AHA: Wegovy improves survival in outcomes trial

Novo Nordisk’s obesity therapy Wegovy has cut the risk of death by 19% in the SELECT trial, mirroring the benefits of the drug in cardiovascular outcomes in people who are overweight or obese and had pre-existing heart disease, but who did not have diabetes.

The data – reported at the American Heart Association (AHS) annual meeting and simultaneously published in the New England Journal of Medicine – is viewed as critical to persuading healthcare systems and insurers around the world to pay for treatment with the GLP-1 agonist.

Novo Nordisk said in the summer that the SELECT trial showed a reduction in major adverse cardiovascular events (MACE) – defined as cardiovascular death or a non-fatal heart attack or stroke – by 20% with Wegovy (semaglutide).

Now, with nearly 40 months of follow-up, the data shows that the MACE benefit has been sustained at 20%, occurring in 6.5% of the Wegovy group and 8% of those on placebo. The risk of a non-fatal heart attack was 28% lower with the drug, while cardiovascular deaths were down 15%, but there was no significant difference between the groups on non-fatal stroke.

Those on Novo Nordisk’s drug experienced an average 9.4% reduction of their body weight over that timeframe compared to a 0.9% reduction with placebo – which is less pronounced than seen in earlier trials – but the company said the benefits from treatment seemed to kick in before patients started losing weight. That might suggest the benefits are not simply down to weight loss.

Serious adverse events were less common with Wegovy than in the placebo group, and there were no cases of pancreatitis, which has been an issue with other drugs in the same class as Wegovy.

According to the researchers, the results are the first time that any medication or lifestyle therapy has been proven to reduce cardiovascular events in overweight adults or those with obesity who do not have type 1 or type 2 diabetes.

“It’s been estimated that within about 10 years, over half of the world’s population will [be] overweight or [have] obesity,” said lead study author Michael Lincoff of the Cleveland Clinic, who noted that many patients without diabetes do not get access to GLP-1 agonists due to access to care issues, insurance coverage, or other factors.

“We have a chance to significantly reduce their risk of a secondary cardiovascular event, including death,” he told the AHA congress.

Not all commentators were quite so convinced by the data, including Eric Topol, director of the Scripps Research Translational Institute, who pointed out that the absolute reduction of the primary endpoint “is only 1.5 per 100 people treated, with the people in the trial representing a very high-risk cohort.”

In a blog post, Topol noted they had to be treated for three years or more to get that benefit at a monthly $1,349 cost for Wegovy treatment at list prices, ahead of any discounts or rebates.

“It is likely that insurers, and Medicare, will revise their coverage on the basis of the trial to cover the drug for high-risk patients that fit the entry criteria of the trial, but that will represent a very large economic burden to cover the drug cost,” he said.

Some insurance companies have baulked at providing coverage for GLP-1 drugs for obesity, saying the cost is too great unless there is clear evidence of health benefits beyond weight loss.

The full dataset from SELECT has emerged shortly after a rival obesity therapy from Eli Lilly – dual GLP-1 and GIP agonist Zepbound (tirzepatide) – got FDA approval with a list price around 20% lower than Wegovy.

Other outstanding questions include the benefit of GLP-1 drugs in a less ill patient population, and whether dual- or triple-agonist therapies may lower risk even further. Topol also said more research needs to be undertaken on the effects of the drugs on muscle mass and bone density, and the effects of discontinuing therapy.

The SELECT investigators said that additional analyses of the findings are planned, including studies aimed at identifying the mediators of the cardiovascular benefit to determine to what extent the results were driven by reduction of metabolically unhealthy body fat, positive impacts on inflammation or blood sugar, direct effects of the medication itself on plaque build-up in the arteries, or a combination of one or more variables.