Wegovy for Cardiovascular Prevention: Evidence Summary

What the FDA label actually covers

Wegovy injection was first approved on June 4, 2021 [4]. The cardiovascular indication arrived through a supplement dated March 8, 2024 [4]. The current label reads: to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with established cardiovascular disease and either obesity or overweight [1]. Wegovy tablets carry the same cardiovascular indication, in adults [1]. The labeled dose for cardiovascular risk reduction is 2.4 mg weekly, or 1.7 mg weekly, for the injection [1].

The indication wording says obesity or overweight and names no BMI cutoff. SELECT, the trial behind the indication, enrolled adults aged 45 and older with a BMI of 27 or higher and preexisting cardiovascular disease [2]. The indication wording does not limit it to people without diabetes [1].

Ozempic also contains semaglutide, but its cardiovascular indication is for adults with type 2 diabetes and established cardiovascular disease [5].

SELECT: the trial behind the indication

SELECT randomized 17,604 adults with established cardiovascular disease, a BMI of 27 or higher and no diabetes to semaglutide 2.4 mg weekly or placebo, 1:1 [2].

The primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% on semaglutide versus 8.0% on placebo (HR 0.80, 95% CI 0.72 to 0.90) over a mean follow-up of 39.8 months [2].

The label breaks out the components. Cardiovascular death was 2.5% versus 3.0% (HR 0.85, 95% CI 0.71 to 1.01), and superiority for that component alone was not confirmed in the prespecified testing hierarchy [1]. Fatal or non-fatal myocardial infarction was 2.8% versus 3.8% (HR 0.72) [1]. Stroke had a hazard ratio of 0.89 (95% CI 0.72 to 1.11), a confidence interval that includes 1 [1]. All-cause death was 4.3% versus 5.2% (HR 0.81) [1].

Treatment was stopped for adverse events in 16.6% on semaglutide versus 8.2% on placebo [1]. Mean weight change at week 104 was -9.4% versus -0.9% [1].

Is primary prevention off-label?

The labeled cardiovascular indication requires established cardiovascular disease [1], so using Wegovy to prevent a first event falls outside the labeled population.

Other semaglutide cardiovascular trials were done in people with type 2 diabetes. PIONEER 6 randomized 3,183 adults with type 2 diabetes at high cardiovascular risk to oral semaglutide up to 14 mg or placebo; 84.7% were aged 50 or older with established cardiovascular or kidney disease, and the others were 60 or older with risk factors only [3]. Major adverse cardiovascular events occurred in 3.8% versus 4.8% (HR 0.79, 95% CI 0.57 to 1.11) over a median 15.9 months, and the trial was designed to rule out excess cardiovascular risk rather than to prove a reduction [3].

SUSTAIN-6 randomized 3,297 adults with type 2 diabetes, 83% of whom had established cardiovascular disease, chronic kidney disease, or both, to semaglutide 0.5 or 1 mg or placebo for 104 weeks: 6.6% versus 8.9% (HR 0.74, 95% CI 0.58 to 0.95) [6]. Those are Ozempic doses, not the Wegovy dose.

How semaglutide might reduce cardiovascular risk

Semaglutide is a GLP-1 receptor agonist that binds and activates the GLP-1 receptor, including receptors in brain regions that regulate appetite and calorie intake, and it delays gastric emptying [1]. In SELECT, mean weight fell 9.4% on semaglutide versus 0.9% on placebo by week 104 [1]. The label says the exact mechanism of cardiovascular risk reduction is not established [1].

What the label says to watch for

The Wegovy label lists a mean heart rate increase of 1 to 4 beats per minute, with a rise of 20 beats per minute or more in 26% versus 16% on placebo, and advises monitoring heart rate at regular intervals [1].

Gastrointestinal reactions are the most common: any GI reaction in 73% versus 47%, and severe GI reactions in 4.1% versus 0.9% in the adult weight-management trials [1]. Acute pancreatitis has been observed with GLP-1 receptor agonists including semaglutide, and the label says to discontinue if pancreatitis is suspected [1].

Gallbladder disease appeared as cholelithiasis in 1.6% versus 0.7% and cholecystitis in 0.6% versus 0.2% of adults in the injection trials [1]. Hypoglycemia risk rises when semaglutide is used with insulin or an insulin secretagogue such as a sulfonylurea [1]. Acute kidney injury from volume depletion occurred in 0.4 versus 0.2 cases per 100 patient-years [1]. In a two-year trial of semaglutide 0.5 or 1 mg in type 2 diabetes with high cardiovascular risk, retinopathy complications occurred in 3% versus 1.8% [1]. Pulmonary aspiration during general anesthesia or deep sedation has been reported, and the label says to instruct patients to tell their healthcare providers about planned procedures [1]. Because gastric emptying is delayed, the label advises increased clinical or laboratory monitoring for oral drugs with a narrow therapeutic index [1]. The boxed warning covers thyroid C-cell tumors in rodents, with unknown human relevance, and a contraindication for a personal or family history of medullary thyroid carcinoma or MEN 2 [1].

Dosing for the cardiovascular indication

The label gives the injection schedule as 0.25 mg weekly for 4 weeks, then 0.5 mg for weeks 5 to 8, 1 mg for weeks 9 to 12, 1.7 mg for weeks 13 to 16, with maintenance from week 17 [1]. For cardiovascular risk reduction the label specifies 2.4 mg weekly (recommended), or 1.7 mg weekly [1]. For the tablets, the label gives a recommended maintenance dose of 25 mg once daily for cardiovascular risk reduction in adults [1]. SELECT tested the 2.4 mg injection [2].