SELECT Trial: Major CVD Event Risk Cut by 20% in Overweight or Obese Adults Without Diabetes

Research Highlights:

• In a large, international clinical trial, people with obesity or overweight but not diabetes taking semaglutide for more than 3 years had a 20% lower risk of heart attack, stroke or death due to cardiovascular disease and lost an average of 9.4% of their body weight. Semaglutide is a GLP-1 medication primarily prescribed for people with Type 2 diabetes. It is also FDA-approved for weight loss in people with obesity.
   
• The double-blind, randomized trial enrolled more than 17,500 adults in 41 countries with overweight or obesity and who had previously experienced a heart attack, stroke and/or had peripheral artery disease but who did not have either Type 1 or Type 2 diabetes.
   
• According to the researchers, the results of the SELECT trial are the first time that any medication or lifestyle therapy has been proven to reduce cardiovascular events in adults with overweight or obesity who did not have Type 1 or Type 2 diabetes.

PHILADELPHIA — In a large, international clinical trial, people with obesity or overweight but not diabetes taking semaglutide for more than 3 years had a 20% lower risk of heart attack, stroke or death due to cardiovascular disease and lost an average of 9.4% of their body weight. Semaglutide is a GLP-1 medication primarily prescribed for people with Type 2 diabetes. It is also FDA-approved for weight loss in people with obesity.

These results were shared in a late-breaking science presentation at the American Heart Association’s Scientific Sessions 2023. The meeting, Nov. 11-13, in Philadelphia, is a premier global exchange of the latest scientific advancements, research and evidence-based clinical practice updates in cardiovascular science. The full manuscript is also simultaneously published in The New England Journal of Medicine.

“This news is very encouraging for people with overweight or obesity because no treatment specifically directed at the management of obesity and overweight in people without Type 1 or Type 2 diabetes has been tested in a randomized trial and been shown to influence cardiovascular outcomes,” said lead study author A. Michael Lincoff, M.D., vice chairman for research of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine and an interventional cardiologist in the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic.

While prior research has confirmed the benefits of semaglutide in managing blood sugar, decreasing cardiovascular disease events and reducing weight in people with Type 2 diabetes, this study specifically investigated the potential impact of semaglutide on cardiovascular disease in people with overweight or obesity and cardiovascular disease who did not have either Type 1 or Type 2 diabetes.

Study participants were randomly assigned to take either 2.4 milligrams of semaglutide (the FDA-approved semaglutide dose for weight management) or a placebo once a week, which is higher than the FDA-approved semaglutide dose limit for Type 2 diabetes of 2.0 mg/week. Each person in the study used a “pen” to inject the medicine or placebo into a skin fold in their stomach, thigh or upper arm each week on the same day, and the dose started at 0.24 mg and gradually increased every four weeks up to 2.4 mg, and mean follow-up for all participants was 40 months. No one involved in the study — not the participants, the health care professionals or trial investigators — knew which participants were receiving semaglutide or placebo.

In addition to taking either semaglutide or placebo for the trial, all participants also received standard of care treatment for cardiovascular disease, such as cholesterol modifying medications, antiplatelet therapies, beta blockers or other treatments. The authors note that heart disease diagnoses varied among the participants, therefore, treatment was adjusted to meet each individual’s diagnosis and needs, as well as the treatment guidelines in their country of residence.

The study ran from October 2018 through June 2023, and the results indicated the following:

• There was a 20% reduction in the risk of heart attacks, strokes or death due to cardiovascular disease in the participants who took semaglutide, compared to the participants in the placebo group.
   
• In the semaglutide group, the participants’ body weight was reduced, on average, by 9.4% compared to a reduction of 0.9% among the adults in the placebo group.
   
• There were no new safety concerns found in the study, which researchers note is encouraging since the SELECT trial is the largest and longest (4.5 years) trial of semaglutide in adults without Type 1 or Type 2 diabetes.
   
• The number of serious adverse events was lower in the semaglutide group. Previous studies of medications of the GLP-1 receptor agonist class have shown an association with gallbladder disorders, and in SELECT, there was a slightly higher rate of gallbladder disorders in the semaglutide vs. placebo group (2.8% vs. 2.3%, respectively).
   
• Semaglutide was stopped more frequently than placebo for gastrointestinal intolerance, a known side effect of this class of medications; however, there was no higher rate of serious gastrointestinal events.
   
• The researchers noted that this medication did not lead to an increased rate of pancreatitis, which has been a concern with prior medications of this type.
   
• Of note, other weight-loss medications that are not GLP-1 receptor agonists have been associated with increased risks of psychiatric disorders or cancer; these risks were not elevated with semaglutide in the SELECT trial.

“It’s been estimated that within about ten years, over half of the world’s population will have overweight or obesity,” said Dr. Lincoff. “And while GLP-1 medications are frequently prescribed for patients with vascular disease and Type 2 diabetes, there is a significant number of people who do not have Type 1 or Type 2 diabetes but do have vascular disease and overweight or obesity for whom these medications are often not available due to access to care issues, insurance coverage or other factors. This population may now potentially benefit from semaglutide, and importantly, our results indicate the magnitude of cardiovascular risk reduction with semaglutide among people without Type 1 or Type 2 diabetes is the same as what we have seen in people with Type 2 diabetes. Our findings expand the opportunity to treat patients who have overweight or obesity and existing heart disease without Type 1 or Type 2 diabetes, and we have a chance to significantly reduce their risk of a secondary cardiovascular event including death.”

The study had some limitations. The trial only included adults with prior cardiovascular disease, therefore, it did not investigate primary prevention of cardiovascular disease (people with no history of a heart attack, stroke and/or peripheral artery disease). In addition, 28% of the study participants were female, which is not proportionate to the number of women with cardiovascular disease and overweight or obesity in the general population.

Study authors note that additional analyses of the findings are planned, including studies aimed at identifying the mediators of the cardiovascular benefit to determine to what extent the results were driven by reduction of metabolically unhealthy body fat, positive impacts on inflammation or blood sugar, direct effects of the medication itself on plaque build-up in the arteries, or a combination of one or more variables.

Study background:

• The international study enrolled over 17,500 people; 72% were male adults across 41 countries beginning in 2018.
• All of the participants were 45 years of age or older with a body mass index (BMI) of 27 kg/m2 or greater, and over 70% had a BMI of 30 or higher, which indicates obesity.
• Everyone enrolled in the study had a history of cardiovascular disease: a prior heart attack, stroke or peripheral artery disease.
• None of the participants had Type 1 or Type 2 diabetes when they joined the study, although about two-thirds of the participants had an A1C level (the percentage of hemoglobin in the red blood cells that has glucose or sugar attached to it) between 5.7% to 6.4%, which meets the criteria for a diagnosis of prediabetes, which is the precursor to Type 2 diabetes.
• The semaglutide dose in SELECT, 2.4 mg/week, is same maximum dose that is FDA-approved for weight loss but different from the approved doses for Type 2 diabetes (usually between 1.0-2.0 mg/week).

There have been increases in obesity rates in most countries since the 1980s, and the 2023 World Obesity Atlas estimates that 51% of the world’s population will have overweight or obesity by 2035 . This is concerning since obesity contributes directly to the risk for developing cardiovascular disease and premature cardiovascular death, as noted in the Association’s 2021 scientific statement on obesity and cardiovascular disease.

Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, a class of medications that simulate the functions of the body’s natural incretin hormones, which help to lower blood sugar levels after a meal. Adjusting these hormone levels also makes people feel full, thereby, lowering their daily calorie intake, and most lose some weight over time. Semaglutide was first approved by the FDA for treatment of Type 2 diabetes and, in 2021, it was approved for chronic weight management in adults with obesity.

Co-authors, disclosures and funding sources are listed in the abstract and manuscript.

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