The drug semaglutide, the active ingredient in Ozempic and Wegovy, is already known to treat diabetes and help rapid weight lossand possibly even curb drug and alcohol addictions. Now, a new trial by the drug’s maker, Novo Nordisk, has shown that together it can reduce the risk of heart attack, stroke and death from cardiovascular disease by 20 percent.
Semaglutide belongs to a class of medications known as GLP-1 receptor agonists, which regulate appetite hormones by lowering blood sugar and slowing stomach emptying. This makes people feel full for longer, so they avoid eating and lose weight. In the closely watched trial, known as Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT), more than 17,000 people considered overweight or obese and who had cardiovascular disease but not diabetes took semaglutide or a placebo for a period of time. average of almost three years. People who took the drug lost a significant amount of weight, so reducing your risk of heart complications, but experts say the amount of improvement suggests the drug’s cardiac effects likely occurred through mechanisms other than weight loss alone. Novo Nordisk published the results on November 11 in the New England Journal of Medicine and announced them in a presentation at the American Heart Association meeting in Philadelphia the same day.
Doctors are excited about the possibility of having a new way to reduce cardiovascular risk in certain people, although their enthusiasm is somewhat tempered by the cost of the drug and its side effects. American scientist spoke with Massachusetts General Hospital cardiologist James Januzzi, who was not involved in the study, about how we should view their new findings.
(Below is an edited transcript of the interview.)
Were these results expected?
I think we expected to see an effect, but maybe not necessarily as profound an effect. It is an impressive result for several reasons. Although we recognized that these GLP-1 receptor agonists reduce the risk of major cardiovascular events in people with diabetes, understanding their value in people with obesity without diabetes required more data. And the study really makes it very clear.
What’s also quite notable to me is that including people with a body mass index (BMI) of 27 or more is a much, much larger population of heart disease patients than people with obesity (those with a BMI of 30 or more). , for whom semaglutide is normally prescribed). A BMI of 27 is considered overweight, but certainly not obese, and reductions in cardiovascular risk appeared somewhat greater in people with a relatively lower BMI. So while patients lost about 9.5 percent of their body weight (on average) in SELECT, the drug’s benefits clearly appear to be beyond simple weight loss.
If it doesn’t just cause weight loss, how does it improve cardiovascular health?
We just don’t know. There are central effects in the brain with GLP-1 receptor agonists that clearly play a role in downstream biological effects. There is no way that weight loss alone explains the benefits of this trial. In the article, the researchers speculate that it may have to do with acute effects on blood pressure or reduction of inflammation.
My personal opinion is that the drug most likely has a direct effect on blood flow through the vessels, along with an acute reduction in blood pressure. The level of blood pressure reduction the team observed would be expected to improve the risk of cardiovascular events.
This would by no means be the first time, nor will it be the last, that we see a notable clinical impact from a therapy and have no idea why. But it is not a problem because we have been using GLP-1 receptor agonists for years and we know their risks and benefits.
What are some of the risks?
About one in five patients taking semaglutide in SELECT had to stop treatment. The most common reason was gastrointestinal intolerance, and that’s what we see in clinical practice. It is not unusual, especially during the initiation of treatment and while the dose is increased, for patients to develop nausea, vomiting, and diarrhea. And as the body metabolizes fat during rapid weight loss, it causes the liver to secrete additional cholesterol into the bile, which can cause gallstones. But that’s more of a byproduct of the drug’s success in helping people lose weight, not the drug itself.
There are relatively few long-term adverse risks, but one is that the effects of GLP-1 receptor agonists include loss of both fat tissue and muscle. This is something we must pay attention to, especially in our most fragile patients. This has generated great interest in the development of weight loss drugs that may not have as much of an effect on skeletal muscle mass as semaglutide.
Based on the new findings, should doctors prescribe semaglutide to prevent heart problems? And if so, who should receive a prescription?
Simply saying that anyone with a BMI of 27 who has had a previous heart attack should be treated would be describing an enormous number of patients. Given Wegovy’s price ($700 to $1,300 per month), treating each potentially eligible patient would be a financial burden on the health system. It is reasonable to say that we need better tools to recognize who would benefit most from treatment with semaglutide or other GLP-1-related drugs, so that we can focus our therapies more precisely.
Was the drug really as effective as it seems?
In SELECT, the primary endpoint was nonfatal heart attack, nonfatal stroke, or cardiovascular death. And the number needed to treat (NNT) is how many patients in the trial needed to receive semaglutide versus placebo to reduce one of those serious events. That number is more than 60, meaning that there were (more than) 59 patients who were not prevented from experiencing any events, at least within three years of follow-up.
There are other cardiovascular therapies that have a much lower NNT for reducing an event. Given the cost of semaglutide, would we feel good about treating 60 patients to reduce one event over a three-year period? Whether it’s clinical variables, blood tests, measures of inflammation, genetic testing, or even imaging tests, there are certainly ways to measure the risk of future events that I suspect will provide greater clarity about who would benefit most from treatment. In the meantime, the question is whether (insurers) will be willing to cover the drug for this indication.
Novo Nordisk has asked the US Food and Drug Administration to expand its approval of semaglutide to include cardiovascular uses. What can we expect from regulators?
The FDA is not going to make a recommendation based on the NNT; will make the recommendation based on the merits of the trial. The study not only met its primary endpoint, but actually achieved remarkably impressive results. I fully expect it (Novo Nordisk) to get regulatory approval.
Which are the next steps?
This is the first of several trials that will truly revolutionize the way we treat people with obesity and cardiovascular disease. There are studies looking at variations of semaglutide-like medications that target multiple appetite hormones. And then there are drugs that are completely unrelated to GLP-1 that are being explored. There is currently enormous enthusiasm to explore different ways to safely lose weight pharmacologically, with the parallel goal of reducing cardiovascular risk.
Another important area to think about is the fact that obesity complicates heart failure. There is very good reason to believe that effective treatment of obesity and heart failure would reduce cardiovascular risk, so this is an area that absolutely needs further exploration.
