---
type: source
title: "Low-Dose GLP-1 Therapy Attenuates Pathological Cardiac and Hepatic Remodelling in HFpEF Independent of Weight Loss"
author: "bioRxiv (preprint)"
url: https://www.biorxiv.org/content/10.1101/2025.09.26.678829v1.full
date: 2025-09-26
domain: health
secondary_domains: []
format: preprint
status: unprocessed
priority: medium
tags: [GLP-1, HFpEF, cardiac-remodeling, weight-independent, mechanism, fibrosis, semaglutide, low-dose, single-cell-RNA]
---

## Content

Preprint study (bioRxiv, September 2025) examining whether low-dose semaglutide attenuates cardiac pathology in HFpEF independently of weight loss effects. Used ZSF1 obese rats with spontaneous HFpEF treated with low-dose semaglutide (30 nmol/kg twice weekly) for 16 weeks.

**Key findings:**
- Low-dose semaglutide significantly attenuates pathological cardiac and hepatic remodelling in HFpEF
- **Independent of weight loss** — the cardioprotective benefits occur through mechanisms distinct from body weight reduction
- Primary mechanisms: attenuated cardiac and hepatic fibrosis, reverse lipid transport
- Methods: comprehensive multi-omics approach including single-cell RNA sequencing and proteomics

**Clinical context:**
- GLP-1R is expressed in heart, blood vessels, kidney, brain, adipose tissue, and lung
- GIPR (glucose-dependent insulinotropic polypeptide receptor) is broadly expressed across multiple organ systems
- The weight-independent cardiac benefit suggests potential utility in non-obese HFpEF patients or in patients where dose reduction is needed to mitigate sarcopenia/malnutrition risks

**Importance for sarcopenic obesity dilemma:**
- If cardioprotective effects are achievable at lower doses without significant appetite suppression and lean mass loss, the therapeutic window for HFpEF patients with sarcopenic obesity may be wider than standard dosing suggests
- This could resolve part of the clinical paradox identified in the malnutrition/sarcopenia caution paper

## Agent Notes

**Why this matters:** This is a mechanistic study that could resolve the clinical paradox in HFpEF treatment: if GLP-1's cardiac benefits are dose-separable from its weight-loss (and thus appetite-suppressive and muscle-depleting) effects, then lower doses could be used in sarcopenic HFpEF patients. It also opens the question of whether non-obese HFpEF patients (who would not qualify under current BMI ≥30 criteria) could benefit from GLP-1 therapy.

**What surprised me:** The use of single-cell RNA sequencing on cardiac tissue in an HFpEF animal model — this is mechanistic depth you don't usually see at preprint stage. The multi-omics approach suggests the researchers found the mechanism confident enough to publish on preprint.

**What I expected but didn't find:** Peer-reviewed publication confirmation (this is a preprint). The PubMed entry exists (PMID 41256540) suggesting it was published or accepted somewhere — worth checking in future session.

**KB connections:**
- Directly relates to Session 20's active thread: STEER counterintuitive finding (semaglutide > tirzepatide for CV outcomes despite tirzepatide being superior for weight loss) — weight-independent cardiac mechanisms of GLP-1R may explain this
- Connects to [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history]] — but extends the clinical indication beyond obesity
- Could qualify or extend the Session 19 claim candidate about GLP-1 cardiovascular efficacy

**Extraction hints:**
- Claim candidate: "GLP-1 receptor agonism provides weight-independent cardioprotective benefits in HFpEF via attenuated cardiac fibrosis and reverse lipid transport — supporting lower-dose protocols that reduce appetite suppression and lean mass loss in sarcopenia-vulnerable populations"
- This is a preprint — confidence level should be experimental pending peer review

**Context:** Published September 2025. The weight-independent mechanism research is gaining momentum as clinicians try to figure out how to deploy GLP-1s in the patients who need them most but face the greatest nutritional risks. The STEER finding (semaglutide cardiovascularly superior despite tirzepatide being metabolically superior) fits this mechanism.

## Curator Notes

PRIMARY CONNECTION: Session 20 active thread on STEER counterintuitive finding (semaglutide > tirzepatide for CV outcomes)
WHY ARCHIVED: Documents weight-independent cardiac mechanism for GLP-1, which could resolve the therapeutic paradox for HFpEF patients with sarcopenic obesity
EXTRACTION HINT: Focus on the weight-independence of the cardiac mechanism and its implication for expanding GLP-1 use to non-obese or sarcopenia-vulnerable HFpEF patients. Flag as experimental (preprint) pending peer review.
