Therapies for Cardiovascular‐Kidney‐Liver‐Metabolic Syndrome: Reappraisal of Fibrates
8 affiliations
- 1Centre for Outcomes Research and Evaluation Research Institute of the McGill University Health Centre Montreal Quebec Canada
- 2DREAM‐CV Lab, McGill University Health Centre McGill University Montreal Quebec Canada
- 3Division of Cardiology, McGill University Health Centre McGill University Montreal Quebec Canada
- 4Division of Clinical and Translational Research, Department of Medicine McGill University Montreal Quebec Canada
- 5McGill University Health Centre McGill University Montreal Quebec Canada
- 6Division of Nephrology, Department of Medicine McGill University Health Centre and Research Institute Montreal Québec Canada
- 7RISE‐Health, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina Universidade do Porto Porto Portugal
- 8Université de Lorraine INSERM, Centre d'Investigations Cliniques 1433, CHRU de Nancy, Inserm 1116 and INI‐CRCT (Cardiovascular and Renal Clinical Trialists) F‐CRIN Network Nancy France
Abstract
Cardiovascular disease, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), obesity and metabolic dysfunction‐associated steatohepatitis (MASH) frequently coexist and share overlapping pathophysiology, forming the proposed cardiovascular‐kidney‐liver‐metabolic (CKLM) syndrome. Although contemporary therapies such as sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and non‐steroidal mineralocorticoid receptor antagonists (nsMRA) have improved cardiovascular and renal outcomes, diabetes‐related microvascular complications remain common. Fibrates, traditionally used to lower triglycerides and increase high‐density lipoprotein cholesterol, activate peroxisome proliferator‐activated receptor‐α (PPAR‐α) and influence pathways involved in metabolic and vascular injury, including inflammation, oxidative stress, endothelial dysfunction, mitochondrial metabolism, lipid handling, fibrosis and angiogenesis. This review reappraises the potential role of fibrates within the CKLM syndrome framework, focusing on diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, peripheral artery disease and metabolic dysfunction‐associated steatotic liver disease. Clinical evidence is the strongest for diabetic retinopathy, where fenofibrate reduces retinopathy progression and the need for retinal laser therapy. Post hoc analyses also suggest favourable effects on albuminuria progression and chronic estimated glomerular filtration rate (eGFR) decline, although fibrates may cause a reversible rise in serum creatinine. Evidence for diabetic neuropathy remains limited, while clinical trials and real‐world studies suggest reductions in lower‐extremity amputations and diabetic foot complications. In liver disease, fenofibrate has shown modest benefit, whereas selective PPAR‐α modulators may more favourably influence liver enzymes, inflammation and non‐invasive fibrosis markers. Overall, fibrates may complement contemporary cardiometabolic therapies by targeting residual microvascular and liver‐related risk. However, dedicated outcome trials and improved patient stratification are needed before broader clinical implementation.
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BibTeX
@article{anagnostopoulou2026therapies,
title = {{Therapies for Cardiovascular‐Kidney‐Liver‐Metabolic Syndrome: Reappraisal of Fibrates}},
author = {Virginia Anagnostopoulou and Christoforos K. Travlos and Lucas Lage Marinho and Thomas A. Mavrakanas and João Pedro Ferreira and Abhinav Sharma},
journal = {Diabetes, Obesity \& Metabolism},
year = {2026},
month = aug,
doi = {10.1111/dom.71230},
url = {https://doi.org/10.1111/dom.71230},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Therapies for Cardiovascular‐Kidney‐Liver‐Metabolic Syndrome: Reappraisal of Fibrates
AU - Virginia Anagnostopoulou
AU - Christoforos K. Travlos
AU - Lucas Lage Marinho
AU - Thomas A. Mavrakanas
AU - João Pedro Ferreira
AU - Abhinav Sharma
PY - 2026
DA - 2026/08/17
JO - Diabetes, Obesity & Metabolism
DO - 10.1111/dom.71230
UR - https://doi.org/10.1111/dom.71230
AB - Cardiovascular disease, chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), obesity and metabolic dysfunction‐associated steatohepatitis (MASH) frequently coexist and share overlapping pathophysiology, forming the proposed cardiovascular‐kidney‐liver‐metabolic (CKLM) syndrome. Although contemporary therapies such as sodium‐glucose cotransporter‐2 inhibitors (SGLT2i), glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) and non‐steroidal mineralocorticoid receptor antagonists (nsMRA) have improved cardiovascular and renal outcomes, diabetes‐related microvascular complications remain common. Fibrates, traditionally used to lower triglycerides and increase high‐density lipoprotein cholesterol, activate peroxisome proliferator‐activated receptor‐α (PPAR‐α) and influence pathways involved in metabolic and vascular injury, including inflammation, oxidative stress, endothelial dysfunction, mitochondrial metabolism, lipid handling, fibrosis and angiogenesis. This review reappraises the potential role of fibrates within the CKLM syndrome framework, focusing on diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, peripheral artery disease and metabolic dysfunction‐associated steatotic liver disease. Clinical evidence is the strongest for diabetic retinopathy, where fenofibrate reduces retinopathy progression and the need for retinal laser therapy. Post hoc analyses also suggest favourable effects on albuminuria progression and chronic estimated glomerular filtration rate (eGFR) decline, although fibrates may cause a reversible rise in serum creatinine. Evidence for diabetic neuropathy remains limited, while clinical trials and real‐world studies suggest reductions in lower‐extremity amputations and diabetic foot complications. In liver disease, fenofibrate has shown modest benefit, whereas selective PPAR‐α modulators may more favourably influence liver enzymes, inflammation and non‐invasive fibrosis markers. Overall, fibrates may complement contemporary cardiometabolic therapies by targeting residual microvascular and liver‐related risk. However, dedicated outcome trials and improved patient stratification are needed before broader clinical implementation.
SN - 1462-8902
SN - 1463-1326
ER -