Beyond adherence: refractory dyslipidaemia, the mediterranean diet, and the case for personalized diet-drug...

Cardiovascular disease (CVD) remains the leading cause of death worldwide, and atherogenic dyslipidaemia is one of its most modifiable drivers. The Mediterranean diet (MedDiet) is among the most extensively studied and best-supported dietary patterns for cardiovascular protection, yet meta-analyses show only modest and heterogeneous effects on the conventional lipid panel: typically 5%-15% reductions in LDL cholesterol, 10%-20% reductions in triglycerides and 3%-6% increases in HDL cholesterol, with very high between-study heterogeneity (I ² often >90%). Lipoprotein(a) [Lp(a)] is genetically determined and largely diet-resistant. Rather than re-asking whether the MedDiet "works", this narrative review addresses a clinically more useful question: who are the lipid non-responders to a well-adhered MedDiet, and how should the diet be combined with contemporary lipid-lowering pharmacotherapy to close the residual-risk gap? Drawing on PubMed, Scopus and Web of Science (January 2015-April 2026) and seminal earlier trials, we synthesize five themes: genetic and metabolic non-responder phenotypes; the gut microbiota-metabolome axis; inflammaging; MedDiet on top of statin and non-statin therapy; and the obligatory partnership of physical activity, weight loss and smoking cessation. The MedDiet should be reframed not as an alternative to lipid-lowering drugs but as a foundational lifestyle component, personalized by genotype, inflammatory status, microbiota composition and treatment goals.