FGF21 Emerges as Both Biomarker and Drug Target in Heart Failure
A new review reveals how the metabolic hormone FGF21 protects the failing heart and how analogs already in trials may offer cardiovascular benefit.
Summary
Fibroblast growth factor 21 (FGF21) is a liver- and heart-derived hormone that regulates fat burning, glucose uptake, and mitochondrial health. In heart failure, FGF21 levels rise sharply — tracking disease severity and poor outcomes — possibly as a compensatory response to cardiac stress. In animal models, FGF21 shields the heart from pressure overload, ischemia-reperfusion injury, chemotherapy toxicity, and diabetic cardiomyopathy by reducing inflammation, fibrosis, and oxidative damage. Long-acting FGF21 analogs already tested for fatty liver disease — including pegozafermin and efruxifermin — improve triglycerides, insulin sensitivity, and fat accumulation, suggesting cardiovascular benefit may follow. Key unknowns include whether elevated FGF21 actively modifies disease or merely reflects stress, which signaling receptors to target, and long-term safety around bone density and muscle wasting.
Detailed Summary
Heart failure remains one of the leading causes of death and disability in aging adults, and identifying new metabolic targets is a research priority. FGF21, a hormone secreted primarily by the liver but also by fat tissue and heart muscle cells, has attracted growing attention for its ability to coordinate whole-body energy metabolism and protect tissues under stress.
This review from researchers at New York Medical College synthesizes molecular, preclinical, and clinical evidence on FGF21's role in heart failure. The hormone signals through the FGFR1/β-Klotho receptor complex to enhance fatty acid oxidation, mitochondrial function, autophagy, and antioxidant defenses while suppressing inflammation and fibrosis — all processes that deteriorate in the failing heart.
In experimental models, FGF21 protects against a wide range of cardiac insults: pressure overload-induced hypertrophy, ischemia-reperfusion injury, doxorubicin cardiotoxicity, and diabetic cardiomyopathy. In human heart failure patients across multiple phenotypes, circulating FGF21 levels are consistently elevated and correlate with NT-proBNP, inflammatory cytokines, adverse cardiac remodeling, and worse prognosis. The authors propose this reflects a state of "FGF21 resistance," analogous to insulin resistance, where the body produces more of the hormone but tissues respond inadequately.
Therapeutically, long-acting FGF21 analogs developed for metabolic liver disease — pegozafermin and efruxifermin — demonstrate improvements in triglycerides, insulin sensitivity, and ectopic fat deposition that could translate to cardiovascular benefit. Whether dedicated heart failure trials will confirm this remains to be seen.
Several critical gaps limit translation: it is unclear whether high FGF21 is causative or reactive, receptor isoform specificity (especially FGFR4-driven hypertrophy in diabetes) is unresolved, standardized assays and reference ranges are absent, and long-term safety signals around bone loss and cachexia need prospective evaluation. Summary based on abstract only.
Key Findings
- FGF21 levels are elevated across all heart failure phenotypes and correlate with NT-proBNP and poor prognosis.
- FGF21 protects animal hearts from ischemia-reperfusion, pressure overload, chemo toxicity, and diabetic cardiomyopathy.
- FGF21 analogs pegozafermin and efruxifermin improve triglycerides, insulin sensitivity, and ectopic fat in metabolic disease trials.
- Elevated FGF21 in heart failure likely reflects compensatory upregulation amid 'FGF21 resistance' rather than true excess.
- FGFR4 receptor isoform may drive cardiac hypertrophy in diabetic settings, complicating therapeutic targeting.
Methodology
This is a narrative review integrating molecular biology, animal model experiments, and human clinical data on FGF21 in heart failure. No original data were collected; the authors synthesize existing preclinical and clinical literature. Summary is based on the abstract only, as the full text is not open access.
Study Limitations
The review is based on the abstract only, so the full depth of evidence and methodology cannot be assessed. FGF21's role as an active disease modifier versus a passive stress marker in humans remains unresolved. Standardized assays, reference ranges, and long-term safety data on bone density and muscle wasting for FGF21 analogs are lacking.
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