What the SELECT Trial Really Tells Us About Semaglutide, Heart Health, and Obesity—Without Diabetes
For years, obesity has been recognized as a major risk factor for cardiovascular disease, yet medical treatment has largely focused on managing downstream conditions like high blood pressure, cholesterol, and diabetes rather than addressing obesity itself as a cardiovascular risk modifier. Until recently, we lacked strong evidence that treating obesity, independent of diabetes, could directly reduce heart attacks, strokes, or cardiovascular death.
That changed with the publication of the SELECT trial.
Why the SELECT Trial Matters
The SELECT trial was designed to answer a very specific and long-standing question in medicine:
Can treating obesity reduce cardiovascular events in people who do not have diabetes but already have heart disease?
Previous lifestyle and medication trials targeting weight loss failed to demonstrate meaningful reductions in cardiovascular events. As a result, obesity treatment was often framed as optional or cosmetic rather than cardioprotective. SELECT challenges that narrative with rigorous data.
Study Design at a Glance
Researchers enrolled 17,604 adults aged 45 and older who met all of the following criteria:
Body mass index (BMI) ≥ 27
Established cardiovascular disease (prior heart attack, stroke, or symptomatic peripheral artery disease)
No diagnosis of diabetes
Participants were randomly assigned to receive either:
Semaglutide 2.4 mg once weekly, or
Placebo, in addition to standard cardiovascular care
They were followed for nearly four years, making this one of the longest and largest trials in obesity medicine to date .
The Primary Outcome: Fewer Major Cardiovascular Events
The primary endpoint was a composite of:
Cardiovascular death
Nonfatal heart attack
Nonfatal stroke
Over the follow-up period, semaglutide reduced the risk of these major cardiovascular events by 20% compared with placebo (hazard ratio 0.80, 95% CI 0.72–0.90, P<0.001) .
This is a clinically meaningful reduction, comparable to what we see with statins or blood pressure medications, and importantly, it occurred in people without diabetes.
Weight Loss Was Significant but Not the Whole Story
Participants receiving semaglutide lost an average of 9.4% of body weight over two years, compared with less than 1% in the placebo group. Waist circumference, inflammatory markers (including high-sensitivity CRP), blood pressure, lipid profiles, and glycemic markers all improved.
However, cardiovascular benefits appeared early in treatment, suggesting that mechanisms beyond weight loss alone, such as reduced inflammation, improved endothelial function, and metabolic signaling effects of GLP-1 receptor agonists, likely played a role .
Safety and Tolerability: Important Context
Serious adverse events were actually less common in the semaglutide group overall. That said, medication discontinuation was higher, largely due to gastrointestinal side effects such as nausea, vomiting, and diarrhea.
Gallbladder-related events were slightly more frequent, consistent with prior GLP-1 data, but there were no significant increases in pancreatitis, kidney failure, cancer, or psychiatric events compared with placebo .
This reinforces what clinicians already know: GLP-1 medications are effective, but they require careful dose titration, monitoring, and individualized decision-making.
Who This Study Does and Does Not Apply To
SELECT studied secondary prevention, meaning all participants already had cardiovascular disease. It does not tell us whether semaglutide prevents first-time heart attacks or strokes in people without known heart disease.
The study population was also predominantly male and White, which limits generalizability and underscores the need for more inclusive research moving forward.
What This Means for Midlife Women
For midlife women, especially those navigating perimenopause or menopause, this study adds an important layer to the conversation. Cardiovascular risk rises sharply after menopause, often in the absence of diabetes. SELECT provides evidence that obesity treatment can be part of a comprehensive, cardioprotective strategy when clinically appropriate.
That does not mean semaglutide is right for everyone, nor does it replace foundational pillars like nutrition, movement, sleep, stress management, and metabolic health. What it does mean is that obesity is no longer a “non-modifiable” risk factor in cardiovascular care.
The Bottom Line
The SELECT trial reframes obesity treatment as cardiovascular risk reduction, not cosmetic intervention. In people with established heart disease and overweight or obesity, without diabetes, semaglutide significantly reduced major cardiovascular events when added to standard care.
This is a shift in how medicine may approach obesity, heart health, and prevention moving forward…one that emphasizes evidence, individualized care, and long-term outcomes rather than short-term weight loss alone .
