Survodutide Meets Cardiovascular Safety Endpoint in Phase 3 Obesity Trial

Investigational survodutide, a dual glucagon/glucagon-like peptide-1 (GLP-1) receptor agonist, met its primary cardiovascular safety endpoint in adults with overweight or obesity and elevated cardiovascular risk, according to phase 3 findings presented at the American Heart Association (AHA) Scientific Sessions 2026, held November 6-9 in Chicago, Illinois.¹˒²

In the SYNCHRONIZE-CVOT trial, the primary composite endpoint of cardiovascular death, nonfatal stroke, nonfatal myocardial infarction (MI), ischemia-related coronary revascularization, or heart failure events occurred in 3.7% of participants receiving survodutide compared with 4.1% receiving placebo (hazard ratio [HR], 0.89; 95% CI, 0.67-1.18; P<.0001 for noninferiority).¹

The findings established that survodutide was noninferior to placebo for cardiovascular safety, meeting the trial's prespecified noninferiority margin. However, the study did not demonstrate a statistically significant reduction in cardiovascular events compared with placebo.

The results were presented November 9 at AHA Scientific Sessions and simultaneously published in The Lancet. The findings represent the first phase 3 cardiovascular outcomes data for survodutide, an investigational once-weekly injectable medication being developed by Boehringer Ingelheim and Zealand Pharma for obesity and metabolic dysfunction-associated steatohepatitis (MASH).¹˒²

Investigators led by Biykem Bozkurt, MD, PhD, of Baylor College of Medicine, conducted the global, randomized, double-blind, placebo-controlled SYNCHRONIZE-CVOT study (NCT06077864) to evaluate the cardiovascular safety of survodutide among adults with overweight or obesity and established cardiovascular disease, chronic kidney disease (CKD), or multiple obesity-related complications or cardiovascular risk factors.¹

How Was Cardiovascular Safety Evaluated in SYNCHRONIZE-CVOT?

SYNCHRONIZE-CVOT was a multicenter, event-driven phase 3 trial conducted at 524 clinical sites across 34 countries.

The study enrolled adults aged 18 years and older with a body mass index (BMI) of at least 27 kg/m² and established cardiovascular disease or at least 2 obesity-related complications or cardiovascular risk factors. Participants with CKD were eligible if they had a BMI of at least 30 kg/m².¹

Between November 2023 and November 2024, investigators randomized 5530 participants to receive once-weekly subcutaneous survodutide, titrated to either 3.6 mg or 6.0 mg, or placebo.

Of the 5507 participants who received at least 1 dose, 1836 received survodutide 3.6 mg, 1835 received survodutide 6.0 mg, and 1836 received placebo. Women accounted for 39.8% of the study population, and 78.7% of participants were White.

The median time in the study was 22 months.

The primary endpoint was time to first occurrence of a 5-component major adverse cardiovascular event (MACE), including cardiovascular death, nonfatal MI, nonfatal stroke, ischemia-related coronary revascularization, or a heart failure event.

The trial was designed to establish noninferiority rather than superiority, with an upper 95% confidence interval boundary below 1.65 required to meet the primary objective.

Did Survodutide Reduce Major Cardiovascular Events?

Survodutide met the prespecified noninferiority criterion for the primary composite cardiovascular endpoint, demonstrating no increased cardiovascular risk compared with placebo within the trial's specified margin.

The primary endpoint occurred in 136 of 3671 participants (3.7%) receiving pooled survodutide doses compared with 76 of 1836 participants (4.1%) receiving placebo (HR, 0.89; 95% CI, 0.67-1.18; P<.0001 for noninferiority).¹

A key secondary analysis evaluating the traditional 3-point MACE composite of cardiovascular death, nonfatal stroke, or nonfatal MI also demonstrated noninferiority with survodutide compared with placebo (HR, 0.84; 95% CI, 0.60-1.18; P<.0001 for noninferiority).²

However, neither result established cardiovascular superiority over placebo, as the confidence intervals included 1.0.

The findings are particularly relevant given survodutide's dual mechanism of action. Unlike medications that selectively activate the GLP-1 receptor, survodutide also activates the glucagon receptor, which has effects on energy expenditure and hepatic metabolism.

Establishing cardiovascular safety is therefore an important component of evaluating this investigational treatment in patients with obesity and substantial cardiometabolic disease burden.

How Did Survodutide Affect Weight and Cardiometabolic Risk Factors?

In addition to meeting its cardiovascular safety endpoint, survodutide was associated with improvements in several cardiometabolic measures, including body weight, systolic blood pressure, and waist circumference.²

According to Boehringer Ingelheim, participants receiving survodutide achieved weight loss of up to 13.7% at week 72, compared with 2.0% among placebo recipients, using a supplementary secondary estimand assessing expected treatment effects with continued therapy.

At the same time point, mean systolic blood pressure reductions reached 6.68 mmHg with survodutide, compared with 1.76 mmHg with placebo (P=.0001).

Waist circumference decreased by up to 11.96 cm among survodutide recipients, compared with 2.74 cm among placebo recipients.

The company also reported improvements in triglycerides and high-sensitivity C-reactive protein, a marker of systemic inflammation.

Although these findings suggest potential benefits across multiple cardiometabolic risk factors, the improvements should not be interpreted as evidence of reduced cardiovascular morbidity or mortality, which was not established in the trial.

What Were the Most Common Adverse Events With Survodutide?

Gastrointestinal adverse events were substantially more common among participants receiving survodutide than placebo.

Overall adverse events occurred in 93.0% of participants receiving survodutide 3.6 mg, 93.1% receiving 6.0 mg, and 85.6% receiving placebo.¹

The most frequently reported gastrointestinal events included:

• Nausea: 48.0% with survodutide 3.6 mg, 49.0% with 6.0 mg, and 12.1% with placebo.
• Vomiting: 31.7% with survodutide 3.6 mg, 34.0% with 6.0 mg, and 4.8% with placebo.
• Gastrointestinal adverse events leading to treatment discontinuation: 19.3% with survodutide 3.6 mg, 20.8% with 6.0 mg, and 1.9% with placebo.

Serious adverse events occurred at similar rates across treatment groups, affecting 22.5% of participants receiving survodutide 3.6 mg, 20.8% receiving 6.0 mg, and 23.9% receiving placebo.

Fatal adverse events were reported in 0.9% of participants in each survodutide group and 0.6% receiving placebo. These events were primarily attributed to cardiac disorders.¹

Notably, only 56.0% of participants in the survodutide 3.6-mg group and 56.6% in the 6.0-mg group remained on treatment through study closeout, compared with 59.0% in the placebo group.

Boehringer Ingelheim noted that gastrointestinal-related discontinuations generally occurred during dose escalation, when the initial study protocol provided limited flexibility for slower titration, dose adjustments, or extended treatment interruptions.²

Future studies are expected to incorporate more flexible titration strategies to improve treatment tolerability.

What Do the Findings Mean for Obesity Management in Primary Care?

The findings provide important cardiovascular safety data for an investigational obesity medication targeting both glucagon and GLP-1 receptors, particularly among patients with established cardiovascular disease, CKD, or multiple cardiometabolic risk factors.

For primary care physicians, who frequently manage obesity alongside hypertension, type 2 diabetes, dyslipidemia, and cardiovascular disease, the results highlight the importance of evaluating both cardiometabolic efficacy and treatment tolerability when considering emerging obesity therapies.

Although survodutide was associated with improvements in weight, blood pressure, and waist circumference, the trial was designed primarily to rule out an unacceptable increase in cardiovascular risk, not to establish cardiovascular event reduction.

The comparatively high rates of nausea, vomiting, and treatment discontinuation also underscore the potential challenges of maintaining long-term treatment, particularly in patients with multiple chronic conditions.

The study had several limitations. The trial's noninferiority design does not establish cardiovascular superiority, and the median follow-up of 22 months limits conclusions about longer-term cardiovascular outcomes.

Additionally, participants were selected based on elevated cardiovascular risk, and the results may not generalize to individuals with obesity who have fewer comorbidities or lower baseline cardiovascular risk.

Survodutide remains investigational and is not FDA approved. Boehringer Ingelheim announced that it intends to pursue global regulatory submissions for obesity based on findings from the broader SYNCHRONIZE clinical development program.²

The investigators concluded that survodutide demonstrated cardiovascular safety compared with placebo among adults with overweight or obesity and increased cardiovascular risk, meeting the prespecified noninferiority criterion for the primary composite endpoint.

The findings support further evaluation of survodutide as a potential obesity treatment with broader cardiometabolic effects, although its clinical benefit-risk profile will need to account for the substantial gastrointestinal tolerability burden observed in SYNCHRONIZE-CVOT.

References

1. Bozkurt B, le Roux CW, Wharton S, et al. Cardiovascular outcomes with survodutide in adults with obesity at increased cardiovascular risk (SYNCHRONIZE-CVOT): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. Published online November 9, 2026. doi:10.1016/S0140-6736(26)02140-9
2. Boehringer Ingelheim. Boehringer Ingelheim's survodutide is the first glucagon/GLP-1 dual agonist to demonstrate a favorable cardiovascular safety profile in global phase III SYNCHRONIZE-CVOT trial alongside significant cardiometabolic benefits. News release. November 9, 2026. https://www.boehringer-ingelheim.com/us/human-health/metabolic-diseases/obesity/synchronize-cvot-trial-results-presented-aha
3. ClinicalTrials.gov. SYNCHRONIZE-CVOT: cardiovascular outcomes trial of survodutide in adults with overweight or obesity at increased cardiovascular risk. NCT06077864. https://clinicaltrials.gov/study/NCT06077864