What the results of Wegovy’s longest clinical trial to date show on weight loss, side effects and heart protection

New analyzes of the longest-ever clinical trial of the weight-loss drug Wegovy shed light on how quickly it helps people lose weight, how long they maintain that weight loss and how safe the drug is over four years. ‘use.

The analyzes – from a trial called Select, whose results last year showed that Wegovy significantly reduced heart risk in addition to helping with weight loss – also suggest that the drug may protect the heart beyond the weight loss alone, the researchers said, raising new questions. on how the very popular drugs 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 result for heart failure. “We have not encountered a drug that provides this magnitude of benefit for the heart.”

In the United States, more than 25,000 people start Wegovy each 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’s more than 15 million Americans.

An important question about these blockbuster drugs is to what extent – ​​and for how long – they have been studied. The Select trial, funded by Novo Nordisk, showed last year that Wegovy reduced the risk of heart attack, stroke or cardiac death by 20% in people with existing cardiovascular risk with obesity or overweight. It included more than 17,600 people from 41 countries between 2018 and 2021 and followed them for several years.

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

Weight loss continued for over a year

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

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

It lasted up to four years

The results showed that the average weight loss of 10% among people using Wegovy was maintained for 208 weeks, or four years.

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

However, not everyone gained that much weight back. The study also looked at how many people maintained at least 80% of their weight loss after the first 36 weeks, and while many more people who continued taking the drug did so – almost 90% – closer 17% of people who switched to a placebo maintained their weight loss. so much weight loss without medication.

Results vary for everyone

In the new analysis, researchers reported that after two years, about 68% of people taking Wegovy had lost at least 5% of their body weight, compared to 21% of people taking a placebo. Nearly 23% of people on Wegovy lost at least 15% of their body weight, compared to 1.7% on placebo. And almost 5% of people taking the drug lost more than 25% of their body weight, compared to 0.1% taking the placebo, showing that the main study results are only averages; Everyone has a different experience with medications.

No safety surprises for up to four years

Overall, more people on Wegovy decided to stop participating in the trial due to side effects than people who received a placebo: 17% of those taking the drug versus 8% on the placebo, a previously reported result. And the side effects were those that are widely known with these drugs: mainly gastrointestinal disturbances like nausea, diarrhea, vomiting and constipation, which usually affected people during the first months of the study at as the dose of the drug increased.

The researchers noted that no new safety signals were observed in the latest analyses. Acute pancreatitis, or inflammation of the pancreas, was not seen at a higher rate in people taking Wegovy than in people taking placebo, although gallbladder disorders like gallstones were 2.8%. for people on Wegovy, compared to 2.3% for people on placebo. Both are included in the warnings in the drug’s prescribing information because they have already been observed in trials.

Benefits Beyond Weight Loss

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

Indeed, reduced risk of heart attack or other events was seen even in people using Wegovy who did not lose weight.

“You probably don’t even need to lose weight to get cardiovascular benefits” with semaglutide and similar drugs, said Dr. Daniel Drucker, a pioneer in GLP-1 research at the University of Toronto. , who did not participate in the new project. analyzes. “That’s because that’s what GLP-1 does: it’s cardio-protective, at least in animals, whether or not you have diabetes, whether or not you have obesity, and you don’t You don’t need to lose weight – that’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 people taking Wegovy, compared to placebo, was similar in people who lost 5% or more of their body weight and those who lost less. than that or even those who have gained weight.

“This suggests alternative mechanisms for improving cardiovascular outcomes beyond reducing adiposity,” or body fat, the researchers concluded.

A separate study released Monday in heart failure, for which Wegovy demonstrated major benefit, suggests the same thing, Krumholz said.

“These two studies show that these obesity drugs are also heart health drugs,” he wrote in an email. “Benefits to the heart of people with established cardiovascular disease or some type of heart failure occur regardless of the extent of weight loss.”

A benefit in reducing inflammation

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

“We can’t ignore reducing blood pressure or triglycerides, and reducing body weight has to help a little, and glucose has to help a little too,” 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 have increased inflammation in their blood vessels and in their heart. »

Drucker said studies have shown that GLP-1 drugs alleviate harmful inflammation, which his lab is studying. He even noted that he was receiving communications from people suffering from conditions such as Covid-related brain fog, ulcerative colitis and arthritis – caused by inflammation – who believe their symptoms have improved with use of GLP-1 drugs. These links should be confirmed by clinical studies to be considered definitive.

The results of the Select trial, he said, raise the question of whether people who do not have obesity or are not overweight but who have had a heart attack or stroke might benefit of taking a drug like Wegovy to prevent another event – ​​another thing that might be worth investigating.

And, Drucker said, the findings suggest that insurers should cover drugs more broadly, which cost about $1,000 a month or more without them.

“We probably really need to rethink these drug reimbursement criteria because they’re not going to actually help improve health, save lives and save health care dollars,” he said. “You don’t even need to lose weight to reduce heart attacks, strokes and deaths.”

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