Obesity drug “effective treatment” to reduce cardiovascular events in overweight adults, experts flag

14 Nov 2023 — An international clinical trial found that semaglutide therapy lowered cardiovascular events by 20% in overweight or obese adults who don’t have diabetes. This effect was on top of evidence-based care for cardiovascular disease the patients received in the trial. While therapies are limited for obesity and overweight, the researchers note the study demonstrates the effectiveness of a new pathway to reduce risks associated with obesity. 

The risk reductions were similar in men and women and across different ethnicities, patient ages and body weight at baseline. On average, patients treated with the medication also lost 9.4% of their body weight. 

Speaking to Nutrition Insight, the study’s lead author, Dr. Michael Lincoff, vice chair for research in Cleveland Clinic’s department of cardiovascular medicine, hopes these outcomes will help improve access to weight management therapies to improve cardiovascular health in patients.

“We have an evidence basis for years for hypertension, cholesterol, diabetes and antiplatelet therapy that show they improve outcomes,” Lincoff states. “Overweight and obesity have been a different situation.” 

“For many, it’s considered a lifestyle or a cosmetic treatment. In the US, we don’t have insurance coverage for weight management. Now that we’ve shown there’s a reduction independently in cardiovascular outcomes with treatment of overweight and obesity, with this kind of therapy, we’re hoping that it’ll be much easier for patients to get coverage for it and that cardiologists incorporate it into their toolbox.” 

Semaglutide — a GLP-1 (glucagon-like peptide-1) receptor agonist medication — can be prescribed to adults with type 2 diabetes and is approved for chronic weight management in overweight adults with at least one other health issue. 

SELECT trial  
The Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity (SELECT) trial tested whether adding semaglutide to standard care would be superior to a placebo in reducing the risk of major adverse cardiovascular events among overweight or obese patients with a pre-existing cardiovascular disease. 

The semaglutide treatment had an additional effect of 20% on top of other evidence-based therapies for cardiovascular disease.The study, published in the New England Journal of Medicine, was presented at the American Heart Association’s Scientific Sessions 2023. 

In total, 17,604 patients in 41 countries were enrolled in the trial. All had a BMI over 27, were over 45 years and had established cardiovascular disease. The participants were randomly assigned to two groups that either received semaglutide or a placebo for an average period of 34 months, with an average follow-up period of 40 months. 

Of patients receiving a weekly semaglutide injection of 2.4 mg, 6.5% experienced death from cardiovascular causes, nonfatal heart attack or nonfatal stroke. At the same time, this occurred in 8% of patients treated with a placebo. 

The researchers reveal: “Semaglutide improved cardiovascular outcomes in this trial, whereas lifestyle and pharmacologic interventions for overweight or obesity tested in previous trials have uniformly failed to do so.” 

Cause and effect 
Discussing whether semaglutide or the resulting weight loss results were the main drivers of the identified cardiovascular benefits, Lincoff expects the effects were not only attributable to the magnitude of weight loss as patients were getting these benefits “well before they lost most of their weight.” 

“We saw differences between the treatment groups and their cardiovascular outcomes very early on after initiation of treatment within the first several months, whereas the maximum weight loss took 65 weeks to occur fully.”

“Part of it may well be the physiologic changes in the process of losing weight, such as the negative energy balance and changes that occurred in the adipose cells, before substantial weight loss has occurred.” 

He explains that semaglutide also improves glycemic control, which helps improve cardiovascular health, for example, by reducing blood pressure, inflammation and glucose levels. 

Lincoff expects the cardiovascular benefits were not solely attributable to weight loss.Moreover, animal models have shown direct effects of the GLP-1 agonists on vascular tissue and cardiac muscle, which may be part of the issues relating to heart failure. 

“There are many different potential mechanisms. We could try to tease some of them, but those kinds of analyses are intrinsically limited,” cautions Lincoff. “We are in the process of trying to do different kinds of mediation analysis, but those are complex. We hope to have some information in the future, but we don’t know if we’ll ever be able to say for certain, at least based on this data.”

Adverse events 
More patients discontinued semaglutide (16.6%) than the placebo (8.2%), mainly due to gastrointestinal symptoms, including nausea and diarrhea. However, the medication was not associated with a higher risk for severe gastrointestinal disorders, pancreatitis, psychiatric disorders or kidney injury. 

“When patients come off the drug, it weakens your power to see an effect,” highlights Lincoff. “Even though more patients were off the drug in the semaglutide arm, we could still show the treatment effect.” 

He details that the majority of adverse events that led to study drug discontinuation were gastrointestinal side effects. “Those are well described with this class of drug, particularly when patients start the drug or during dose escalation for the first four or five months.”  

“This means that some patients can’t tolerate [semaglutide], or at least they can’t tolerate a somewhat rapid escalation,” he continues. “We increased the dose every month in five steps, which is recommended, and we also allowed practitioners to slow down the dose escalation if patients were having a problem stepping back to previous doses to take drug causes.” 

He explains that while the research team tried to make the protocol flexible, some practitioners may be prolonging each step to allow people to get used to it. While the protocol used is well-known and described, it is unclear whether it mirrors what happens in practice. 

“Interestingly, more patients came off placebo for the perception that they weren’t getting an effect because perhaps they weren’t losing as much weight. The overall difference in drug discontinuation was about 26.7% in the semaglutide group versus 23.6% in the placebo group. They stopped for different reasons.”

Novo Nordisk has filed for a label update of its semaglutide medication based on the study’s outcomes in the US and EU.Novo Nordisk 
The clinical trial was sponsored by Novo Nordisk, the company that developed semaglutide. Lincoff notes that, as with most large-scale trials and therapeutics, the study was industry-sponsored, but there was independent confirmation of the analyses. 

“Novo Nordisk did the analyses, but the raw databases were sent to an independent statistical organization, which confirmed the analysis independently and provided signed affidavits of that and their analysis to the investigators.” 

“When this goes to the Food and Drug Administration (FDA), they’re also going to confirm the analysis independently, they will get the raw data set and then redo the analysis.” 

The Danish pharmaceutical company has filed for a label update of its semaglutide medication, Wegovy, in the US and EU to include an “indication for risk reduction of major adverse cardiovascular events in adults with a BMI of less than 27 kg/m2 and established cardiovascular disease.”

While Novo Nordisk expects a decision in 2024, the FDA has recently granted priority review for adding the SELECT trial data to the medication’s label in the US. 

By Jolanda van Hal

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