Survodutide, Novel Dual GLP-1/Glucagon Agonist, Achieves ~19% Weight Loss in People with Overweight, Obesity

Carel le Roux, MBChB, PhD

_{Courtesy American Diabetes Association}

The novel dual glucagon-like peptide 1 receptor (GLP-1R)/glucagon receptor (GCGR) agonist survodutide was associated with weight loss of up to 18.7% in individuals with overweight or obesity according to results of a phase 2 dose-finding clinical trial¹ presented Sunday, June 25, 2023, at the 83rd Scientific Sessions of the American Diabetes Association (ADA), in San Diego, CA.

“By activating both the glucagon and GLP-1 receptors, survodutide may inhibit both appetite and improve energy expenditure. The findings not only show significant weight loss with increasing doses of survodutide, but we also saw a favorable safety profile, reinforcing the potential clinical benefits,” said principal investigator Carel le Roux, MBChB, PhD, professor of experimental pathology at University College Dublin, School of Medicine in an ADA news release.²

le Roux and colleagues enrolled 387 participants with a body mass index (BMI) of 27 kg/m² or higher in the double-blind, randomized, placebo-controlled trial.¹ Participants were assigned randomly to receive weekly injections of survodutide at either 0.6 mg, 2.4 mg, 3.6 mg, or 4.8 mg or a placebo for 46 weeks. During the initial 20 weeks, doses were titrated rapidly on a biweekly schedule and maintained for the remaining 26 weeks, according to the study. The investigators defined the study's primary endpoint as percentage change in bodyweight from baseline to week 46. Secondary endpoints were the proportion of participants achieving at least 5%, 10%, and 15% weight loss from enrollment to week 46.

“By activating both the glucagon and GLP-1 receptors, survodutide may inhibit both appetite and improve energy expenditure. The findings not only show significant weight loss with increasing doses of survodutide, but we also saw a favorable safety profile, reinforcing the potential clinical benefits.”

The 387-participant cohort was 31.8% men and had a mean age of 49.1 years. At baseline, mean bodyweight was 105.7 kg and BMI 37.1 kg/m². The 5 randomly assigned treatment groups numbered approximately 77 participants each, according to the study abstract.

FINDINGS

At week 46, the authors report, all 4 groups receiving survodutide had substantial weight loss compared to the placebo group. le Roux et al reported increasing doses of survodutide were correlated with greater loss of body weight in a clear dose-response relationship.

Compared to weight loss of -2.8% in the group receiving placebo, mean reductions according to survodutide dose were:

• 0.6 mg -6.2%
• 2.4 mg -12.5%
• 3.6 mg -13.2%
• 4.8 mg -14.9%

Participants who reached and maintained treatment on the highest dose of survodutide (4.8 mg) at 46 weeks achieved weight loss of 18.7%. Further the majority (82.8%) of participants in this group reached weight loss of at least 5% at the 46-week mark, compared to 25.9% in the placebo group. Weight loss of at least 10% was reached by 68.8% of those receiving the 4.8 mg dose and a loss of 15% or more achived by by 54.7% in this high-dose group, compared to 11.1% and 5.6% of those receiving placebo, respectively.

Safety profile. In their analysis of the survodutide safety profile, researchers reported adverse events in 90% of those in the active treatment groups, primarily of a gastrointestinal nature. Among placebo-treated participants, adverse events were reported in 75.3%. Approximately one-quarter (24.6%) of participants treated with survodutide discontinued treatment which le Roux and team note occurred mainly during the 20-week dose escalation, titration during which they have described as rapid.

Among patients in the placebo group, 3.9% discontinued treatment, also during the weeks of dose escalation. The incidence of serious adverse events was comparable between the survodutide group (4.2%) and the placebo group (6.5%). However, investigators write there were no unexpected safety concerns over the 46-week trial period.

“We are encouraged by the significant weight loss observed in the phase 2 study results which will pave the way for further research,” said le Roux. le Roux along with his study coauthors anticipate phase 3 trials which they note are upcoming and "are committed to continuing to explore the potential of survodutide to provide a much-needed treatment option for the billions of people with obesity."

References

1. le Roux C, Steen O, Lucas KJ, et al. A phase 2, randomized, double-blind, placebo-controlled, dose-finding study of BI 456906 in people with overweight/obesity. Abstract presented at American Diabetes Association 83rd Scientific Sessions; June 23-26, 2023; San Diego, CA.

2. American Diabetes Association. Late breaking weight loss innovations: new drug therapies shown to offer positive outcomes for obesity and type 2 diabetes management. News release. American Diabetes Association. June 25, 2023, 2023. Accessed June 26, 2023.