Semaglutide, independent of weight loss, attenuates cardiac and hepatic remodelling in experimental heart failure with preserved ejection fraction
- Design
- Animal study · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Not human evidenceVERY_INDIRECT: male ZSF1 Obese rats and female Göttingen minipigs with induced HFpEF; no human data.
- Could weight loss explain it?
- Specifically testedSpecifically tested: semaglutide was given at doses chosen not to induce weight loss, and the benefits occurred without significant weight loss or change in total body weight, so weight loss is separated by design; glycaemic change is not reported in the abstract.
Adjusted for: body-weight change - Study tier
- Study tier 4VERY_LOW: preclinical rat and minipig studies with 4 to 12 animals per group.
- Assessment
- Version 2 · Two independent AI reviews agreed · Oct 19, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75.
In obese rats and minipigs with an experimental form of heart failure with preserved ejection fraction, semaglutide was given at doses chosen not to cause weight loss. It improved heart filling pressure (LVEDP down by ∼60% in rats), reduced heart thickening (by ∼30% in rats) and scarring, and reversed liver scarring in minipigs without changing total body weight. This is animal evidence only.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- doses empirically determined to be non-weight-loss inducing
- Comparator
- not reported in abstract
- Primary outcome
- cardiac and hepatic remodelling (diastolic function, hypertrophy, fibrosis, ectopic fat)
- Effect
- In ZSF1 Obese rats semaglutide reduced LVEDP by ∼60% and cardiac hypertrophy by ∼30% without significant weight loss; in minipigs it attenuated hypertrophy, normalized PCWP and reversed hepatic bridging fibrosis
- 95% confidence interval
- not reported in abstract
- Follow-up
- Not stated
- Adverse events
- not reported in abstract
- Limitations
- Small animal studies (4 to 12 animals per group) in obesity-associated HFpEF models; the authors say dose equivalence and cardiac and hepatic GLP-1 receptor engagement still need to be confirmed.
Who was studied
- Sex distribution
- male rats; female minipigs
- Obesity status
- required (obesity-associated HFpEF models)
- Diabetes status
- not reported in abstract
- Cvd status
- experimental heart failure with preserved ejection fraction required (animal)
- Ckd status
- not reported in abstract
- Baseline condition
- experimentally induced HFpEF in ZSF1 Obese rats and 'two-hit' Göttingen minipigs
Study quality details
- Study design
- Preclinical (animal)
- Sample size
- not extracted
- Randomization
- n/a
- Blinding
- not stated
- Comparator
- not reported in abstract
- Follow up duration
- not stated
- Outcome type
- intermediate
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- VERY_INDIRECT
- Statistical precision
- no CI reported; 12 rats per group, 4 to 5 minipigs per group
- Risk of bias
- not assessed
- Funding conflicts
- unclear
- Peer review status
- yes
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- not reported in abstract
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
[BACKGROUND AND AIMS] Heart failure with preserved ejection fraction (HFpEF) remains a significant therapeutic challenge. While GLP-1 receptor agonists (GLP-1RAs) show clinical promise, it remains unknown if their benefits are driven solely by weight loss or involve weight loss-independent mechanisms. We investigated the weight loss-independent effects of semaglutide in two preclinical models of cardiometabolic HFpEF: the ZSF1 Obese rat and the Göttingen HFpEF minipig. [METHODS] Male ZSF1 Obese rats (n = 12/group) and female Göttingen minipigs with 'two-hit' induced HFpEF (early intervention: n = 5/group; delayed intervention: n = 4/group) were treated with semaglutide at doses empirically determined to be non-weight-loss inducing. Comprehensive assessments included invasive hemodynamic (LVEDP, PCWP), echocardiography, and histological quantification of fibrosis and lipid burden. Delayed intervention utilized Cardiac MRI to quantify subcutaneous and ectopic fat depots. In rats, advanced multi-omics (NULISA plasma proteomics, single-cell RNA sequencing and tissue proteomics) were utilized to explore molecular mechanisms. [RESULTS] In ZSF1 Obese rats, semaglutide significantly improved diastolic function (reducing LVEDP by ∼60%) and attenuated cardiac hypertrophy (by ∼30%), interstitial fibrosis, and cardiac lipid deposition in the absence of a significant weight loss. These functional benefits were conserved in the minipig HFpEF model, where treatment attenuated cardiac hypertrophy, left ventricular E/e', normalized pulmonary capillary wedge pressure (PCWP) and reversed advanced hepatic bridging fibrosis. Delayed intervention in established HFpEF minipigs reversed diastolic dysfunction and significantly reduced ectopic lipid depots (intramyocardial, epicardial, and hepatic fat) without affecting subcutaneous fat or total body weight. Mechanistically, multi-omics analyses in the rat heart revealed that these benefits were driven by suppression of pro-fibrotic and hypertrophic signals and up-regulation of branched-chain amino acid (BCAA) catabolism and fatty acid oxidation pathways in cardiomyocytes. [CONCLUSIONS] Semaglutide attenuates cardiac and hepatic remodelling in preclinical models of obesity-associated cardiometabolic HFpEF in the absence of profound weight loss. The conservation of these effects across male rodents and female swine supports their translational relevance, while future studies are needed to define dose equivalence and confirm GLP-1 receptor engagement in cardiac and hepatic tissues. These findings support further mechanistic investigation of weight loss-independent GLP-1 receptor agonist signalling in this HFpEF phenotype.
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| pubmed | Oct 11, 2026 | 42830666 first ingestion |
| pubmed | Oct 11, 2026 | 42830666 duplicate matched on doi |
| pubmed | Oct 11, 2026 | 42830666 duplicate matched on doi |
| pubmed | Oct 18, 2026 | 42830666 duplicate matched on doi |
| pubmed | Oct 18, 2026 | 42830666 duplicate matched on doi |
| pubmed | Oct 18, 2026 | 42830666 duplicate matched on doi |