Therapies for Cardiovascular-Kidney-Liver-Metabolic Syndrome: Reappraisal of Fibrates

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.