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LONDON -- The clinical benefits of semaglutide (Wegovy) went beyond expectations in the SELECT trial, given the reductions in non-cardiovascular and infectious disease deaths observed.

Among people with overweight or obesity and pre-existing cardiovascular disease, the drop in all-cause deaths associated with weekly semaglutide injections versus placebo (4.3% vs 5.2%, HR 0.81, 95% CI 0.71-0.93) was broken down to a nonsignificant trend toward less cardiovascular death (2.5% vs 3.0%, HR 0.85, 95% CI 0.71-1.01) while non-cardiovascular deaths were significantly reduced (1.7% vs 2.2%, HR 0.77, 95% CI 0.62-0.95).

Notably, the lower rate of non-cardiovascular mortality was driven by a reduction in infectious deaths (HR 0.71, 95% CI 0.51-0.98) -- in particular COVID-19-related deaths (HR 0.66, 95% CI 0.44-0.96), Benjamin Scirica, MD, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, told the audience here at the European Society of Cardiology annual congress.

It is unknown if effects of weight loss or another pathway might have played a role in semaglutide reducing non-cardiovascular mortality. The authors suggested that "it is plausible that the decreased risk of infectious deaths is caused by weight loss, which was 5 kg greater in patients assigned to semaglutide compared to placebo by 1 year, the average time to COVID-19 diagnosis after randomization."

In any case, the present results support "the hypothesis that there may be several mechanisms that led to the reduction in CV [cardiovascular] and non-CV death, some of which may be unrelated to atherothrombosis," Scirica and colleagues wrote of their prespecified SELECT analysis, simultaneously published in the .

"The SELECT trial is the first randomized study to demonstrate that a specific therapy that acts through multiple potential metabolic pathways and induces meaningful weight loss also reduces all-cause death and does so consistently across multiple different populations," study authors emphasized.

The main result of the SELECT trial, reported last fall, had been semaglutide's reduction of combined mortality from cardiovascular causes, myocardial infarction (MI), and stroke with more than 3 years of follow-up.

This led to the GLP-1 receptor agonist winning FDA approval for cardiovascular prevention this spring.

The SELECT investigators had taken advantage of the opportunity to conduct the study during the most severe waves of the COVID-19 pandemic. They prospectively collected COVID treatment and outcomes data soon after the onset of the pandemic, "thus providing the opportunity to evaluate the effect of COVID-19 on patients who were at high risk of COVID-19-related complications and death given their underlying comorbidities," the researchers explained.

They found that semaglutide did not prevent incident COVID-19 in SELECT. However, it was associated with fewer COVID-19-related serious adverse events among infected individuals (2.6% vs 3.1%, P=0.04).

One important observation in the trial was that non-cardiovascular death appeared to be a competing risk for cardiovascular death. This may explain the "unanticipated convergence" of cardiovascular survival curves between groups, Scirica's group suggested.

"Among trial participants, COVID-19 was the third leading cause of death, replicating population-level data -- and this includes follow-up time (2019-early 2020) when dying from SARS-CoV-2 was not yet possible. Among trial participants reporting COVID-19, the disease was the single leading cause of death," observed Jeremy Faust, MD, MS, of Mass General Brigham and Harvard Medical School in Boston, who was not involved with SELECT.

"The present study implies that, in just a short period, semaglutide was adequate to reduce SARS-CoV-2 mortality. This is akin to a vaccine against the indirect effects of a pathogen, except here, we would expect the efficacy to augment over time, rather than wane. Moreover, the benefit could apply to many infections, not just SARS-CoV-2," Faust noted in .

The SELECT trial included over 17,000 patients at least 45 years of age, with overweight and obesity and established cardiovascular disease (i.e., prior MI, prior stroke, or symptomatic peripheral artery disease) but no diabetes.

Participants were randomized to once-weekly semaglutide doses targeting 2.4 mg or placebo injections.

With each person followed for 3.3 years on average, there were 833 deaths recorded (58% of them cardiovascular deaths and 42% non-cardiovascular).

The most frequent causes of cardiovascular death with semaglutide relative to placebo were sudden cardiac death (HR: 0.89; 95% CI 0.68-1.17) and undetermined death (HR 0.85, 95% CI 0.63-1.15), neither comparison reaching statistical significance.

Investigators acknowledged the difficulty of adjudicating deaths during the pandemic, among other limitations.

"These data appear to represent the longest follow-up period to date among any randomized trial assessing COVID-19 outcomes, including Moderna's and Pfizer-BioNTech's vaccine trials," Faust maintained.