---
type: source
title: "SCORE and STEER Studies: Semaglutide Real-World Cardiovascular Outcomes in Overweight/Obese ASCVD Patients"
author: "Smolderen et al. (SCORE, Diabetes Obesity Metabolism 2025); STEER investigators (2026)"
url: https://pmc.ncbi.nlm.nih.gov/articles/PMC12515752/
date: 2026-01-01
domain: health
secondary_domains: []
format: journal-article
status: unprocessed
priority: high
tags: [GLP-1, semaglutide, tirzepatide, cardiovascular, MACE, real-world-evidence, ASCVD, heart-failure]
---

## Content

**SCORE Study (2025 — Diabetes, Obesity and Metabolism):**
Design: 9,321 individuals with ASCVD + overweight/obesity (no diabetes) initiated semaglutide 2.4mg, matched to 18,642 controls not on semaglutide. Mean follow-up: 200 days.

Results:
- Semaglutide associated with significantly lower revised 3-point MACE (rMACE-3): HR 0.43 (p<0.001)
- Revised 5-point MACE (rMACE-5): HR 0.55 (p<0.001)
- All-cause mortality reduced
- Cardiovascular-related mortality reduced
- Hospitalization for heart failure reduced

**STEER Study (2026 — PubMed/PMC):**
Design: Semaglutide vs. tirzepatide in people with overweight/obesity and established ASCVD without diabetes. 10,625 matched patients.

Results:
- Semaglutide: 29% lower risk of revised 3-point MACE vs tirzepatide
- Semaglutide: 22% lower risk of revised 5-point MACE vs tirzepatide
- Per-protocol analysis: 43% and 57% reductions respectively
- Counterintuitive: tirzepatide achieves greater weight loss but semaglutide appears superior for cardiovascular outcomes

**GLP-1 + HFpEF (Pooled SELECT/FLOW/STEP-HFpEF Analysis, Lancet 2024):**
- Semaglutide HR 0.72 (95% CI 0.60-0.87) for MACE in HF patients at baseline
- 40%+ reduction in hospitalization/mortality vs sitagliptin in HFpEF patients (real-world)
- HFpEF specifically (pooled analysis): MACE HR 0.69 (95% CI 0.51-0.91)

## Agent Notes

**Why this matters:** These are the first real-world studies (not trial populations) showing strong semaglutide CV benefit in non-diabetic ASCVD patients. The SCORE hazard ratio (0.43 for rMACE-3) is stronger than SELECT trial (~0.80), likely reflecting selection bias (treated patients with better access/adherence), but still meaningful as real-world signal.

**What surprised me:** STEER finding that semaglutide outperforms tirzepatide for CV outcomes despite tirzepatide's superior weight loss. Suggests GLP-1 receptor-specific cardiac mechanisms (not just weight-mediated benefit). GLP-1 receptors are expressed in cardiac tissue; tirzepatide acts on both GIP and GLP-1 receptors, and GIP receptor activity in the heart may be different. This is genuinely novel — the assumption has been that tirzepatide's greater weight loss would produce proportionally greater CV benefit.

**What I expected but didn't find:** Population-level mortality signal in general (non-ASCVD) populations. Both SCORE and STEER are specifically in established ASCVD patients — the highest-risk, highest-benefit subgroup. This is not the general population with obesity. The population-level mortality signal remains elusive.

**KB connections:** Relates to SELECT trial claim already in KB. Extends it to real-world settings. The HFpEF data connects to the CVD bifurcation pattern (HF at all-time high) — GLP-1 is showing efficacy against exactly the failure mode that's rising, but access is inverted (those with ASCVD + no diabetes + commercial insurance are getting treated; those with Medicaid who are obese + pre-diabetic are losing coverage).

**Extraction hints:** Three potential claims: (1) Real-world semaglutide associated with 43-57% MACE reduction in ASCVD patients (SCORE/STEER); (2) Semaglutide cardiovascular benefit exceeds tirzepatide despite inferior weight loss (GLP-1R-specific cardiac mechanism); (3) GLP-1 therapy reduces HFpEF hospitalization/mortality by 40%+ — directly targeting the rising HF burden.

**Context:** SCORE is Novo Nordisk-funded (semaglutide manufacturer). STEER appears independent. Pooled HFpEF analysis includes SELECT (Novo Nordisk). Funding source is relevant for interpretation. Real-world studies have selection bias toward treated patients who are more adherent, healthier, and better-resourced.

## Curator Notes (structured handoff for extractor)

PRIMARY CONNECTION: GLP-1 agonists largest therapeutic category launch in history; Healthcare AI Jevons paradox (analogous capacity/access tension)
WHY ARCHIVED: First real-world CV outcomes signal matching SELECT trial direction, with counterintuitive finding on semaglutide vs tirzepatide. Also directly evidences GLP-1's efficacy against the specific HF failure mode driving CVD bifurcation.
EXTRACTION HINT: The semaglutide > tirzepatide for CV outcomes finding is the most novel claim here. The extractor should scope this carefully — it applies only to established ASCVD patients, not general obesity population. Funding bias from Novo Nordisk must be noted.