.8 percentage points with semaglutide 2 mg. Retatrutide 12 mg met the primary objective of noninferiority to semaglutide for A1C reduction and was also superior (p<0.001, controlled for type 1 error). Retatrutide 9 mg met noninferiority as a key secondary endpoint; its superiority for A1C reduction was nominally significant (p<0.001) but not controlled for multiple comparisons. Weight loss averaged 44.3 lb (20.1 kg; 19.5%) with retatrutide 9 mg and 47.4 lb (21.5 kg; 20.9%) with retatrutide 12 mg, compared with 20.9 lb (9.5 kg; 9.4%) with semaglutide 2 mg (p<0.001 for both doses). Retatrutide also produced greater improvements in non-high-density lipoprotein cholesterol, triglycerides and systolic blood pressure, although numerical estimates were not reported. The most common adverse events were gastrointestinal: diarrhea (28.3% with retatrutide 9 mg, 32.7% with 12 mg and 26.4% with semaglutide), nausea (21.2%, 23.8% and 21.3%), constipation (14.2%, 13.1% and 19.8%), vomiting (10.2%, 15.0% and 13.2%) and dyspepsia (10.4%, 8.5% and 11.6%); most were mild to moderate. Dysesthesia was more frequent with retatrutide (4.8% and 6.5%) than with semaglutide (2.7%). Treatment discontinuation due to adverse events occurred in 4.8% with retatrutide 9 mg, 7.9% with retatrutide 12 mg and 2.7% with semaglutide. These results are based on the efficacy estimand, representing outcomes if randomized participants remained on treatment for 80 weeks without starting additional antihyperglycemic medication. Limitations include the open-label design, topline reporting and absence of peer-reviewed publication. The release did not report confidence intervals, the noninferiority margin, per-arm sample sizes, treatment-regimen estimand results, serious adverse events or hypoglycemia rates. This single study suggests that retatrutide may provide greater glycemic and weight reduction than semaglutide 2 mg in this population, pending review of the full results.

Source: Eli Lilly and Company.

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