The combination of cagrilintide with semaglutide (CagriSema) in a single weekly injection was associated with a significantly greater weight loss in adults with overweight or obesity regardless of type 2 diabetes (T2D) status compared with placebo or either drug alone, according to results from the REDEFINE 1 and REDEFINE 2 phase 3a trials, presented at the American Diabetes Association Scientific Sessions and published simultaneously June 22 in The New England Journal of Medicine.

The REDEFINE 1 study included 3,417 adults without T2D and with a BMI ≥30 kg/m² (or ≥27 kg/m² plus one or more obesity-related complication) randomly assigned 21:3:3:7 to receive 2.4 mg each of cagrilintide-semaglutide (n=2,108), semaglutide alone (n=302), cagrilintide alone (n=302) or placebo (n=705) once weekly, plus lifestyle interventions.

Results showed that at week 68 the estimated mean percent change in body weight from baseline was –20.4% with CagriSema vs. –3.0% with placebo (estimated difference, –17.3 percentage points; p<0.001). Notably, for the coprimary endpoint of a reduction in body weight of ≥5%, this was achieved more frequently with CagriSema vs. placebo, achieving targets 5%, ≥20%, ≥25%, and ≥30% (p<0.001 for all comparisons).

CagriSema recipients were more likely to achieve weight-loss targets of ≥5%, ≥20%, ≥25%, and ≥30% (p<0.001 for all comparisons) vs. placebo. More patients taking CagriSema than placebo experiences gastrointestinal adverse effects (80% vs. 40%).

The REDEFINE 1 authors, led by W. Timothy Garvey, MD, et al., write that "the mean weight reduction observed with CagriSema is in the highest range of that observed with existing weight-loss interventions," possibly due to "the complementary effect of the two molecules on appetite regulation through direct actions in brain regions known to be involved in hedonic and homeostatic appetite regulation."

As for REDEFINE 2, the trial included 1,206 adults with a BMI of ≥27 kg/m², glycated hemoglobin level of 7-10% and randomized to either CagriSema (2.4 mg of each drug) once weekly (n=904) or placebo (n=302), plus lifestyle interventions.

Results revealed that at 68 weeks the estimated mean change in body weight from baseline to week 68 was −13.7% with CagriSema and −3.4% with placebo (estimated difference, −10.4 percentage points; p<0.001). More patients taking CagriSema vs. placebo had a weight loss of ≥5% (p<0.001), ≥10%, ≥15% and ≥20% (p<0.001 for the last comparison).

Importantly, findings also showed that 74% of patients with T2D receiving CagriSema achieved a glycated hemoglobin level ≤6.5% vs. 15.9% with placebo.

The REDEFINE 2 authors, led by Melanie J. Davies, MD, et al., write the results "support the use of cagrilintide–semaglutide as a promising treatment option in this population" with T2D. Indeed, "cagrilintide–semaglutide improved glycemic control and was associated with a low incidence of hypoglycemia."