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New analyses of the longest clinical trial yet of the weight-loss drug Wegovy are shedding light on how quickly it helps people lose weight, how long they sustain that weight loss and how safe the medicine is over four years of use.

The analyses – of a trial called Select, whose results showed last year that Wegovy significantly reduced heart risk in addition to helping with weight loss – also suggest that the drug may protect the heart in ways beyond weight loss alone, researchers said, raising new questions about how the wildly popular medicines in this drug class should be used – and covered by insurers.

“The implications are profound,” said Dr. Harlan Krumholz, a cardiologist and scientist at Yale University and Yale New Haven Hospital who was not involved in the research, noting that a second study this week showed a similar finding for heart failure. “We have not encountered a drug with such a breadth of heart benefits.”

More than 25,000 people in the US are starting Wegovy every week, drugmaker Novo Nordisk said this month. And in a KFF poll released Friday, 6% of respondents said they were currently using a drug in this class, known as GLP-1 receptor agonists. That translates to more than 15 million Americans.

One important question about these blockbuster medicines is how widely – and how long – they’ve been studied. The Select trial, which was funded by Novo Nordisk, showed last year that Wegovy reduced the risk of a heart attack, stroke or heart-related death by 20% in people with existing cardiovascular risk with obesity or who are overweight. It included more than 17,600 people from 41 countries between 2018 and 2021 and followed them for several years.

Researchers have continued to mine the data, and the new analyses, presented Monday at the European Congress on Obesity and published in the journal Nature Medicine, show results for people taking Wegovy as long as four years. Here are some major takeaways:

The analysis showed an average weight loss of just over 10% for people who used semaglutide, the active ingredient in Wegovy, compared with 1.5% for study participants who got a placebo. The researchers, led by Dr. Donna Ryan of Pennington Biomedical Research Center in Baton Rouge, Louisiana, noted that the trend showed that participants on the medication typically lost weight for about 65 weeks, or a year and three months, before reaching a plateau.

A previous clinical trial showed even greater average weight loss for Wegovy: about 15% on average over 68 weeks, compared with 2.4% for people who got a placebo. The researchers on the new analysis noted that, in addition to some differences in the people who enrolled in each trial, the previous study was designed specifically for weight loss and included more structured lifestyle interventions about diet and exercise compared with the Select trial, which was designed to test whether the drug prevented cardiac events.

The results showed that the 10% average weight loss for people using Wegovy was sustained for up to 208 weeks, or four years.

Patients stayed on the medicine while they sustained the weight loss. Other studies have shown that many people regain weight after stopping the drugs, including one published in December from Novo Nordisk competitor Eli Lilly: People using the GLP-1 drug Zepbound, which uses the active ingredient tirzepatide and targets a second hormone called GIP, lost an average of 21% of their body weight over 36 weeks. The participants were then split into two groups, and those who stayed on the medicine lost an additional 5.5% of their body weight, while those who unknowingly switched to a placebo regained 14% of their weight.

However, not everybody regained so much weight. The study also looked at how many people maintained at least 80% of the weight loss after the initial 36 weeks, and while many more who continued on the drug did – almost 90% – almost 17% of people who were switched to a placebo maintained that much weight loss without the drug.

In the new analysis, the researchers reported that after two years, about 68% of people taking Wegovy had lost at least 5% of their body weight, while 21% of people on a placebo did. Almost 23% of people on Wegovy lost at least 15% of their body weight, compared with 1.7% on a placebo. And almost 5% of people on the drug lost more than 25% of their body weight, compared with 0.1% on placebo, showing that the top-line findings from studies are just averages; everyone has a different experience with medicines.

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Overall, more people on Wegovy decided to stop participating in the trial because of side effects than people who got a placebo: 17% of those on the drug versus 8% on placebo, a result that was previously reported. And the side effects were ones that are widely known with these medicines: mainly gastrointestinal disorders like nausea, diarrhea, vomiting and constipation, which usually affected people in the first few months of the study as the dose of the medicine increased.

The researchers noted that there were no new safety signals seen in the latest analyses. Acute pancreatitis, or inflammation of the pancreas, wasn’t seen at a higher rate among those on Wegovy than placebo, although gallbladder disorders like gallstones were: 2.8% for people on Wegovy, compared with 2.3% for people on placebo. Both are included in warnings in the drug’s prescribing information because they’d been seen previously in trials.

A key question when the full results of the Select trial were initially presented was whether the 20% reduction in heart risk was driven by weight-loss alone or some other protective effect of the drug. The new analysis suggests that there is something else at play.

That’s because the reduction in risk of heart attack or other events was seen even in people using Wegovy who didn’t lose weight.

“You probably don’t even need to lose weight to get the cardiovascular benefit” with semaglutide and similar medicines, said Dr. Daniel Drucker, a pioneer of research into GLP-1 at the University of Toronto who wasn’t involved in the new analyses. “That’s because that’s what GLP-1 does: It’s cardio-protective, at least in animals, independent of whether or not you have diabetes, independent of whether you have obesity, and you don’t require weight loss – it’s not the whole story.”

An analysis led by John Deanfield of University College London found that the reduction in major adverse cardiovascular events in the study for those on Wegovy, compared with placebo, was similar among people who lost 5% or more of their body weight and those who lost less than that or even those who gained weight.

“This suggests alternative mechanisms of improved cardiovascular outcome beyond reduction in adiposity,” or body fat, the researchers concluded.

A separate study published Monday about heart failure, for which Wegovy has shown a major benefit, suggested the same thing, Krumholz said.

“These two studies show that these anti-obesity medications are also heart-health drugs,” he wrote in an email. “The benefits to the heart for people with established cardiovascular disease or a certain type of heart failure occur regardless of the amount of weight loss.”

Drucker suspects that GLP-1 drugs provide these kinds of benefits by reducing inflammation.

“We can’t ignore the reduction in blood pressure or triglycerides, and the reduction in body weight must help a little bit, and glucose must help a little as well,” he said.

But based on his lab’s research, he said, “one of my favorite theories is inflammation, because we know that people with cardiovascular disease do have increased inflammation in their blood vessels and in the heart.”

Drucker said studies have shown that GLP-1 drugs tamp down harmful inflammation, which his lab is studying. He even noted that he receives communications from people with conditions like Covid-related brain fog, ulcerative colitis and arthritis – driven by inflammation – who think their symptoms have improved while using GLP-1 medicines. Those links would need to be borne out in clinical studies to be considered definitive.

The results in the Select trial, he said, raise the question of whether people who don’t have obesity or aren’t overweight but who have had a heart attack or stroke could benefit from taking a drug like Wegovy to prevent another event – another thing that would need to be studied.

And, Drucker said, the results suggest that insurers should cover the medicines, which cost about $1,000 per month or more without it, more widely.

“We probably really need to rethink these criteria for reimbursing the medicines, because they are not going to be helpful in terms of actually improving health and saving lives and saving health care dollars,” he said. “You don’t even need to lose weight to have a reduction in heart attack, strokes and death.”