The drug semaglutide, the active ingredient in Ozempic and Wigovy, is already known to treat diabetes, aid in rapid weight loss, and may even curb drug and alcohol addiction. A new trial by the drug’s manufacturer, Novo Nordisk, showed it could reduce the combined risk of heart attack, stroke, and death from cardiovascular disease by 20%.
Semaglutide is a type of drug known as a GLP-1 receptor agonist that regulates appetite hormones by lowering blood sugar levels and slowing the rate of gastric emptying. This causes people to feel fuller longer, avoid eating, and lose weight. The closely watched trial, known as the Effects of Semaglutide on Cardiovascular Disease in Overweight or Obese People (SELECT), found that more than 17,000 people who were considered overweight or obese, had cardiovascular disease but did not have diabetes, On average, nearly 3 years on either semaglutide or a placebo. People who took the drug lost significantly more weight and lowered their risk of heart complications, but experts believe this improvement was caused by a mechanism by which the drug’s effect on the heart goes beyond weight loss. This suggests that the possibility is high.Novo Nordisk announced this result on November 11th. New England Medical Journal The announcement was made the same day at the American Heart Association conference in Philadelphia.
Doctors are excited about the possibility of finding new ways to reduce cardiovascular risk in certain people, but their enthusiasm is tempered somewhat by the drug’s price and its side effects. scientific american We spoke to James Januzzi, a cardiologist at Massachusetts General Hospital who was not involved in the study, about what to make of the new findings.
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[An edited transcript of the interview follows.]
Were these results as expected?
I think the effect was expected, but it doesn’t necessarily mean it’s that big of an effect. This is an impressive result for several reasons. We recognized that these GLP-1 receptor agonists reduce the risk of major cardiovascular events in diabetic patients, but more is needed to understand their value in non-diabetic obese individuals. data was needed. And this study shows that very clearly.
Also, what is very remarkable to me is that the population of heart patients is much larger than the obese people, as it includes people with a body mass index (BMI) of 27 and above. [those with a BMI of 30 or higher, to whom semaglutide is typically prescribed]. A BMI of 27 is considered overweight, but certainly not obese. The reduction in cardiovascular risk appears to be slightly greater for people with a relatively low BMI. Therefore, the patient’s weight decreased by approximately 9.5 percent. [on average] In SELECT, the drug’s benefits clearly seem to go beyond just weight loss.
If it’s not just about weight loss, how does cardiovascular health improve?
we simply don’t know. GLP-1 receptor agonists have central effects in the brain and clearly play a role in downstream biological effects. There is no way to explain the benefits of this trial in terms of weight loss alone. In their paper, researchers speculate that it may be related to acute effects on blood pressure and reducing inflammation.
My personal feeling is that this drug is very likely to directly affect blood flow through the blood vessels, along with a sharp drop in blood pressure. The level of blood pressure reduction the research team observed would be expected to improve the risk of cardiovascular events.
This is by no means the first time, nor will it be the last, that a treatment has had a significant clinical effect and we have no clue as to why. But that doesn’t matter because we have been using GLP-1 receptor agonists for many years and know their risks and benefits.
What are the risks?
Approximately one in five patients taking semaglutide in SELECT had to discontinue treatment. The most common reason for this is gastrointestinal intolerance, and that is what we see in clinical practice. It is not uncommon for patients to develop nausea, vomiting, and diarrhea, especially during initiation of treatment or while increasing dosage. Also, when your body metabolizes fat during rapid weight loss, your liver secretes extra cholesterol into your bile, which can lead to gallstones. But it’s not the drug itself, but a byproduct of the drug’s success in losing weight.
Long-term adverse risks are relatively small, one of which is that the effects of GLP-1 receptor agonists include loss of both adipose tissue and muscle. This is something we always need to pay attention to, especially in frail patients. For this reason, there is great interest in developing weight loss drugs that may not affect skeletal muscle mass as much as semaglutide.
Based on new findings, should doctors prescribe semaglutide to prevent heart problems? If so, who should get the prescription?
Simply saying that anyone with a BMI of 27 who has had a previous heart attack should be treated would account for a huge number of patients. Considering the price of Wegovy [between $700 and $1,300 per month], treating all potentially eligible patients would be a financial burden on the health care system. It is fair to say that we need better tools to recognize who will benefit most from treatment with semaglutide or other GLP-1 related drugs so that treatment can be focused on more precise issues. .
Was the drug actually as effective as you thought?
In SELECT, the primary endpoint was nonfatal heart attack, nonfatal stroke, or cardiovascular death. And the number needed to treat (NNT) is the number of patients in the trial who required administration of semaglutide and a placebo to reduce one of these serious events. There are over 60 of them. [more than] Fifty-nine patients had no preventable event within at least 3 years of follow-up.
There are other cardiovascular treatments that lower NNT much lower to reduce events. Given the cost of semaglutide, is it okay to treat 60 patients to reduce one event over three years? Clinical variables, blood tests, inflammation measurements, genetic testing, even imaging? But I think there are certainly ways to measure the risk of future events, which could make it clearer who would benefit most from treatment.Meanwhile, the problem is [insurers] We are happy to cover medications for this indication.
Novo Nordisk has asked the U.S. Food and Drug Administration to expand approval of semaglutide for cardiovascular use. What can we expect from regulators?
FDA does not intend to make recommendations based on the NNT. We will make a recommendation based on the merits of the case. Not only did this study meet its primary endpoint, but it also produced truly surprising results.I fully expect it [Novo Nordisk] Regulatory approval is obtained.
What’s the next step?
This is the first of several trials that could revolutionize the way people with obesity and cardiovascular disease are managed. There are studies investigating variations of drugs similar to semaglutide that target multiple appetite hormones. Additionally, drugs that are completely unrelated to GLP-1 are also being studied. There is currently great enthusiasm in exploring different ways to safely reduce weight pharmacologically, with the parallel goal of reducing cardiovascular risk.
Another important area to consider is the fact that heart failure is exacerbated by obesity. There is good reason to believe that effectively treating obesity and heart failure will reduce cardiovascular risk, so further research is definitely needed in this area.
