The drug semaglutide, the active ingredient in Ozempic and Wegovy, is already known to treat diabetes, aid rapid weight loss, and possibly even curb drug and alcohol addictions. Now a new trial by the drug’s manufacturer, Novo Nordisk, has shown that it can collectively lower the risk of heart attack, stroke and death from cardiovascular disease by 20 percent.
Semaglutide is one of a class of drugs known as GLP-1 receptor agonists, which regulate appetite hormones by lowering blood sugar and slowing the stomach’s rate of emptying. This causes people to feel full 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 who were considered overweight or had obesity and who had cardiovascular disease but not diabetes took either semaglutide or a placebo for an average of nearly three years. People who took the drug lost a significant amount of weight, thus reducing their risk of cardiac complications, but experts say that the amount of improvement suggests the drug’s heart effects likely occurred through mechanisms besides 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 on the same day.
Physicians are excited to potentially have a new way of reducing cardiovascular risk in certain people, although their enthusiasm is somewhat tempered by the cost of the drug and its side effects. Scientific American spoke with Massachusetts General Hospital cardiologist James Januzzi, who was not involved in the study, about how we should view its new findings.
[An edited transcript of the interview follows.]
Were these results expected?
I think we expected to see an effect but maybe not necessarily quite such a profound effect. It’s an impressive result for a few reasons. Although we recognized that these GLP-1 receptor agonists reduce risk for major cardiovascular events in people with diabetes, understanding their value in individuals who have obesity without diabetes required more data. And the study really delivers that very clearly.
What is also quite remarkable to me is that the inclusion of folks with a body mass index (BMI) of 27 or greater is a much, much larger population of patients with heart disease than people with obesity [those with a BMI of 30 or higher, to whom semaglutide is typically prescribed]. A BMI of 27 is considered overweight but certainly isn’t obese, and the reductions in cardiovascular risk seemed somewhat larger in people with a relatively lower BMI. So while patients lost about 9.5 percent of their body weight [on average] in SELECT, the benefits of the drug seem quite clearly to be above and beyond weight loss alone.
If it’s not just causing weight loss, how is it improving cardiovascular health?
We simply don’t know. There are central effects in the brain with GLP-1 receptor agonists that clearly play a role in the downstream biological effects. There’s no way that weight loss alone explains the benefits in this trial. In the paper, the researchers speculate that it may have to do with acute effects on blood pressure or reduction in inflammation.
My personal feeling is the drug very likely has a direct effect on blood flow through vessels, along with an acute lowering of blood pressure. The level of blood pressure reduction that the team saw would be expected to improve risk for cardiovascular events.
This would not be, by any stretch, the first time, nor will it be the last time, that we see a remarkable clinical impact of a therapy and have no clue as to why. But it’s not a problem because we’ve been using GLP-1 receptor agonists for years and 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 for that was gastrointestinal intolerance, and that’s what we see in clinical practice. It’s not unusual, particularly during initiation of treatment and while ramping up the dosage, that patients develop nausea, vomiting and diarrhea. And as the body metabolizes fat during rapid weight loss, it causes the liver to secrete extra cholesterol into bile, which can cause gallstones. But that’s more a by-product of the success of the drug 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 that we need to keep our eye on, particularly in our more frail patients. This has led to a large interest in the development of weight-loss drugs that may not have as much of an effect on skeletal muscle mass as semaglutide does.
Based on the new findings, should doctors prescribe semaglutide to prevent cardiac problems? And if so, who should receive a prescription?
To simply say anyone with a BMI of 27 with a prior heart attack should be treated would be describing a massive number of patients. Given the price of Wegovy [between $700 and $1,300 per month], treating every patient who’s potentially eligible would be financially burdensome to the health care system. It’s 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 in a more precise matter.
Was the drug actually 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, which means that there were [more than] 59 patients who did not have an event prevented, at least within the three years of follow-up.
There are other cardiovascular therapies that have a much lower NNT to reduce an event. Given the cost of semaglutide, are we going to 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 tests or even imaging tests, there certainly are ways to measure risk for future events that I suspect will provide greater clarity about who would most benefit from being treated. In the meantime, the issue is whether [insurers] will be willing to cover the drug for this indication.
Novo Nordisk has asked the U.S. Food and Drug Administration to expand its approval of semaglutide to include cardiovascular uses. What can we expect to see from the regulators?
The FDA is not going to make a recommendation based on the NNT; it’s going to make the recommendation based on the merits of the trial. The study not only met its primary end point but really had remarkably impressive results. I fully expect that [Novo Nordisk] will get the regulatory approval.
What are the next steps?
This is the first of several trials that will really revolutionize how we manage people with obesity and cardiovascular disease. There are studies looking at variations of drugs similar to semaglutide that target multiple appetite hormones. And then there are drugs that are completely unrelated to GLP-1 that are being explored. There’s a huge enthusiasm now to explore different ways to pharmacologically lose weight safely, with a parallel goal of reducing cardiovascular risk.
Another important area to think about is the fact that having obesity complicates heart failure. There’s very good reason to believe that effective treatment of obesity and heart failure would reduce cardiovascular risk, so this is an area absolutely in need of further exploration.
