Survodutide achieves up to 13.1% weight loss in Phase 3 trial, with improved blood glucose and gastrointestinal tolerability challenges

For adults with overweight or obesity and type 2 diabetes, treatment often needs to address both weight and blood glucose. A Phase 3 trial of the investigational drug survodutide provides new evidence on these two interconnected problems: after 76 weeks, average weight loss reached up to 13.1%, and blood glucose measures also improved. However, the proportion of participants who discontinued treatment because of gastrointestinal discomfort reveals another hurdle for long-term treatment.

Boehringer Ingelheim and Zealand Pharma announced the SYNCHRONIZE-2 results on October 1, and AJMC also reported the trial data. This double-blind, placebo-controlled study enrolled 755 adults and compared weekly injections of 3.6 mg or 6.0 mg of survodutide with placebo over 76 weeks. Both co-primary endpoints—percentage change in body weight and the proportion of participants who lost at least 5% of their weight—were met. The results were presented at the annual meeting of the European Association for the Study of Diabetes and simultaneously published in The New England Journal of Medicine.

Understanding the 13.1% figure requires first examining how the analysis handled treatment discontinuation. This was the highest average weight loss under the “efficacy estimand,” which estimates the effect if participants continued treatment until the end of the study; the placebo group lost 3.1%. Under the same estimand, the proportion losing at least 5% of their weight reached up to 79.3%, compared with 32.7% in the placebo group. The study also met both primary endpoints under the “treatment-regimen estimand,” which accounts for the effects of treatment discontinuation or additional treatment. However, 13.1% cannot be directly interpreted as the average result for all participants regardless of whether they continued taking the drug.

Beyond weight, improvements in blood glucose provide another dimension of clinical significance. Under the efficacy estimand, glycated hemoglobin (HbA1c) fell by up to 1.21 percentage points from a mean baseline of 7.4%, compared with a decline of just 0.03 percentage points in the placebo group. Waist circumference decreased by 11.1 and 3.5 cm, respectively. During treatment, up to 29.5% of participants in the survodutide groups reached the normal blood glucose range of HbA1c below 5.7%, compared with 4.0% in the placebo group. These are improvements in measures during treatment and do not yet establish lasting diabetes remission.

Survodutide activates both GLP-1 and glucagon receptors, aiming to improve weight and blood glucose through two metabolic signaling pathways. Glucagon is generally associated with raising blood glucose, making the ability of this dual receptor strategy to maintain blood glucose control while promoting weight loss an important research question. These results support its clinical potential, but do not separately establish how much each signaling pathway contributes to the effects.

Tolerability gives the efficacy figures more concrete practical limits. Common adverse events included nausea, vomiting, diarrhea, and constipation, mostly mild to moderate. However, 18% of participants in the survodutide groups discontinued treatment because of gastrointestinal adverse events, compared with 1.2% in the placebo group. AJMC noted that discontinuations occurred mainly during dose escalation, when the trial protocol allowed limited flexibility for adjustments to manage side effects. The companies said subsequent studies would use more flexible dose adjustments. Whether this can effectively reduce discontinuation rates remains to be answered by new data.

Zealand Pharma licensed survodutide to Boehringer Ingelheim for global development and commercialization, and it has not yet been approved for use. This study used placebo as the comparator and cannot determine how it compares with other weight-loss or glucose-lowering drugs. Improvements in weight, HbA1c, and waist circumference also cannot be directly translated into fewer cardiovascular events. The companies expect to announce results from the SYNCHRONIZE-CVOT cardiovascular outcomes trial later this year, adding another piece of evidence for assessing its long-term clinical value.