A study published in the New England Journal of Medicine, Nov. 11, 2023 has pumped up an already very hot drug—semaglutide. You know it better as Wegovy for weight loss or Ozempic for type 2 diabetes. Should millions of people now start taking semaglutide to prevent heart attacks, strokes and other cardiovascular complications?
The Semaglutide “SELECT” Study:
This was a big multicenter clinical trial. That means there were 804 clinical sites in 41 countries participating in the SELECT (“Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity”) trial. Of the 17,604 patients who signed up, 8,803 got semaglutide and 8,801 received placebo. These people did not have diabetes.
The participants received the max dose of semaglutide: 2.4 mg injected once weekly.
These were high-risk patients:
“More than three quarters of the patients had had a previous myocardial infarction, and nearly one quarter had chronic heart failure.”
Put another way, these were patients who were primed to suffer a serious cardiovascular event.
Results: How Good was Semaglutide to Prevent Heart Attacks, etc.?
Wired (Nov. 11, 2023) made the drug seem fantastic:
The website Freethink* also used the phrase:
“slashes heart attack risk”
to describe the semaglutide SELECT trial:
“Novo Nordisk has published the results of its massive SELECT trial, which found that the weight-loss drug semaglutide (brand name Wegovy) reduced participants’ risk of a serious cardiovascular event — heart attack, stroke, and death from heart disease — by 20%.”
So far, it seems as if this this drug is almost too good to be true. Not only does semaglutide help people control their type 2 diabetes, it also enables people to lose weight. And now, perhaps millions more people should be using semaglutide to prevent heart attacks, strokes and other cardiovascular complications by a whopping 20%.
Absolute Risk Vs. Relative Risk with Semaglutide to Prevent Heart Attacks:
Drug companies, newspapers and websites love the idea of relative risk reduction. This stat makes drugs seem like breakthroughs!
Let’s look at the big picture. Of the 8,803 patients in the semaglutide group, there were 569 who experienced one of the following: death from cardiovascular causes, nonfatal heart attack or nonfatal stroke. Put another way, 6.5% of those taking the drug had a big-time cardiovascular event.
Of the 8,801 patients on placebo, 701 had one of those major cardiovascular events (or died). That was 8.0%. So, the absolute difference between those on semaglutide and placebo was 1.5%. That’s not nearly as impressive as the 20% relative risk reduction bannered in the headlines.
What About Death?
Let’s look exclusively at death from cardiovascular causes. In the semaglutide group there were 223 patients who died (2.5%). There were 262 patients who died in the placebo group (3.0%). That’s a difference of 0.5%. The researchers calculated the statistical significance at P=0.07. They admit that did not meet their criteria for statistical superiority over placebo.
We do not want to downplay the value of semaglutide to prevent cardiovascular complications. We do want to distinguish between a 20% relative risk reduction, which sounds amazing and a 1.5% absolute risk reduction which doesn’t seem quite so impressive.
The Downsides of Taking Semaglutide to Prevent Heart Attacks:
There were semaglutide side effects. Where there is a clinical trial of this magnitude, we always like to look at the number of people who decided to opt out of the study because of adverse drug reactions.
Here is what happened in the SELECT trial:
“Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001).”
In case you have forgotten your high school statistics class, a P value of <0.001 is highly significant. We can say with a great deal of certainty that the people who dropped out of the trial did so because of drug side effects.
What were the side effects? Not surprisingly, gastrointestinal disorders (nausea, vomiting and diarrhea) dominated. There were 880 people (10%) who complained of GI disorders that led to their discontinuation of the study. That compared to 172 patients (2.0%) who stopped in the placebo group.
There is something confusing about the SELECT trial when it comes to reported adverse reactions, though. The people who dropped out because of side effects seem to have disappeared from the final tally of adverse reactions.
The authors state that:
“Serious adverse events were reported in 2941 patients (33.4%) in the semaglutide group and 3204 patients (36.4%) in the placebo group (P<0.001).”
Taken at face value, that suggests there were more “serious adverse events” in the placebo group than in the semaglutide group. As a result, some doctors might conclude that the drug did not cause side effects.
The researchers go on to state:
“Adverse events leading to permanent discontinuation of semaglutide or placebo occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001); these events included gastrointestinal disorders in 880 patients (10.0%) in the semaglutide group and 172 patients (2.0%) in the placebo group (P<0.001) and gallbladder related disorders in 246 patients (2.8%) and 203 patients (2.3%), respectively (P = 0.04).”
Again, that data is puzzling and here is why. If you go to the official prescribing information for Wegovy (semaglutide) at the same 2.4 mg dose, you will discover that in the clinical trials for weight loss, the drug caused nausea in 44% of patients whereas placebo caused nausea in 16%. Diarrhea occurred in 30% of patients taking semaglutide and in 16% of those on placebo. Vomiting impacted 24% of the Wegovy patients and 6% of the placebo group. Those numbers are dramatically higher than those reported in the SELECT trial.
There is another hard-to-understand aspect of the SELECT trial. In table S3, “Expanded Listing of Investigator-Reported Adverse Events,” in the group of 8,803 patients who received semaglutide, only 343 experienced “gastrointestinal disorders.” That was only 3.9%. Of the 8,801 volunteers on placebo, 323 experienced “gastrointestinal disorders.” That was 3.7%. The conclusion might be that the drug did not cause more GI complaints than placebo. And yet we know from the official prescribing information that is not the case. We find this puzzling.
Semaglutide is one of the hottest drugs in the U.S. right now. It has been in short supply for months. With headlines that it can help people lose weight, control blood sugar and also “slash” the risk of heart attacks and strokes, the popularity of this medicine is only likely to increase.
We have thrown a lot of numbers at you. Sorry. But this is important. The clinical trial makes it seem as if there were more serious adverse events in the placebo group (36.4%) than in the drug group (33.4%). Of course, that could be in part because all the people who dropped out because of side effects were not counted in those numbers.
If you would like to see another article about semaglutide and read some responses from readers, here is a link. Please share your own experience with the drug in the comment section below.
We do our best to put drug information into perspective. We know how complicated this information is. Please let us know if this analysis is understandable or if we need to modify it to make it easier to grasp. And thank you for supporting our independent voice. Google makes it much harder to find our material than that of the drug companies. If you think this article was worthwhile, please share it with friends and family members.