---
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", "semaglutide-outperforms-tirzepatide-cardiovascular-outcomes-despite-inferior-weight-loss", "semaglutide-outperforms-tirzepatide-cardiovascular-outcomes-despite-inferior-weight-loss-suggesting-glp1r-specific-cardiac-mechanism", "glp1-receptor-agonists-provide-cardiovascular-benefits-through-weight-independent-mechanisms", "real-world-semaglutide-shows-stronger-mace-reduction-than-select-trial", "semaglutide-cardiovascular-benefit-is-67-percent-independent-of-weight-loss-with-inflammation-as-primary-mediator"]
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.

## Extending Evidence

**Source:** 23andMe Research Institute, Nature 2026

The GIPR genetic variant predicts tirzepatide-specific side effects but not semaglutide side effects, providing a mechanism-based rationale for drug selection beyond just cardiovascular vs. weight loss outcomes. Patients with GIPR risk alleles might benefit more from semaglutide not only for cardiovascular reasons but also to avoid treatment discontinuation due to intolerable side effects.
