Oral Semaglutide Improves Heart Function and Blood Flow in Pigs with Coronary Artery Disease

Semaglutide improved left ventricular ejection fraction at rest and during rapid pacing (both p<0.03), increased perfusion to the most ischemic myocardium at rest and during pacing (both p<0.03), reduced perivascular and interstitial fibrosis (both p<0.03), and decreased apoptosis (p=0.008). Mechanism: increased AMPK activation (p=0.005) with downstream eNOS upregulation (p=0.014).

Randomized controlled animal study. 17 Yorkshire swine received ameroid constrictors on the left circumflex coronary artery. Treatment group (n=8): oral semaglutide 1.5→3 mg over 5 weeks. Control group (n=9): no drug. Cardiac function measured by pressure-volume loop catheterization, perfusion by microsphere injection. Tissue analysis by immunoblotting, immunohistochemistry, and immunofluorescence.

This is the first study showing oral semaglutide directly improves heart function in coronary artery disease — in a large animal model without diabetes or obesity. It suggests semaglutide's cardiovascular benefits aren't just from metabolic improvement but from direct cardiac effects, potentially offering hope for patients with refractory angina who have no other options.

The cardiovascular outcome trials for GLP-1 drugs showed clear benefits, but couldn't determine whether the heart protection was direct or secondary to metabolic improvements. This study provides strong evidence for a direct cardiac effect — semaglutide actually improves blood flow and reduces scarring in ischemic hearts, independent of diabetes or weight loss.

Preprint (bioRxiv) — not yet peer reviewed. Relatively small group sizes (8-9 per group). Short treatment duration (5 weeks). Ameroid constrictor model creates gradual stenosis that may not fully replicate human coronary disease. Oral semaglutide doses may not be directly comparable to human doses. No long-term follow-up data.