Investigational Glucagon Receptor/GLP-1 Receptor Dual Agonist Bests Semaglutide for Weight Loss in T2D Patients

ObesityWeek® 2022

BI 456906, an investigational glucagon receptor (GCGR)/glucagon-like peptide-1 (GLP-1) receptor dual agonist, was associated with greater dose-dependent loss of body weight in patients with type 2 diabetes (T2D) when compared to placebo and to the GLP-1 receptor analogue semaglutide, according to findings reported during ObesityWeek® 2022, held in San Diego, CA, and virtually, November 1-4, 2022.

Julio Rosenstock, MD, director of the Dallas Diabetes Research Center and clinical professor of medicine at the University of Texas Southwestern Medical Center and colleagues report that the GCGR/GLP-1 receptor dual agonist BI 456906 in a previous study reduced HbA1c in a dose-dependent manner in patients T2D receiving stable metformin therapy but not at goal. The investigators report here on dose-dependent bodyweight reductions with the GCGR/GLP-1 R dual agonist in the same cohort.

In the phase 2 randomized, placebo-controlled multiple-dose study (NCT04153929) adults with T2D (≥6 months) and BMI 25–50 kg/m2 were randomized to receive subcutaneous, dose-escalated BI 456906 (0.3, 0.9, 1.8 or 2.7 mg once weekly or 1.2 or 1.8 mg bi-weekly), or placebo, or open-label semaglutide (1.0 mg once weekly) as a reference control for 16 weeks, according to the study abstract presented.

The primary endpoints of interest were relative change from baseline in bodyweight and proportion of patients reaching bodyweight reductions of ≥5% week 16.

The full cohort numbered 411 and had a baseline mean age of 57 years, mean bodyweight of 97 kg (214 lbs), and mean BMI of 34 kg/m2. Participants were randomized approximately 50 per study arm.

The researchers report that over the 16-week study period, BI 456906, compared to placebo and semaglutide, was associated with dose-dependent reductions in body weight of:

BI 456906 doses ≥1.8 mg once-weekly were associated with greater bodyweight reductions than recorded for semaglutide once-weekly (−5.4%).

Analysis of bodyweight reductions of ≥5% and ≥10% for the 3 groups found the following proportions achieving each goal: 57% and 35%, respectively, of those treated with BI 456906 1.8 mg biweekly, 6.8% and 0%, respectively, for those receiving placebo, and 38% and 16%, respectively, for participants in the arm receiving semaglutide 1.0 mg once weekly.

Among study participants randomized to BI 456906, 77.8% reported adverse events, primarily gastrointestinal in nature, and 15.9% discontinued treatment, according to the abstract. Both increased as dose increased every 1-2 weeks. The authors suggest that dose-related adverse events could be mitigated with slower dose escalation.

Rosenstock et al summarize their findings noting greater bodyweight loss with BI 456906 1.8 mg biweekly (-9.0%) vs semaglutide 1.0 mg once weekly (-5.4%) in patients with T2D and BMI 25–50 kg/m2. They note that GCGR agonism may enhance the weight-reducing effects of GLP-1 receptor agonists via mechanisms such as increased lipolysis and energy expenditure.


Reference: Rosenstock J, Bluher M, Schoelch C, Hoefler J, Hennige A. Glucagon/GLP-1 receptor dual agonist BI 456906 reduces bodyweight in patients with type 2 diabetes. Presented at ObesityWeek® 2022; November 1-4, 2022; San Diego, CA.