GLP-1 Drugs and Heart Health: What the SELECT and SUSTAIN-6 Trials Show

The cardiovascular story for GLP-1 drugs has evolved substantially since semaglutide was first approved. What started as glucose-lowering therapy has accumulated two separate cardiovascular outcomes trial approvals — one for T2D patients with CVD, and one for obese patients with CVD who do not have diabetes.

This article awaits medical-reviewer signoff.

Background: cardiovascular outcomes trials (CVOTs)

When the FDA required CVOTs for new diabetes drugs in 2008, the initial goal was to demonstrate cardiovascular safety. GLP-1 drugs went further: they showed cardiovascular benefit — actively reducing cardiac events rather than merely not increasing them.

The two key trials for semaglutide:

SUSTAIN-6: Ozempic's CV indication (T2D patients)

Published: NEJM, 2016
Population: 3,297 T2D patients with established cardiovascular disease or high CV risk
Drug: Semaglutide 0.5 mg or 1 mg weekly (Ozempic doses)
Duration: 104 weeks

Primary endpoint: MACE — composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke

Result: Semaglutide reduced MACE by 26% versus placebo (HR 0.74, 95% CI 0.58–0.95).

FDA consequence: January 2020 — an additional indication added to Ozempic's label: "to reduce the risk of major adverse cardiovascular events (MACE) in adults with type 2 diabetes mellitus and established cardiovascular disease."

This made Ozempic one of the first T2D drugs with an FDA-approved cardiovascular benefit indication.

SELECT: Wegovy's CV indication (obesity, no T2D required)

Published: NEJM, 2023
Population: 17,604 adults with established CVD and BMI ≥27, without T2D
Drug: Semaglutide 2.4 mg weekly (Wegovy dose)
Duration: approximately 3.5 years

Primary endpoint: MACE — cardiovascular death, nonfatal MI, nonfatal stroke

Result: Semaglutide 2.4 mg reduced MACE by 20% versus placebo (HR 0.80, 95% CI 0.72–0.90). This was achieved without a T2D requirement — purely an obesity-with-CVD population.

FDA consequence: March 2024 — an additional indication added to Wegovy's label: "to reduce the risk of serious cardiovascular events such as death, heart attack, or stroke in adults with established cardiovascular disease and either obesity (BMI ≥30) or overweight (BMI ≥27)."

Wegovy became the first obesity drug with an FDA-approved cardiovascular benefit indication.

Why SELECT is significant

The SELECT trial's enrollment criterion — cardiovascular disease plus obesity, without T2D — targets a large patient population that had previously not had pharmacological CV risk reduction options specifically for the obesity component of their risk.

The traditional approach: risk factor management (statins for cholesterol, RAAS blockers for blood pressure, antiplatelet agents). These address lipid and pressure-mediated risk. SELECT showed that addressing the metabolic-inflammatory risk component of obesity with a GLP-1 provides additional benefit on top of existing standard-of-care treatment.

Most SELECT participants were on statins and antiplatelet therapy. The 20% MACE reduction was incremental to these existing treatments.

The mechanism questions

Is the CV benefit from weight loss alone? Partially. Significant weight loss independently reduces cardiovascular risk through blood pressure, glycaemic, and inflammatory pathway improvements. But the weight loss explanation does not fully account for the early separation of Kaplan-Meier curves (which begin diverging before major weight loss has occurred) or the cardiovascular outcomes trial data in T2D patients where weight loss magnitude was more modest.

Direct GLP-1 receptor effects in the heart: GLP-1 receptors are expressed in cardiomyocytes and vascular endothelium. Direct GLP-1 agonism appears to reduce cardiac fibrosis, improve endothelial function, and modulate inflammatory signalling in ways independent of weight loss. The relative contributions of weight-loss-mediated vs. direct receptor-mediated effects are an active research area.

Tirzepatide: the next chapter

Tirzepatide's cardiovascular outcomes data is accumulating. SURPASS-CVOT (T2D patients with established CVD) was ongoing as of 2026. Preliminary data suggests cardiovascular benefit consistent with the class effect. Tirzepatide does not yet have an approved cardiovascular indication comparable to Ozempic or Wegovy.

Clinical implications

For patients with established CVD (prior heart attack, stroke, peripheral artery disease) and obesity:

Wegovy now has an FDA indication for this exact situation. The SELECT data supports its use in this population, and the updated label reflects it. This may open insurance pathways for patients with CVD and obesity who had difficulty getting GLP-1 coverage via the obesity indication alone.

For patients with T2D and established CVD: Ozempic (semaglutide) has the T2D + CV indication. Mounjaro (tirzepatide) has T2D indication but not yet a CV indication.

These decisions involve coordination with the cardiologist or cardiovascular risk manager, as drug interactions, recent cardiac events, and other medications affect the suitability of any specific drug.

Editorial note: This article awaits medical-reviewer signoff. Cardiovascular management is a specialised clinical domain. Decisions about GLP-1 therapy in patients with established CVD should involve the prescribing cardiologist or primary care provider managing cardiovascular risk.