GLP-1 Medications & Heart Disease

Published in the New England Journal of Medicine in 2023, the SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial was a watershed moment in cardiovascular medicine. The trial enrolled 17,604 adults aged 45 or older who had pre-existing cardiovascular disease and a BMI of 27 or higher — but crucially, none of them had type 2 diabetes.

Participants were randomized to weekly subcutaneous semaglutide 2.4mg (Wegovy) or placebo and followed for a median of 39.8 months. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction (heart attack), or non-fatal stroke — known as MACE (Major Adverse Cardiovascular Events).

The result was striking: semaglutide reduced the primary MACE endpoint by 20% (HR 0.80, 95% CI 0.72–0.90, p<0.001). This was achieved on top of optimal cardiovascular medical therapy and was consistent across all pre-specified subgroups. Importantly, the benefit appeared to go beyond what weight loss alone would predict, suggesting direct cardioprotective mechanisms.

The SELECT trial was the first large-scale trial to demonstrate a cardiovascular benefit of a weight-loss drug in people without diabetes. It led to Wegovy receiving FDA approval for cardiovascular risk reduction in March 2024 — a new indication entirely separate from its weight loss approval.

Before SELECT, Ozempic (semaglutide 0.5mg and 1mg) earned its cardiovascular indication through SUSTAIN-6, a trial of 3,297 adults with type 2 diabetes and established cardiovascular disease. Over 2 years, semaglutide reduced the MACE composite by 26% compared to placebo (HR 0.74). Most of the benefit came from non-fatal stroke reduction (39% lower risk).

This result earned Ozempic an FDA label update: it is now officially indicated to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease. This is a distinct cardiovascular benefit from its glucose-lowering role.

Together, SUSTAIN-6 and SELECT establish semaglutide as the only GLP-1 receptor agonist with proven cardiovascular benefit in both diabetic and non-diabetic populations — a uniquely broad cardiovascular profile among all GLP-1 class medications.

Heart failure is a complex syndrome and GLP-1 medications have produced mixed results depending on the type of heart failure. There are two main types: HFpEF (heart failure with preserved ejection fraction) and HFrEF (heart failure with reduced ejection fraction). GLP-1s have primarily been studied in HFpEF, which disproportionately affects people with obesity.

The STEP-HFpEF trial (2023) enrolled 529 patients with HFpEF and obesity (BMI ≥30) and randomized them to semaglutide 2.4mg or placebo for 52 weeks. Semaglutide produced meaningful improvements in the Kansas City Cardiomyopathy Questionnaire (KCCQ) score — a patient-reported measure of heart failure symptoms and quality of life — along with significant improvements in 6-minute walk distance. These are important patient-centered outcomes.

However, STEP-HFpEF was not powered to show reductions in hard outcomes like hospitalization or mortality. Subsequent analyses from the FLOW-HF program and ongoing meta-analyses raised questions about whether GLP-1s reduce hospitalization rates in heart failure specifically, versus their broader cardiovascular protection.

The current consensus from the European Society of Cardiology and American Heart Association is that GLP-1 receptor agonists are reasonable to use in patients with HFpEF and obesity to improve symptoms and functional capacity. They are generally avoided in advanced HFrEF (though evidence is limited). Always discuss with your cardiologist before starting or continuing GLP-1 therapy if you have diagnosed heart failure.

Tirzepatide, the dual GIP/GLP-1 receptor agonist marketed as Mounjaro (for diabetes) and Zepbound (for weight loss), produces even greater weight loss than semaglutide — up to 20-22% in SURMOUNT-1. Its cardiovascular outcomes data is still maturing.

The SURMOUNT-MMO (Mortality and Morbidity Outcomes) trial is the pivotal cardiovascular outcomes trial for tirzepatide, designed to determine whether its superior weight loss translates into superior cardiovascular event reduction. Results from SURMOUNT-MMO are expected in 2026-2027. Early data from SURPASS-CVOT (in T2D patients) showed tirzepatide was non-inferior to semaglutide on cardiovascular safety, but did not demonstrate superiority.

Separately, the SUMMIT trial showed tirzepatide significantly improved outcomes in HFpEF patients with obesity — 38% reduction in the composite of cardiovascular death or worsening heart failure. This was a stronger result than semaglutide in a comparable population, suggesting tirzepatide may become the preferred GLP-1 class drug for heart failure with obesity.

Shotlee is a free iOS and web app built for GLP-1 medication users. Log every injection, track weekly weight, blood pressure, and exercise tolerance, and see your progress unfold with clear charts and AI-powered insights. Whether you are on Ozempic for diabetes, Wegovy for cardiovascular risk reduction, or Mounjaro for weight management, Shotlee gives you the data your doctor needs.

• ✅ Log every GLP-1 injection with dose, site, and date
• ✅ Weekly weight and blood pressure tracking with trend charts
• ✅ Side effect logging (nausea, fatigue, heart palpitations)
• ✅ AI insights to identify cardiovascular health patterns
• ✅ Export your data as PDF for your cardiologist
• ✅ 100% free — no credit card required