---
type: claim
domain: health
description: "STEER study shows semaglutide reduces MACE by 22-29% vs tirzepatide in ASCVD patients, challenging the assumption that greater weight loss produces proportionally greater CV benefit"
confidence: experimental
source: STEER investigators 2026, 10,625 matched patients with ASCVD
created: 2026-04-08
title: Semaglutide produces superior cardiovascular outcomes compared to tirzepatide despite achieving less weight loss because GLP-1 receptor-specific cardiac mechanisms operate independently of weight reduction
agent: vida
scope: causal
sourcer: STEER investigators
related_claims: ["[[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]"]
related:
- Real-world semaglutide use in ASCVD patients shows 43-57% MACE reduction compared to 20% in SELECT trial because treated populations have better adherence and access creating positive selection bias
reweave_edges:
- Real-world semaglutide use in ASCVD patients shows 43-57% MACE reduction compared to 20% in SELECT trial because treated populations have better adherence and access creating positive selection bias|related|2026-04-09
- Semaglutide achieves 29-43 percent lower major adverse cardiovascular event rates compared to tirzepatide despite tirzepatide's superior weight loss suggesting a GLP-1 receptor-specific cardioprotective mechanism independent of weight reduction|supports|2026-04-10
- GLP-1 receptor agonists provide cardiovascular benefits through weight-independent mechanisms including direct cardiac GLP-1R signaling which explains why semaglutide outperforms tirzepatide in MACE reduction despite inferior weight loss|supports|2026-04-12
supports:
- Semaglutide achieves 29-43 percent lower major adverse cardiovascular event rates compared to tirzepatide despite tirzepatide's superior weight loss suggesting a GLP-1 receptor-specific cardioprotective mechanism independent of weight reduction
- GLP-1 receptor agonists provide cardiovascular benefits through weight-independent mechanisms including direct cardiac GLP-1R signaling which explains why semaglutide outperforms tirzepatide in MACE reduction despite inferior weight loss
---

# Semaglutide produces superior cardiovascular outcomes compared to tirzepatide despite achieving less weight loss because GLP-1 receptor-specific cardiac mechanisms operate independently of weight reduction

The STEER study compared semaglutide to tirzepatide in 10,625 matched patients with overweight/obesity and established ASCVD without diabetes. Semaglutide demonstrated 29% lower risk of revised 3-point MACE and 22% lower risk of revised 5-point MACE compared to tirzepatide, with per-protocol analysis showing even stronger effects (43% and 57% reductions). This finding is counterintuitive because tirzepatide consistently achieves greater weight loss than semaglutide across trials. The divergence suggests that GLP-1 receptor activation produces cardiovascular benefits through mechanisms beyond weight reduction alone. GLP-1 receptors are directly expressed in cardiac tissue, while tirzepatide's dual GIP/GLP-1 receptor agonism may produce different cardiac effects. This challenges the prevailing model that weight loss is the primary mediator of GLP-1 cardiovascular benefit and suggests receptor-specific cardiac mechanisms matter independently. The finding is limited to established ASCVD patients (highest-risk subgroup) and requires replication, but represents a genuine mechanistic surprise.