Semaglutide and heart protection: beyond weight loss

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Semaglutide and heart protection: benefits that go beyond weight loss

By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv

Semaglutide and heart protection: beyond the kilograms

Semaglutide and heart protection are a pairing that now occupies cardiologists and obesity physicians alike. Wegovy, Ozempic and Rybelsus all contain the active ingredient semaglutide. Large trials have shown that it lowers the combined risk of heart attack, stroke and death from cardiovascular disease. What’s more, newer research shows that part of this protection does not depend on weight loss. In this article, we look at the evidence, from controlled trials to real-world data.

Why obesity puts the heart at risk

Obesity harms the heart in several ways. It raises blood pressure, disrupts blood sugar control and changes blood lipids. In addition, fat tissue, and especially visceral (belly) fat, releases inflammatory substances. This chronic inflammation speeds up the buildup of atherosclerosis in the arteries. I have written more about this in my article on how obesity is changing cardiology.

The SELECT trial: semaglutide and the heart in people without diabetes

The SELECT trial is the key milestone. It enrolled 17,604 patients aged 45 and over with established cardiovascular disease, overweight or obesity, and no diabetes. Participants received a weekly injection of semaglutide 2.4 mg or placebo and researchers followed them for an average of about three and a quarter years.

The main result: major cardiovascular events, meaning cardiovascular death, heart attack or stroke, occurred in 6.5% of patients on semaglutide, compared with 8.0% on placebo. That is a 20% reduction in risk. Nonfatal heart attacks also fell by 28%. On the other hand, the reduction in cardiovascular death alone did not reach statistical significance.

Following the trial, the FDA approved Wegovy in March 2024 to reduce the risk of cardiovascular events in adults with cardiovascular disease and obesity or overweight. I have reviewed the trial in detail in my article on the SELECT trial.

Additional benefits in the trial

SELECT also showed secondary benefits. The risk of developing diabetes dropped markedly: only 3.5% of patients on semaglutide reached diabetic blood sugar levels, compared with 12.0% on placebo. In addition, an analysis of mortality showed 19% lower all-cause mortality. It is important to note that this was a secondary outcome that the researchers did not formally test for significance, because the hierarchical statistical testing stopped before reaching it.

Heart protection does not depend on weight alone

This is where it gets fascinating. In a prespecified analysis published in The Lancet, researchers examined whether semaglutide heart protection depends on weight. The answer was surprising: the benefit was similar across all categories of starting weight. What’s more, the amount of weight lost in the first months did not predict the later risk of cardiovascular events.

By the researchers’ estimate, the reduction in waist circumference explained only about a third of the benefit. Similarly, another analysis found a benefit regardless of blood sugar level, even in people with completely normal blood sugar. The conclusion: semaglutide has additional protective mechanisms beyond weight loss and improved blood sugar.

Dampening inflammation

One of the main mechanisms is reduced inflammation. An analysis published in 2026 in the journal Circulation looked at hsCRP, a blood protein that reflects chronic inflammation in the blood vessels. Semaglutide lowered hsCRP by 37.8% compared with placebo after two years. The reduction appeared within the first weeks, before any significant weight loss. It also appeared in patients who did not lose weight, and regardless of statin treatment.

Semaglutide also slightly lowers blood pressure and blood lipids. In SELECT, systolic blood pressure fell by 3.8 mmHg, compared with 0.5 on placebo. Researchers suspect there are also direct effects on the blood vessels, but the evidence for this is still incomplete.

Heart failure: a new role for treatment

Heart failure with preserved ejection fraction (HFpEF) is very common in people with obesity. In the STEP-HFpEF trial, 529 patients received semaglutide 2.4 mg or placebo for one year. Their symptom and physical-function score improved by 16.6 points, compared with 8.7 on placebo. In addition, their six-minute walk distance increased by 21.5 meters, compared with just 1.2 meters. A parallel trial in patients with heart failure and diabetes showed a similar improvement in symptoms and function.

A pooled analysis of four trials, including 3,743 patients with heart failure with preserved or mildly reduced ejection fraction, found a 41% reduction in worsening heart failure events. On the other hand, the effect on cardiovascular death alone was not significant. This is also a post hoc analysis, so we should interpret it with caution.

Within SELECT itself, about a quarter of participants, 4,286 people, already had heart failure at the start of the trial. A dedicated analysis of this group found a 28% reduction in major cardiovascular events. The benefit appeared in heart failure with both reduced and preserved ejection fraction.

Semaglutide and the heart in diabetes and kidney disease

Semaglutide heart protection also extends to patients with type 2 diabetes. In the SUSTAIN-6 trial, injectable semaglutide reduced the risk of major cardiovascular events by 26%. However, researchers designed that trial mainly to demonstrate safety, not superiority. In the SOUL trial, which tested the Rybelsus pill, risk fell by 14%. Following that trial, the FDA approved Rybelsus in October 2025 to reduce cardiovascular risk as well.

In addition, in the FLOW trial, which studied patients with diabetes and kidney disease, semaglutide reduced major kidney events by 24%. Cardiovascular death also fell by 29%. Today, doctors call the link between the heart, the kidneys and metabolism cardiovascular-kidney-metabolic (CKM) syndrome.

What real-world data show

Real-world evidence, meaning data from routine care outside clinical trials, tests whether trial results hold up in everyday practice. The SCORE study compared 9,321 patients with cardiovascular disease who started Wegovy with 18,642 similar untreated patients. After about six months, the risk of major cardiovascular events and death from any cause was 57% lower. A large follow-up study, with more than 38,000 patients, found a 45% lower risk. When the analysis counts only cardiovascular death instead of death from any cause, the reduction is smaller: 42% and 34%, respectively.

It is important to understand the limitations. These are short observational studies funded by the manufacturer, and the effects they report are much larger than in the controlled trial. So they support the SELECT findings, but they do not replace them.

Who this applies to

The 2024 European guidelines for chronic coronary syndromes recommend considering semaglutide in patients with coronary artery disease and overweight or obesity who do not have diabetes. In addition, in December 2025 the FDA approved the Wegovy pill, including for reducing cardiovascular risk. In practice, you make the decision about treatment together with your doctor, based on your personal risk, other conditions and preferences. You will find more information in my complete guide to Wegovy and heart disease.

Questions and answers on semaglutide and the heart

Does the treatment protect the heart in people who don’t have heart disease?

SELECT included only people with established cardiovascular disease. A real-world study of more than 48,000 patients aged 45 and over without heart disease but with multiple risk factors found a 41% lower risk of major cardiovascular events and death from any cause. Counting only cardiovascular death, the reduction was 27%. However, this is an observational study, and no controlled trial has yet proven this in primary prevention.

Can I stop taking statins or blood pressure medication?

No. Semaglutide adds protection; it does not replace existing treatments. In SELECT, participants were already receiving standard preventive treatment for their heart disease, and researchers measured the benefit on top of that. In addition, the effect on the inflammation marker appeared regardless of statin treatment.

When does the protection begin?

The drop in the inflammation marker appeared within the first weeks of treatment. However, no study has yet shown that protection against cardiovascular events begins at that point. Researchers measure the effect on cardiovascular events over years, so staying on treatment is especially important.

Does Ozempic protect the heart to the same extent?

Ozempic contains the same active ingredient and treats type 2 diabetes. In SUSTAIN-6 it reduced major cardiovascular events, and in FLOW it also reduced cardiovascular death. So studies have shown semaglutide heart protection both in diabetes and in obesity without diabetes. The choice between products depends on the diagnosis and the goals of treatment.

The bottom line on semaglutide and heart protection

The link between semaglutide and heart protection now rests on several large controlled trials. The drug reduces major cardiovascular events, improves symptoms in heart failure and protects the kidneys. What’s more, semaglutide heart protection does not depend on weight loss alone. Inflammation markers fall within the first weeks, and this may contribute in part to the protection. That means treating obesity today is also preventive treatment for heart disease. Alongside it, a healthy diet, physical activity and quitting smoking remain the foundation.

The information in this article is general and does not replace personal medical advice.