Boehringer Ingelheim reports that its once-weekly injected peptide survodutide did not raise the risk of major cardiovascular events compared with placebo in a phase 3 safety trial of 5,530 adults with obesity or overweight and raised cardiovascular risk. The trial, SYNCHRONIZE-CVOT, was presented on 9 November at the American Heart Association Scientific Sessions in Chicago and published at the same time in The Lancet.
Survodutide activates both the glucagon receptor and the GLP-1 receptor. According to the company, it is the first drug of this dual type to report a global cardiovascular safety trial. It has not been approved for use.
How the trial worked
Participants had overweight or obesity together with established cardiovascular disease, chronic kidney disease, or at least two weight-related complications or cardiovascular risk factors. They were randomly assigned to weekly injections of survodutide 3.6 mg, survodutide 6.0 mg or placebo. The study was double-blind and event-driven, meaning it continued until enough cardiovascular events had occurred.
The main outcome was the time to a first 5-point major adverse cardiovascular event: cardiovascular death, non-fatal heart attack, non-fatal stroke, coronary revascularisation for ischaemia, or a heart failure event. The trial was designed to test non-inferiority, which asks whether survodutide is no worse than placebo, not whether it is better.
What the results showed
For the 5-point measure, the hazard ratio was 0.89 (95% confidence interval 0.67 to 1.18), which met the non-inferiority test (p<0.0001). For the narrower 3-point measure of cardiovascular death, non-fatal stroke or non-fatal heart attack, the hazard ratio was 0.84 (0.60 to 1.18), also non-inferior. Both figures use the treatment-regimen estimand, which analyses everyone as randomised.
At 72 weeks, in a supplementary analysis, systolic blood pressure fell by up to 6.68 mmHg on survodutide against 1.76 mmHg on placebo (P=0.0001). Waist circumference fell by up to 11.96 cm against 2.74 cm, and body weight by up to 13.7% against 2.0%. The company also reports larger falls in the inflammation marker hs-CRP and in triglycerides.
As with other GLP-1-based drugs, the most common side effects were gastrointestinal, mostly mild to moderate: nausea, vomiting, diarrhoea and constipation. Stopping treatment because of these effects occurred in 19.3% of people on 3.6 mg and 20.8% on 6.0 mg, against 1.9% on placebo.
What is still unknown
Both confidence intervals run from well below 1 to 1.18, so the trial shows no excess risk but cannot show that survodutide lowers cardiovascular events. The company release does not give the non-inferiority margin or the number of events in each group. Effects beyond the trial period and tolerability outside a trial are not addressed.
Boehringer says it is preparing regulatory submissions in obesity, and no approval decision has been made. OrientSciences worked from the Boehringer Ingelheim and Zealand Pharma releases and trade coverage and did not read the Lancet paper.