People with heart disease who take Wegovy may be getting cardiovascular protection that weight loss alone does not account for. A new analysis of the SELECT trial, published in the European Heart Journal on Sept. 23, found that changes in weight, waist size, blood sugar, blood pressure, cholesterol, inflammation, and kidney function could not fully explain why semaglutide lowered the risk of heart attacks, strokes, and cardiovascular deaths.
For patients and caregivers, the finding changes nothing about who should take the drug or how. The heart benefit itself is well established; what remains unsettled is why it happens.
Inside the SELECT Mediation Analysis
The SELECT trial enrolled 17,604 adults aged 45 and older who had established cardiovascular disease, a body mass index of 27 or higher, and no diabetes. Participants received weekly semaglutide injections at a target dose of 2.4 milligrams or a placebo. Major cardiovascular events occurred in 6.5% of the semaglutide group and 8.0% of the placebo group, a 20% relative reduction first reported in The New England Journal of Medicine in 2023.
The new paper, led by Prof. Helen Colhoun of the University of Edinburgh, tested how much of that benefit could be traced to changes in 12 known risk factors. Taken one at a time, waist circumference accounted for an estimated 64% of the effect, the inflammation marker high-sensitivity C-reactive protein (hsCRP) for about 42%, and body weight for roughly 20%. When all measured factors were modeled together, they explained an estimated 31%, or about 46% when weight and waist size were left out. In plain terms, no more than about half of the benefit could be linked to the measured risk factors.
These percentages are rough. Every estimate carried very wide confidence intervals, and several ranged from below zero to above 100%, so none should be read as precise. The authors also noted that supplementary analyses suggested the estimates for body weight and waist circumference were unreliable.
"Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty," Colhoun said in a European Society of Cardiology statement. In a University of Edinburgh release, she said semaglutide "should be considered as a cardiovascular disease reduction drug and not just as a weight loss drug."
Limits of the Evidence and Who Paid for It
This is a pre-specified mediation analysis of a randomized, double-blind, placebo-controlled trial. It estimates how much of a proven benefit flows through measured risk factors, but it cannot prove which mechanism is responsible. The results apply to adults with existing heart disease and overweight or obesity who do not have diabetes.
The researchers noted several weaknesses. Their findings rely on estimates of risk, and the COVID-19 pandemic affected data collection during the trial. Some participants may also have lost weight for other reasons, such as frailty, which can raise rather than lower heart risk. Mediation analyses also depend on strong assumptions, including that no important unmeasured factors are skewing the results. Researchers have raised anti-inflammatory effects not captured by the trial's measurements, as well as direct effects on heart muscle or blood vessel linings, as possible explanations, but those remain hypotheses.
The study was funded by Novo Nordisk, which makes Wegovy, and several authors are affiliated with the company. Colhoun has disclosed serving on advisory panels for Novo Nordisk, Roche, and Bayer. Prof. Subodh Verma of the University of Toronto, who wrote an accompanying editorial, agreed that known risk factor changes "could not, with any confidence, explain all of the GLP-1RA effects on major adverse cardiovascular events."
Guidance for Heart Patients and Caregivers
The FDA approved Wegovy's heart indication in March 2024 to reduce the risk of cardiovascular death, heart attack, and stroke in adults with cardiovascular disease and either obesity or overweight. The new analysis does not change that label or who qualifies. It also says nothing about people who do not already have heart disease.
The people most affected are adults with a prior heart attack, stroke, or other diagnosed cardiovascular disease who also carry excess weight. Anyone already taking Wegovy should not stop, change the dose, or restart after a break without speaking with the prescriber.
For those not taking the drug, the finding is not a reason to seek it out for heart protection alone. The FDA says Wegovy should be used alongside a reduced-calorie diet and more physical activity, and nothing in the new paper suggests it can replace statins, blood pressure drugs, or other prescribed heart treatments. Patients can ask a cardiologist whether they meet the heart-risk indication and how it fits with their current plan.
Cost is a practical barrier for many families. Because the heart indication is FDA-approved, some insurers, including Medicare drug plans, may cover Wegovy for that use even when they exclude weight-loss drugs. Patients facing a denial can ask their clinician about prior authorization or an appeal.
Chest pain, sudden shortness of breath, facial drooping, arm weakness, or trouble speaking require a 911 call right away. Persistent vomiting or severe abdominal pain while taking a GLP-1 drug also warrants prompt medical attention.
Open Questions for Researchers
The central question is what drives the rest of the benefit. The authors said further study of additional biomarkers and possible pathways is needed. Until that work is done, the mechanism remains a hypothesis rather than a finding.
The heart benefit itself was shown in a large randomized trial, and this paper explains only part of it. Treatment decisions should stay grounded in that evidence and a conversation with a clinician.
Key Questions Answered
What did the new SELECT analysis find? Changes in 12 known risk factors, including weight, waist size, inflammation, and blood pressure, together explained an estimated 31% of Wegovy's heart benefit, or about 46% when weight and waist size were left out, with wide uncertainty.
Does this mean weight loss does not matter? No. Waist circumference had the largest single estimate, though the authors flagged the weight and waist estimates as unreliable. The finding suggests other, unmeasured effects may also play a role.
Should I start Wegovy to protect my heart? The FDA heart indication applies to adults with cardiovascular disease and obesity or overweight. Anyone considering it should talk with a clinician first.
Should I stop Wegovy if I have side effects? Do not stop or change the dose on your own. Discuss side effects with your prescriber, and seek urgent care for severe symptoms.
Who funded the study? Novo Nordisk, the maker of Wegovy, funded the research, and the lead author has disclosed advisory roles with the company and other drugmakers.
Published by Medicaldaily.com
