PHILADELPHIA — Novo Nordisk’s obesity drug Wegovy notably cut the risk of heart attacks in a landmark cardiovascular trial that affirms the treatment offers health benefits beyond weight loss.
The company in August had announced that in this trial, called Select, Wegovy reduced the overall rate of major heart problems — heart attacks, stroke, or cardiovascular-related death — by 20%. That finding, which was the primary outcome the trial set out to study, was stronger than many were expecting and led Novo’s stock to surge.
But details of the study, including risk reductions for each specific heart complication, were not released until Saturday, when they were presented here — before a standing-room only crowd — as the first major session of the American Heart Association conference.
The overall 20% risk reduction in heart problems translated to 15 complications prevented for every 1,000 patients treated.
Wegovy specifically cut the rate of heart attacks by 28% among patients who were already taking statins and other medications to prevent heart problems, according to the results, simultaneously published in the New England Journal of Medicine. The drug also reduced the rate of cardiovascular-related deaths by 15% and strokes by 7%.
In addition, people on Wegovy experienced a 19% lower rate of death from any causes.
In part due to the way the trial was designed, the primary outcome that looked at overall cardiovascular risk was the only result that was considered statistically significant. Still, doctors hailed the full findings, especially the reductions in rates of heart attacks and all-cause deaths.
The study had “overall really impressive results,” said Nicholas Marston, a cardiologist at Brigham and Women’s Hospital who was not involved in the study, noting that the reduction in general cardiovascular risk emerged early on and continued to increase over the course of the trial.
Wegovy, along with its sister diabetes drug, Ozempic, are part of a growing class of GLP-1-based medications, which have exploded in popularity for causing substantial weight loss. But insurers have been reluctant to pay for the medications, viewing them as cosmetic rather than medical treatments. Select is the first trial to show that an obesity drug improves cardiovascular outcomes, representing a key milestone not only for Novo, but also for the cardiology field.
“This is the first weight management therapy that we’ve proven in a rigorous trial to reduce the excess risk of cardiovascular events associated with overweight and obesity,” A. Michael Lincoff, lead investigator of the trial and an interventional cardiologist at the Cleveland Clinic, said in an interview. “This now establishes overweight and obesity as a new pathway, another modifiable risk factor, that we can treat in patients with cardiovascular disease.”
There are still many questions, though, about how the drug causes cardiovascular benefit, and researchers are probing whether weight loss alone contributed to the outcome or if there are additional factors.
The Select results come as Novo is facing increased competition from Eli Lilly, which just received approval to sell its diabetes drug Mounjaro as an obesity treatment under the name Zepbound. Lilly’s drug has shown potential for greater weight loss, likely making it more attractive to many patients, but Wegovy now has tangible data backing up its cardiovascular benefits.
That could help with convincing payers to increase access. Insurers have balked at the price of the drug, which costs over $16,000 annually and is meant to be taken indefinitely. The Select data could strengthen arguments by Novo that Wegovy will prevent heart problems and reduce costs in the long run.
The results may even help in getting coverage from Medicare, which is prohibited by law from covering weight loss drugs. Doug Langa, head of the company’s North America operations, said in an earnings call last week that the heart data may lead Novo to try asking for an exception for Wegovy.
The longest trial yet for Wegovy
Select enrolled over 17,600 people with obesity and existing heart disease and without diabetes.
It lasted five years, making it the longest trial that’s been conducted for Wegovy and allowing it to provide a window into the long-term efficacy and safety of the drug. Patients on Wegovy lost on average about 10% of their weight and maintained the weight loss throughout the trial. That’s less than the weight loss shown in a previous large Wegovy trial, which was around 15%, but Lincoff noted that the earlier study was specifically studying weight loss and included lifestyle interventions.
About 17% of people on Wegovy discontinued the treatment due to adverse events, more than the 8% who discontinued in the placebo group. The most common reason people stopped the drug was gastrointestinal problems, similar to earlier Wegovy trials.
Concerns have recently surfaced that GLP-1-based drugs may raise the risk of suicidal thoughts. The trial, though, found 0.7% of patients taking Wegovy experienced psychiatric disorders, around the same as the 0.6% of patients taking placebo.
A limitation of the trial is that men made up nearly three-quarters of participants, said Martha Gulati, director of preventive cardiology at Cedars-Sinai Medical Center who wasn’t involved in the study. While she also found the results impressive, she said it was disappointing that there weren’t more women included, especially since there’s been a historic problem of women being underrepresented in heart trials.
Lincoff said that the investigators tried to enroll a diverse group of participants, “but we ultimately ended up with a patient group that does not duplicate a globally representative population of patients.” He doesn’t think that influenced the results of the trial, though, “as the subgroups were meaningfully sized in this large trial and women and men [had] similar treatment effects.”
The trial occurred during the Covid pandemic, presenting a challenge. The researchers are looking into whether some deaths may have been misclassified as not being cardiovascular-related, as researchers may have had less information on patients who didn’t seek care during the pandemic, Lincoff said while presenting the findings.
What drove the cardiovascular benefit?
A key question for researchers and companies developing obesity drugs is how much of the cardiovascular benefit seen in this trial was driven by weight loss or by other drug mechanisms. If weight loss was the primary factor, that suggests that drugs that lead to greater weight loss, such as Lilly’s Zepbound, could also have greater cardiovascular benefit. But if factors other than weight loss were at play in this trial, then it’s harder to infer how much heart benefit other drugs could provide.
Michael Mason, who leads Lilly’s diabetes and obesity unit, raised this point in an earnings call last week, saying that “probably the key question I’m looking at [for the Select trial] is how much of the effect was driven by drug effect versus weight loss.” Lilly is conducting a similar trial looking at the long-term health outcomes of Zepbound, but it isn’t expected to end until 2027.
Lincoff noted that in Select, since the risk reduction in cardiovascular problems occurred early, before big changes in weight, “that implies that there is [an] effect happening that’s independent of how much weight loss,” he said.
Also, the fact that people in the trial did not lose as much weight as seen in previous studies yet still experienced cardiovascular benefits further supports the idea that weight loss is not the only factor at play, said Randy Seeley, director of the Michigan Nutrition Obesity Research Center who was not involved in the study.
Some data suggest GLP-1-based treatments have anti-inflammatory effects, which could be beneficial to the heart. There are also receptors of the GLP-1 hormone located on heart cells, and the drug’s direct effect on those receptors may additionally play a role.
This study did not look at the relationship between the magnitude of weight loss by participants and their cardiovascular risk reduction, but the researchers are planning follow-up analyses, Lincoff said.
Ultimately, he said, “I think it’s a combination of multiple different effects — the magnitude of weight loss, the process and the mechanism by which the weight is lost, and other effects on blood sugar, on inflammation, on blood pressure, and perhaps direct effects of the drug on the heart and blood vessels itself.”
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