GLP-1 Medications for Cardiovascular Risk Reduction

FDA Approval for Cardiovascular Risk Reduction

On March 8, 2024, the FDA approved a new indication for Wegovy (semaglutide 2.4 mg) to reduce the risk of major adverse cardiovascular events (MACE) in adults with established cardiovascular disease and either obesity (BMI of 27 or greater) or overweight. MACE is a composite endpoint that includes cardiovascular death, non-fatal heart attack (myocardial infarction), and non-fatal stroke.

This approval made Wegovy the first weight management medication specifically approved for cardiovascular risk reduction. The FDA's decision was based on the results of the SELECT trial, a large cardiovascular outcomes study designed to determine whether semaglutide could reduce heart-related events in people with obesity or overweight who already had established cardiovascular disease but did not have diabetes.

It is important to distinguish this indication from the cardiovascular data associated with other GLP-1 receptor agonists. Several GLP-1 medications, including Ozempic (semaglutide 1 mg), Trulicity (dulaglutide), and Victoza (liraglutide), have demonstrated cardiovascular benefit in clinical trials. However, those trials, such as SUSTAIN-6, REWIND, and LEADER, enrolled patients with type 2 diabetes. The SELECT trial was specifically designed for patients without diabetes, establishing cardiovascular benefit in an obesity-specific population for the first time.

The SELECT Trial

The SELECT trial (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity; ClinicalTrials.gov identifier NCT03574597) was a randomized, double-blind, placebo-controlled, event-driven trial conducted at over 800 sites across 41 countries. It enrolled 17,604 adults aged 45 years or older who met all of the following criteria: established cardiovascular disease (prior heart attack, stroke, or symptomatic peripheral artery disease), a BMI of 27 or greater, and no history of type 2 diabetes or type 1 diabetes.

Participants were randomized to receive either semaglutide 2.4 mg or placebo, administered as a once-weekly subcutaneous injection, in addition to standard cardiovascular care. The primary endpoint was time to first occurrence of a three-component MACE outcome: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The mean follow-up duration was approximately 40 months (roughly 3.3 years).

The trial results, published in the New England Journal of Medicine in November 2023, demonstrated that semaglutide reduced the risk of the primary MACE endpoint by 20 percent compared to placebo (hazard ratio 0.80; 95% confidence interval 0.72 to 0.90; p < 0.001). This result was statistically significant and met the trial's primary objective.

The reduction in MACE was observed across all three individual components of the composite endpoint, though the trial was powered for the composite rather than individual components. Participants receiving semaglutide also experienced a mean body weight reduction of approximately 9.4 percent compared to placebo over the study period.

The most common adverse events in the semaglutide group were gastrointestinal in nature, including nausea, diarrhea, and vomiting, consistent with the known side effect profile of GLP-1 receptor agonists. The rate of treatment discontinuation due to adverse events was higher in the semaglutide group compared to placebo.

Who May Qualify for Wegovy for Cardiovascular Risk Reduction

Based on the FDA-approved indication, Wegovy for cardiovascular risk reduction is indicated for adults who have established cardiovascular disease (such as a prior heart attack, stroke, or peripheral artery disease) and a BMI of 27 or greater. Notably, this indication does not require a diagnosis of type 2 diabetes, making it the first GLP-1 therapy approved for cardiovascular benefit in a non-diabetic population.

Patients should have a confirmed history of cardiovascular disease established by their healthcare provider. Wegovy is administered as a once-weekly injection at a target dose of 2.4 mg, with a gradual dose escalation schedule over approximately 16 to 20 weeks to reduce gastrointestinal side effects.

As with all GLP-1 receptor agonists, Wegovy carries a boxed warning regarding the risk of thyroid C-cell tumors based on findings in rodent studies. It is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or Multiple Endocrine Neoplasia syndrome type 2. Other warnings include risks of pancreatitis, gallbladder disease, acute kidney injury, diabetic retinopathy complications (in patients with diabetes), increased heart rate, and suicidal behavior or ideation. Patients should consult a healthcare provider to discuss whether Wegovy is appropriate given their individual medical history and risk factors.

Wegovy vs Other GLP-1 Medications for Heart Risk

Several GLP-1 receptor agonists have demonstrated cardiovascular benefits in clinical trials, but there are important distinctions among them regarding their approved indications and study populations.

Ozempic (semaglutide 1 mg) contains the same active ingredient as Wegovy but at a lower dose and is approved for type 2 diabetes with a labeled cardiovascular benefit based on the SUSTAIN-6 trial. That trial enrolled patients with type 2 diabetes and established or at high risk for cardiovascular disease. Ozempic is not approved for cardiovascular risk reduction in patients without diabetes.

Trulicity (dulaglutide) demonstrated a reduction in MACE in the REWIND trial, which also enrolled patients with type 2 diabetes. Its cardiovascular benefit is labeled within its diabetes indication.

Victoza (liraglutide) showed a reduction in MACE in the LEADER trial in patients with type 2 diabetes and high cardiovascular risk. Like Ozempic and Trulicity, its cardiovascular labeling is tied to the diabetic population.

Zepbound (tirzepatide) and Mounjaro (tirzepatide) do not currently have FDA-approved indications for cardiovascular risk reduction. Eli Lilly has been conducting the SURPASS-CVOT trial (NCT04255433) to evaluate tirzepatide's cardiovascular outcomes in patients with type 2 diabetes, but results have not yet led to a cardiovascular indication as of this writing. Tirzepatide does not carry cardiovascular outcome labeling at this time.

The key distinction with Wegovy's SELECT-based indication is that it applies to patients with obesity or overweight and established cardiovascular disease regardless of diabetes status. This represents a different and broader population than the diabetes-focused CV trials of other GLP-1 medications.

Important Limitations

The SELECT trial demonstrated a relative risk reduction in MACE of 20 percent over a mean follow-up of approximately 3.3 years. While statistically significant and clinically meaningful, this should be understood as a relative reduction, not an absolute elimination of cardiovascular risk. Patients taking Wegovy for cardiovascular benefit should continue all other evidence-based cardiovascular therapies recommended by their healthcare provider, including statins, blood pressure medications, antiplatelet agents, and lifestyle modifications.

The mechanism by which semaglutide reduces cardiovascular risk is not fully established. While weight loss is likely a contributing factor, researchers have suggested that anti-inflammatory effects, improvements in metabolic parameters, and direct vascular effects may also play a role. Further research is needed to clarify which mechanisms are most important.

The SELECT trial excluded patients with type 1 diabetes and those with type 2 diabetes. For patients with type 2 diabetes and cardiovascular disease, other GLP-1 medications with diabetes-specific cardiovascular indications (such as Ozempic, Trulicity, or Victoza) may be more appropriate, as they address both glycemic control and cardiovascular risk.

Long-term cardiovascular outcomes beyond the approximately 3.3-year follow-up period of SELECT have not been established. It is not yet known whether the cardiovascular benefit persists, increases, or diminishes with longer-term use.

This content is for informational purposes only and does not constitute medical advice. Individuals should consult a qualified healthcare provider to discuss whether Wegovy or any other treatment is appropriate for their specific medical situation.