Survodutide Meets Cardiovascular Safety Endpoint in Phase III SYNCHRONIZE-CVOT Trial

Key Takeaways

• In SYNCHRONIZE-CVOT, among adults with overweight or obesity at increased cardiovascular risk, survodutide was noninferior to placebo for a five-component composite of major adverse cardiovascular events.
• The primary composite endpoint occurred in 3.7% of participants receiving survodutide and 4.1% of those receiving placebo.
• Nausea, vomiting, and discontinuation due to gastrointestinal adverse events were substantially more frequent with survodutide than with placebo.
• Serious and fatal adverse events occurred at similar rates across treatment groups.

Survodutide, a glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor dual agonist, has improved markers of cardiometabolic health in people with obesity. Investigators examined whether survodutide increased cardiovascular risk compared with placebo in the global, randomized, double-blind, placebo-controlled, event-driven phase III SYNCHRONIZE-CVOT trial, conducted at 524 sites in 34 countries.

Researchers enrolled adults with a body mass index (BMI) of at least 27 kg/m2 and established cardiovascular disease or at least two obesity complications or cardiovascular risk factors. Participants with chronic kidney disease were eligible if their BMI was at least 30 kg/m2. Participants were randomly assigned 1:1:1 to once-weekly subcutaneous survodutide, up-titrated to 3.6 mg or 6.0 mg, or placebo. The primary endpoint was a composite of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction, ischemia-related coronary revascularization, or heart failure event, with a target of 189 primary endpoint events. Investigators assessed noninferiority of pooled survodutide versus placebo in all randomized participants who received at least one dose, using a treatment-regimen estimand.

Between November 20, 2023, and November 8, 2024, investigators screened 7,753 participants and randomized 5,530 (71.3%), of whom 5,507 received treatment. Of those treated, 39.8% were female and 78.7% were White. Median time in study was 22.0 months (interquartile range 20.1–23.7). Through study closeout, 56.0% of the survodutide 3.6 mg group, 56.6% of the 6.0 mg group, and 59.0% of the placebo group remained on treatment.

The primary endpoint occurred in 136 of 3,671 participants (3.7%) receiving survodutide and 76 of 1,836 (4.1%) receiving placebo, with a hazard ratio (HR) of 0.89 (95% confidence interval [CI] 0.67–1.18; P<.0001 for noninferiority).

Adverse events occurred in 93.0% of participants receiving survodutide 3.6 mg, 93.1% receiving 6.0 mg, and 85.6% receiving placebo. Nausea occurred in 48.0% and 49.0% of the survodutide groups versus 12.1% with placebo, and vomiting in 31.7% and 34.0% versus 4.8%. Gastrointestinal adverse events led to treatment discontinuation in 19.3%, 20.8%, and 1.9%, respectively. Serious adverse events occurred in 22.5%, 20.8%, and 23.9%, and fatal adverse events in 0.9%, 0.9%, and 0.6%, most often from cardiac disorders.

SYNCHRONIZE-CVOT was designed to assess cardiovascular safety through noninferiority, and the primary analysis pooled both survodutide doses. More than 40% of participants in each group stopped treatment before study closeout, so the treatment-regimen analysis includes off-treatment time. Median follow-up was under two years, and most participants were White, which may limit applicability to longer-term use and other populations.

In adults with obesity at increased cardiovascular risk, survodutide was not associated with an increased risk of major adverse cardiovascular events compared with placebo. 

Clinician Questions

What noninferiority margin did SYNCHRONIZE-CVOT use?

Noninferiority required the upper limit of the two-sided 95% CI for the hazard ratio to fall below 1.65; the observed upper limit was 1.18.

How did the treatment-regimen estimand handle treatment interruptions?

Bozkurt and colleagues assessed treatment effects regardless of early discontinuation, temporary stops, use of protocol-prohibited obesity medications, or a prolonged dose-escalation period.