Ozempic and Heart Health: What the Cardiovascular Data Actually Shows

When Ozempic was first approved in 2017, its primary selling point was glycemic control. But the cardiovascular story has turned out to be at least as important, and in some ways more consequential for how semaglutide is prescribed today. Two major trials, SUSTAIN 6 and SELECT, have fundamentally changed how cardiologists and endocrinologists think about GLP-1 medications.

SUSTAIN 6: the first signal

The FDA requires that all new diabetes medications demonstrate cardiovascular safety before approval. SUSTAIN 6 was designed primarily as a safety trial, meaning its goal was to show that semaglutide did not increase cardiovascular risk compared to placebo. It enrolled 3,297 patients with type 2 diabetes who were at high cardiovascular risk, meaning they had a prior heart attack, stroke, peripheral vascular disease, or chronic kidney disease.

Over a median follow-up of 2.1 years, semaglutide did more than demonstrate safety. It reduced the primary composite endpoint of major adverse cardiovascular events (MACE), which includes cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke, by 26% compared to placebo. The hazard ratio was 0.74 with a 95% confidence interval of 0.58 to 0.95.

The result was statistically significant and clinically meaningful. But because the trial was designed as a noninferiority study with a relatively modest sample size, there were questions about whether the benefit was primarily driven by stroke reduction (which it was, at 39% reduction) or whether the other components of MACE would show benefit in a larger trial.

Published in the New England Journal of Medicine in November 2016 by Marso and colleagues, SUSTAIN 6 positioned semaglutide alongside liraglutide (which showed a similar cardiovascular benefit in the LEADER trial) as a GLP-1 agonist with cardioprotective properties. This finding led the FDA to add cardiovascular risk reduction as a second approved indication for Ozempic.

SELECT: the landmark trial

SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) was a different kind of trial. Published in the New England Journal of Medicine in November 2023 by Lincoff and colleagues, it asked a question that SUSTAIN 6 could not answer: does semaglutide reduce cardiovascular events in people who have overweight or obesity and established cardiovascular disease but do not have diabetes?

This was a critical distinction. SUSTAIN 6 studied diabetic patients. SELECT studied 17,604 adults aged 45 and older with a BMI of 27 or higher, a history of atherosclerotic cardiovascular disease (prior heart attack, stroke, or symptomatic peripheral artery disease), and no diabetes diagnosis. Participants received either semaglutide 2.4 mg weekly (the Wegovy dose) or placebo, in addition to standard cardiovascular care.

Over a median follow-up of 39.8 months, semaglutide reduced the primary MACE endpoint by 20% compared to placebo. The hazard ratio was 0.80 with a 95% confidence interval of 0.72 to 0.90, and the p-value was less than 0.001. This was a definitive result in a well-powered trial.

Breaking down the components:

• Cardiovascular death was reduced by 15% (not individually statistically significant).
• Nonfatal myocardial infarction was reduced by 28%.
• Nonfatal stroke was reduced by 7% (not individually statistically significant).

The heart attack reduction was the primary driver, which was notable because heart attacks had not been the dominant component in SUSTAIN 6.

Why does semaglutide help the heart?

The mechanisms are likely multiple, and researchers are still working to determine which are most important. Several pathways have been proposed based on clinical and preclinical data:

Weight loss and metabolic improvement. Participants in SELECT lost an average of 9.4% of their body weight on semaglutide versus 0.9% on placebo. Weight loss reduces blood pressure, improves lipid profiles, decreases insulin resistance, and reduces systemic inflammation, all of which are independent cardiovascular risk factors. However, mediation analyses from SELECT suggest that weight loss alone does not fully explain the cardiovascular benefit, accounting for perhaps 40 to 50% of the effect.

Anti-inflammatory effects. Semaglutide has been shown to reduce C-reactive protein (CRP), a marker of systemic inflammation, by approximately 40% in clinical trials. Chronic low-grade inflammation is a key driver of atherosclerotic plaque formation and instability. Reducing inflammation may help stabilize existing plaques, making them less likely to rupture and cause a heart attack or stroke.

Direct vascular effects. GLP-1 receptors are present on endothelial cells and vascular smooth muscle. Preclinical studies have shown that GLP-1 receptor agonists can improve endothelial function, reduce oxidative stress in arterial walls, and inhibit smooth muscle cell proliferation. Whether these effects are clinically significant in humans is still being investigated.

Blood pressure reduction. Semaglutide consistently reduces systolic blood pressure by 3 to 5 mmHg in clinical trials. While modest, this degree of blood pressure reduction, if sustained over years, is associated with meaningful reductions in stroke and heart failure risk at the population level.

What this means for clinical practice

The SELECT results have had a tangible impact on prescribing patterns. For patients with obesity and established cardiovascular disease, semaglutide is no longer just a weight loss drug; it is a cardiovascular risk reduction strategy with level 1 evidence. The American Heart Association and the European Society of Cardiology have both updated their guidelines to reflect this.

There are practical implications for patients. First, insurance coverage has expanded for Wegovy in patients with cardiovascular indications, though access remains uneven. Second, cardiologists are increasingly initiating GLP-1 therapy independently, rather than deferring to endocrinologists. Third, the trial results have strengthened the argument for treating obesity as a cardiovascular risk factor on par with hypertension and hyperlipidemia.

It is worth noting what SELECT did not show. The trial excluded patients with diabetes, so the cardiovascular benefit in this trial cannot be attributed to glucose lowering. SELECT also did not compare semaglutide to other weight loss interventions such as bariatric surgery. And the trial population was predominantly White and male, which limits generalizability to other demographic groups.

The bigger picture

Before semaglutide, the evidence that intentional weight loss reduces cardiovascular events was surprisingly thin. Observational studies suggested a benefit, but the Look AHEAD trial, which tested intensive lifestyle intervention in people with type 2 diabetes, was stopped early in 2012 for futility. It did not show a reduction in cardiovascular events despite meaningful weight loss in the intervention group.

SELECT is the first randomized trial to demonstrate that a weight-related intervention can reduce hard cardiovascular endpoints in a large, high-risk population. Whether that benefit is primarily from weight loss, the drug's anti-inflammatory effects, direct vascular actions, or some combination remains an open question. But the clinical result stands regardless of the mechanism.

For patients with heart disease and excess weight, semaglutide now has the kind of cardiovascular evidence that statins had in the 1990s: large, randomized, placebo-controlled, and convincing. It does not replace statins, blood pressure medications, or lifestyle changes. But it adds a tool that addresses a risk factor, obesity, that the field has historically been unable to treat effectively with medications.