Survodutide, a glucagon receptor–glucagon-like peptide-1 (GLP-1) receptor dual agonist, provides sustained weight loss and improves glycaemic control and other cardiometabolic parameters in individuals with obesity and type 2 diabetes (T2D), primary results of the phase III SYNCHRONIZE-2 trial have shown.
The 76-week, multinational, double-blind phase III trial included 752 adults with BMI ≥27 kg/m2, T2D (HbA1c ≥6.5–<10 percent; treated with diet and exercise alone or oral glucose-lowering medications for ≥3 months before screening), and ≥1 self-reported unsuccessful dietary attempt to lose weight. Patients were excluded if they had ≥5 percent self-reported change in body weight within 3 months before screening; type 1 diabetes; treatment with insulin, amylin analogues, GLP-1 receptor agonists (RAs), GLP-1 receptor–glucose-dependent insulinotropic polypeptide receptor dual agonists, or dipeptidyl peptidase-4 inhibitors within 3 months before screening; previous or planned bariatric surgery; or obesity induced by other endocrinologic disorders or syndromic or genetic causes. [Wharton S, EASD 2026; N Engl J Med 2026;doi:10.1056/NEJMoa2607219]
The participants were randomized 1:1:1 to receive once-weekly subcutaneous survodutide 3.6 mg (n=250) or 6 mg (n=251) or placebo (n=251) as an adjunct to a reduced-calorie diet (deficit of approximately 500 kcal/day relative to estimated total energy expenditure) and moderate-intensity exercise (≥150 minutes/week). A stepwise dose escalation scheme was in place to mitigate survodutide’s gastrointestinal (GI) side effects, with limited dose flexibility allowed during weeks 1–16 of the 24-week dose escalation phase. In the subsequent 52-week dose maintenance phase (ie, weeks 24–76 of the trial), limited flexibility for dose adjustment was allowed during weeks 32–76.
Up to 13.1 percent weight loss at week 76
The participants’ mean age was 55.7 years, 50.7 percent were female, and 25.9 percent were Asian. At baseline, mean BMI was 36.5 kg/m2, mean waist circumference was 115.5 cm, and mean HbA1c was 7.4 percent. Nearly 70 percent had hypertension (69 percent) or dyslipidaemia (67.8 percent).
“Survodutide facilitated susained body weight reductions of up to 13.1 percent in people with obesity and T2D,” said Dr Sean Wharton of the University of Toronto and McMaster University, Canada, at EASD 2026.
At 76 weeks, mean percentage change in body weight (primary endpoint) according to treatment-regimen estimand was -8.2 percent with survodutide 3.6 mg, -9.8 percent with survodutide 6 mg, and -3.9 percent with placebo. “For the efficacy estimand, body weight reduction was 10.4 percent with survodutide 3.6 mg, 13.1 percent with survodutide 6 mg, and 3.1 percent with placebo at 76 weeks,” reported Wharton.
HbA1c reductions by treatment-regimen estimand were 0.9 and 0.8 vs 0.2 percent.
“The HbA1c target of <7 percent was achieved in approximately 82 percent of participants in the two survodutide groups, compared with approximately 41 percent in the placebo group [p<0.0001],” reported Wharton. “HbA1c <6.5 percent was achieved in approximately 71 vs 20 percent of the participants [p<0.0001], while approximately 29 vs 4 percent reached the normal glycaemic range of HbA1c <5.7 percent [p<0.0001].”
“Fasting plasma glucose, fasting plasma insulin, insulin resistance, beta-cell function and fasting C-peptide all changed in healthy directions with survodutide vs placebo,” he added.
Improvements in other cardiometabolic parameters
Other cardiometabolic parameters, including waist circumference, systolic blood pressure (SBP), lipid profile and high-sensitivity C-reaction protein (hsCRP), showed greater improvements with survodutide than placebo.
“Mean waist circumference decreased by 8.42 cm with survodutide 3.6 mg and 11 cm with survodutide 6 mg, compared with 3.46 cm with placebo [efficacy estimand]. SBP decreased by 3.8 and 5.7 mm Hg, respectively, compared with 2.7 mm Hg [efficacy estimand],” said Wharton.
“Total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides all changed in healthy directions with survodutide compared with placebo. hsCRP decreased by >50 percent compared with 17 percent,” he noted.
No new safety signals
“Survodutide demonstrated a safety profile consistent with therapies with GLP-1 RA activity, with no additional safety findings attributable to the inclusion of glucagon receptor agonism,” said Wharton. “Adverse events [AEs] were reported in 91.8 vs 84.9 percent of survodutide vs placebo recipients. Serious AEs were reported in 8.8 vs 10.8 percent, with no significant difference between survodutide and placebo.”
AEs more frequently reported with survodutide vs placebo were mostly GI, of mild-to-moderate severity, and occurred mainly during dose escalation. These included nausea (52.5 vs 11.2 percent) and vomiting (36.7 vs 5.6 percent). GI AEs led to treatment discontinuation in 18 vs 1.2 percent of participants.
